Document 8V4ZXVG52JYgL8pgYoXddKNa5

% < ATTACHMENT VI ANGIOSARCOMA OF THE HUMAN LIVER by Howard L. Richardson, M.D. Environmental Protection Agency Similar terminology or synonyms or semantics used for the same tumor are to be found in the literature. 1. Hemangio-endothelial Sarcoma 2. Malignant vascular tumor of the liver 3. Kupffer Cell Sarcoma 4. Hemangioendothelioma 5. Hemangioblastoma 6. Endothelioblastoma 7. Reticuloendothelioma (Purdy Stout) 8. Angioplastic Sarcoma 9. Primary Hepatic Sarcoma 10. Angioblastic Sarcoma 11. Endothelioma, grades - undifferentiated, well-differentiated, and anaplastic 12. Hemangiosarcoma 13. Malignant Hemangiosarcoma 14. Malignant Hemangioendothelioma 15. Metastasizing Hemangioma Historically, there are many reasons for the above fence sitting type of terminology. In 1940, James Ewing reports in his textbook. Neoplastic Disease, "I do not believe, theneioxe, that the, existence 0(J a truie angiosarcoma. arising (rom blood vessels o{ the liver has been satisfactorily demonstrated. " As late as 1948, Rupert A. Willis in his textbook on Pathology of Tumors states, "We come now to a. difficult question: Vo truly neoplastic angiomatous growths occur? They are very ucc 066123 2 xaxt and ma&t Auppoicd example* ant eithex multifocal hamaxtoma* ox va*culax tumox* of othex kind*." Thorotrast and Angiosarcoma of the Human Liver 1925------Egas Moniz of France first demonstrated that a t radioactive material in the form of colloidal Thorium dioxide could be used in cerebral vessel visualization. 1930------ Heyden Products manufactured Thorotrast for wide distribution in Europe and the United States for use in vascular visualization-arteriographyhepatosplenography- and cerebral graphy. 1932----The Council of Pharmacy of the American Medical Association took a stand against its use. 1940------Thorotrast was still in use, although animal experimentation had demonstrated the formation of cancers and in the liver, angiosarcomas. 1947---Finally discontinued when the human cases of angiosarcomas were reported. It was K.H. Bauer of Germany who compared the time of appearance of neoplasms after the injection of thorotrast, experimentally produced in animals, with their average life expectancy and the average span of life in man. He came to the conclusion that such tumors should appear between the 12th and the 18th year after the injection into the vascular system of man (textbook). ucc 066124 3 1947-------MacMahan, H.E., Murphy, A.S., and Bates, M.I., Endothelial Cell sarcoma of the liver following thorotrast injection. Am J Path, 23^ 585-611. The first case of angiosarcoma from thorotrast was reported in the U.S. The latency period was 17 years. 1961-------Nettleship, A. and Pink, W.J., Neoplasms of the liver following injection of thorotrast, Am J Clin Path, 35, 422-426. This was the 8th reported case of angiosarcoma of the liver due to thorotrast. The latency period was 16 years. 1961------ Suckow, E.G., Henegar, G.G., and Baserza, R., Tumors of the liver following administrations of thorotrast. Am J Path, 38, 663-677. 10 cases of angiosarcoma of the liver were reported due to thorotrast used intravascularly. The latency periods were 3 to 24 years, with the average being 15 years. 1965---Da Silva Horta, J, et al. Malignancy and other late effects following the administration of thoro trast, Lancet, 2, 201-205. 22 additional cases of angiosarcoma of the liver were reported in this article. ucc 066125 4 By this time, hundreds of cases of angiosarcoma of the liver have been produced from this radioactive substance. It was first claimed there was no danger because thorotrast was an alpha emitter. However, the standard dose of 75 ml ordinarily used gives a gamma radiation equivalent of 1.37 micrograms of radium. The half-life of thorium is 1.39 x 10 years, and the radioactivity of thorium dioxide rises after 5 years; the break down products are active and reach a peak after 15 years. With the Kupffer cells being a storage point in the liver, one can easily see the damaging effect of radiation. Arsenic and Angiosarcoma of the Human Liver More than any other element of metal carcinogenesis, arsenic remains one of the enigmas. It is commonly referred to as one of the implicating factors in human cancer formations. One group in Chicago claims it is a producer of angiosarcoma of the human liver, it is for this reason that a short literature review is made. Complicating the interpretations of studies dealing with arsenic is the fact that no satisfactory animal models have been found. 1947------- Neubauer, 0., Arsenical cancers-a review, Brit J Cancer, 1^ 192-251. The author estimated the latency of arsenical cancer to be 18 - 20 years. ucc 066126 1953----Sommers, S.C. and McManus, R.G., Multiple arsenical cancers of the skin and internal organs. Cancer, , 347-359. The estimated latency of arsenical cancer was 13 to 50 years. 1956-- --Roth, F. , Zeit Krebforsch, 61, 287-319. 1957-- --Roth, F., Zeitschrift Krebs Forschung, Bd., 61 (s), 468-503.B. 3. hemai^qioendothelial sarcomas of the liver were described from 27 autopsies in vintner. Latency in the German Vineyard workers was 12 to 17 years. Estimated intake of arsenic was 53.7 gms over a 12 year period. 1959----Roth, F., Zentrelblatt Alleg Pathol, 100, 529-530. hemangiosarcomas of the liver were reported in a study from 82 autopsies. These were vineyard workers exposed to chronic arsenic intoxication in the form of oral ingestion via insecticides, sprays, and dust. 1968------ Regelson, W., Kim, V., Ospina, J., and Holland, J.F., One case of hemangioendothelial sarcoma of liver from Chronic Arsenic Intoxication by Fowler's Solution, Cancer, 21, 514-521. Latency period of 17 years plus 7. The amount of arsenic ingested was estimated to be about 50 grams. 6 An Environmental and Industrial Chemical Registry is needed to face our daily environmental chemical exposure. Most recently, another case of angiosarcoma has been reported with no history of thorium dioxide or arsenic. The case*was from the New York Hospital, Cornell Medical Center, and was in a 46 year old white male. 1974----Sussman, E.B., Nydick, L., and Gray, G.F., One case report of hemangioendothelial sarcoma of liver, AMA Arch of Pathol, 97/ 39-42. In summary, we.have histologically angiosarcomas from thorotrast, arsenic and vinyl chloride, which have the same morphological appearances. Spontaneous Angiosarcomas of the Liver in Animals Rats - In the rat, this is an unknown entity. Dr. K.C. Snell at the National Cancer Institute, in thousands of animals, has never seen this lesion. I have in my files records of over 10,000 rats with many different strains and have never seen this lesion. Mice - In mice, angiosarcomas do spontaneously occur. This is in the Haired and Hairless strain H.R. mouse. Hemangio endotheliomas (angiosarcomas) were observed in 45 out of 251 in the control groups. ucc 066128 7 (Deringer, M.K., J of the Nat Cancer Inst, 1, 437-445, Oct 1951). As would be expected, when O-aminoazotoluene was subcutaneously inoculated, the incidence of angiosarcomas increased. (Ibid., 17, 533-539, 1956). Swiss Albino mice have a spontaneous 5% occurrence of angiosarcoma of the liver. Experimental Angiosarcomas in Animals due to Thorotrast 1936----Capillary angiosarcomas were produced in mice by F. Selbie. Selbie, F., Experimental production of sarcoma with thorotrast. Lancet, 2, 847. 1938------ Reticulosarcomas (angiosarcomas) of the liver were produced by intravenous injections. Onufrio, 0., Su di un caso di reticulosarcoma experimentale do thorotrast. Folia Med, 2, 1245 (probably used a different species). Arsenic Experimentation in Animals and Its Effect on Man An excellent monograph on Arsenicals has been written by A. Furst and will be published in the future by the World Health Organization Working Group on the Evaluation of Carcinogenic Risks of Chemicals to Man. Chemicals Which Produce Angiosarcomas of the Liver in Animals Nitrosodimethylamine -(Magee, P.N., Barnes, J.M., Brit J Cancer, 10, 114, 1956) Orally administered the chemical to rats. ucc 066129 0 H rrold, K.M., J of th Nat Cancer Inst, 39, 1009, 1967. Sub cutaneous administration to Syrian Hamsters. Otsuka, H. and Kuwahara, A., Gann, 2, 147-156, 1971. By oral administration and subcutaneous injection to DDD and BAL b/c strain mice. * Urethane - Deringer, M.K., J of the Nat Cancer Inst, 841-847, 1965. Gave intraperitoneal injections to DBA/2eBDe strains of mice. 1,2-Dimethylhydra2ine Dihydrochloride - Syrian Golden Hamsters were given, in water daily, 0.156 mg to the female and 0.161 mg to the male. Angiosarcomas occurred in 89% of the females and 82% in the males. The tumors were in the liver lung muscle, heart,, and pancreas. No such tumor is seen in the control. (Toth, B., Cancer Res, 3J2, 2818-2827, 1972) Ethylhydrazine hydrochloride - 0.0125% was given in drinking water and 38% vascular tumors were produced in Swiss Albino strain mice. (Toth, B., Scientific Proceedings, AAPB, San Francisco, Ca., 1974) N,Butyl-hydrazine HCL - only lung cancer. 1-carbamyl2-phenylhydrazine - only lung cancer. Control incidence of angio sarcoma in the Swiss Albino mouse is 5%. Methylhydrazine - (a rocket fuel component) Syrian Golden Hamsters received 0.01% in drinking water. Angiosarcoma of th liver (malignant histiocytoma, Kupffer cell sarcoma) was produced in 32% of the females and 54% of the males. Latency period was 70 and 78 weeks. No such tumor was seen in the controls. (Toth, B. and Shimizu, H., Cancer Res, 33, 2744-2753, 1973) ucc 086130 9 l-carbamyl~2-phenylhydrazine - A 0.25% solution in drinking water was given throughout the life span of Swiss mice. Angio sarcomas of the liver occurred in 8 out of 72, and in the controls, 4 out of 44. (Toth, B. and Shimizu, H., J of the Nat Cancer Inst, 52, 241-251, 1974) Are Environmental Hazards in This Group? Hydrazines are used in industry as a rocket propellant. Monomethylhydrazines are used as corrosive agents. Maleic hydrazide used as a herbicide is hydrolysed to hydrazines. 2-Hydroxyethylhydrazine is used to ripen pineapples and is sprayed on. Phenylhydrazine is used in medicine for polycythemia vera. Nephroblastoma Since Professor C. Maltoni mentioned the high incidence of 4 nephroblastoma in rats treated with vinyl chloride, a brief state ment is included for the Interagency Group and the Environmental Protection Agency Task Force. Renal Adenocarcinoma in our population has shown a rapidly increasing incidence with age in both sexes. This is welldocumented by the State of California, Alameda County, Department of Public Health, California Tumor Registry (1960-1969). A review on Cancer of the Kidney - Etiology, Epidemiology, and Pathology has been recently published by J.L. Bennington in Cane r Research, 32, 1017-1029, November 1973. In view of Dr. Maltoni's \ ucc 066131 10 experiments, should not the vinyl chloride workers and famili s be studied with this lesion in mind, as well as the liver? Howard L. Richardson, M.D. Medical Officer Pathologist Pesticide Office Program Environmental Protection Agency April 17, 1974 / ucc 066132 u ADDENDUM TO "ANGIOSARCOMA OF THE HUMAN LIVER" by Howard L. Richardson, M.D. Thorotrast 1972-------Thorotrast induced hepatoma, Smoron, C.L. and Battifora, H.A., Cancer, 30, 1252-1259. A case of thorotrast hepatoma is presented in a 60 year old female with a latency period of 20 years. This article is an excellent review and states that an increase has taken place in Japan and Scandinavian countries. No increase in American U.S. citizens. 1973-------Thorotrast induced hepatoma presented as hyper thyroidism, Kiely, J.M., Titus, J.L., and Orvis, A.L., Cancer, 31, 1312-1314, 1973. Since 1947, approximately 115 additional cases of malignant tumors of the liver have been noted. It is estimated there are still 50,000 to 100,000 carriers of this radioactive contrast media. Ref; Minn Med, 53, 1137-1139, 1970. Primary liver sarcomas 22 years after the administration. This contrast media is still the host for visualization of the cerebral vessels and is used for this purpose. Benefit versus risk ratio. Arsenic and Human Cancer Formation Tseng, W.P., et al. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan, J Natl Cancer Institute, 40, 453--, 1968. The arsenic level in some drinking water is above 0.6 ppm. In areas of high concentration skin cancer are 21.4 per 1,000 of population. In areas of low concentration - 2.6 per 1,000 of population. In view of the reported cases of human arsenic angiosarcomas, a review of the histopathological material present in the Taiwan pathological laboratories is warranted because of the following report in the literature: \' ucc 066133 ) 12 Ti n-Wu Lin, et al. Serum alpha-fetoglobulin and primary cancer of the liver in 7V;iv;&n, Cancer, 30, 435-443, 1972, From the Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan, Republic of China (Taiwan also laa a large vinyl chloride manufacturing plant). Primary cancer of the liver is as high as that of Africa and other Asian countries. 5.5% of all autopsies. 19.5% of all male cancer patients at the above hospital in the last 10 years. No histological classifications were given. A Review of Malignant Hemangioendotheliomas in Infants and Children (Angiosarcomaj 1961------Kauffman, S., and Stout, A., Malignant hemangioendo thelioma in infants and children, Cancer, 14, 1189--, 1?61. Malignant vascular tumors are rare at all ages, but almost curiosities in children. 129 cases are recorded in the Laboratories of Columbia University College of Physicians and Surgeons, New York, New York, during the past 54 years. 9 cases were in children less than 16 years of age or 7%. In a review of the literature only 9 other acceptable cases could be located in the neck, jaw & mouth, arm, femur, gluteal muscle, and leg. The 9 cas s of Kauffman and Stout were distributed as follows: (1) Age 9, male, lymph node of the neck with metastasis to the lung. (2) Age 8, female, scapula tumor. (3) Age 14, male, right erestor spinal muscles. (4) Age 23 months, female, liver angiosarcoma. (S) Age 13, female, distal phalanx of the right toe. (6) Age 12, male, scalp. (7) Age 17, female, right upper eyelid. (8) Age 15, male, middle right finger (fifth). (9) Age 7, female, thigh. 1969--Blumenfeld, T., Flemming, I., and Johnson, W., Juvenile hemangioendothelioma of the liver: Report of a case and review of the literature. Cancer, 24, 853--, 1969. Prior to 1961, these authors had four cases that survived surgery and two cases after. It is not clear what their yearly distributions were in their review, but they are as follows: UCC 066134 13 (1) Case of hemangioendothelioma in a 2% year old female. The solitary nodule was removed and the patient still survived. (2) 4 cases of solitary nodules successfully removed in children 2h months and above in age. (3) 36 cases with multiple liver tumors - all died within 6 months. 1973------- Hansen, R.C., et al. Cancer, 32, 136-141, 1973. Describes a case in a 7 month old female of mesenteric hemangioendothelioma with thrombocytopenia which received radiation therapy and had a resolution after 1000 rads. Statistical Occurrence of Hepatoblastoma in Children from Autopsy 1971----El-Domeiri, A.A., Huvos, A.G., Goldsmith, H.S., and Foote, F.W., Jr., Primary malignant tumors of the liver, Cancer, 27, 7-11, 1971. This study represents a twenty year review at the Memorial Hospital, New York City, betv/een 1947-1966. (1) 137 primary malignant tumors of the liver cells. (2) 23 found in children (16%) under the age of 14 years with the youngest one 8 months of age. All had been diagnosed by the pathologists as hepatocellular carcinoma of the adult or embryonal type. Adenocarcinoma Synonyms and related terms: alveolar carcinoma, clear cell adenocarcinoma, dark cell adenocarcinoma, granular cell carcinoma, Grawitz tumor, hypernephroid carcinoma, hypernephroma, papillary cystadenocarcinoma, parenchymal carcinoma. Nephroblastoma This was the term used by Professor Maltoni, and in view of the vinyl chloride problem, needs histopathological clarification at the earliest possible date. Synonyms'and related terms: adenomyosarcoma, adenosarcoma, alveolar carcinoma, blastoma tumor, blestoma mesoblastica polyvalentia, carcinosarcoma, chondrosarcoma, developmental tumor, dysembryoma, dysembryoplasia, embryoma, embryonal adenocarcinoma, embryonal adenomyosarcoma, embryonal adenosarcoma, embryonal carcinoma, embryonal mixed tumor, embryonal nephroma, embronal UCC 066135 T 14 sarcoma, embryonary nephroma, fibro-lipo-osteoad nom atypique, fibrosarcoma, hypernephroid sarcoma, leiomyoadenosarcoma, leiomyosarcoma, malignant embryoma, malignant leiomyoma, malignant nephroma, malignant teratoma, mesenchymal tumor, mesoblastic nephroma, mesoblastic sarcoma, mesothelioma, mixed teratoid tumor, myoblaBtic sarcoma, myochondroadenosarcoma, myochondrosarcoma, myofibrosarcoma, myoma sarcomatodes, myosarcoma striocellulare, nephrogenous dysembryoma, osteoblastoma, rhabdomyosarcoma, round cell sarcoma, sarcoma fusocellulare, sarcoma mucculaire, spindle cell sarcoma, teratoma, unclassifi d embryonal tumor, Wilm's tumor. In view of the above bewildering nomenclature, I have written to Professor Maltoni on behalf of the Environmental Protection Agency to bring representative slides to New York on May 8-11, 1974 for the National Academy of Sciences' vinyl chloride meeting. I have also requested slides and block for the National Cancer Institute's Small Animal Tumor Registry. Carcinoma of tfte Kidney in a 15 Year Male 1973---Pratt-Thomas, H.R., Spicer, S.S., Upshur, J.JC., and Greene, W.B., Cancer, 31, 719-725, 1973. Until 1934, renal celt carcinoma in children was controversial and in doubt. However, by 1973, we now have a total number of 59 cases reported in the English literature. \ ucc 066136