Document LJyEdkkObJj8G476p2G42m4Kq

MANUFACTURING CHEMISTS ASSOCIATION 1825 CONNECTICUT AVENUE, N.W, WASHINGTON, D. C. 20009 (202) 483-6126 R&tilfcJ March 21, 1975 MAR z 4 1975 R. N. WHEELER, JR. TO: Technical Task Group on Vinyl Chloride Research SUBJECT: Items related to Vinyl Chloride Attached for your information are the following: 1, A copy of the paper presented by Dr. Gordon of Industrial BIO-TEST Laboratories at the March 5 meeting of the International Academy of Pathology in New Orleans entitled "Comparison of the Morphologic Features of Hepatic Angiosarcoma in Man and Rodents Following Prolonged Exposure to Vinyl Chloride." 2. A news release on the availability of a new .book entitled "The Determination of Vinyl Chloride - A Plant Manual," published by the Chemical Industries Association Limited, Alembic House, 93 Albert Embankment, London SE1 7TU Sincerely MF/etv Attachments Milton Freifeld, Project Manager UCC 001087 MAR 1 4 1375 TOXICOLOGY environmental SCIENCES CHEMISTRY PLANT SCIENCES MEDICAL SCIENCES 9ndiuOuxd BIO - T E S T JlaJmcrfomb, 9m. 1810 FRONTAGE ROAD NORTHBROOK, ILLINOIS 60062 March 11, 1975 AftCA CODE 111 TELEPHONC *T-3030 Mr. Milton Freifield Manufacturing Chemists Association 1825 Connecticut Avenue, N. W. Washington, D. C. 20009 Dear Mr. Freifield*. Enclosed is a copy of the full text of the paper which I presented on March 5, 1975, at the International Academy of Pathology meeting in New Orleans. As I indicated, this particular scientific session was arranged in cooperation with the Society of Pharmacological and Environ mental Pathologists (SPEP) and the proffered papers were submitted and presented by members of this organization. Most of the papers dealt with chemically-induced carcinogens, their morphologic features and diagnosis. I am also enclosing a copy of the abstract of my paper as it appeared in the program (Abstracts of Papers) and also appeared in Laboratory Investigation, Vol. 32, No. 3, 1975. The paper was well received. Dr. Squire, Head of the Tumor Pathology Branch at the National Cancer Institute in Bethesda, Maryland, informed me that Dr. Maltoni plans to visit their facility in early April to present his pathologic findings to date. I have been invited and plan to attend unless MCA has some objections. Sincerely; DEG:gz cc: Dr. J. C. Calandra Dr. M. L. Keplinger Donovan E. Gordon, D. V. M. , Ph. D. Section Head, Pathology UCC 001088 9nduii/uaL BIO-TEST Jtaityiattyueii, jW. MANUSCRIPT FOR PRESENTATION AT THE INTERNATIONAL ACADEMY OF PATHOLOGY MEETING ON MARCH 5, 1975, IN NEW ORLEANS, ENTITLED "COMPARISON OF THE MORPHOLOGIC FEATURES OF HEPATIC ANGIOSARCOMA IN MAN AND RODENTS FOLLOWING PROLONGED EXPOSURE TO VINYL CHLORIDE. " D. E. Gordon, L. B. Thomas, J. C. Calandra, H. Popper and G. Kent - Industrial BIO-TEST Laboratories, Inc. , Northbrook, Illinois; National Cancer Institute, Bethesda, Maryland; Northwestern University Medical School, Chicago, Illinois; Mount Sinai School of Medicine, New York, New York; and Northwestern Memorial Hospital, Chicago, Illinois. Ladies and Gentlemen: Vinyl chloride monomer (VCM) is a gas at ambient temperature and atmospheric pressure. It is made by several processes that involve the chlorination of ethylene or acetylene. VCM is used primarily in the manu facture of polyvinyl chloride (PVC), a resin which serves as the parent compound for a number of plastics. In May of 1970, Dr. Viola, from Italy, presented a paper at the 10th In ternational Cancer Congress in Houston, Texas, on the carcinogenic effects of vinyl chloride (VC) in rats. He reported tumors in the skin (para-aural carcinomas), lung (epidermoid and adenocarcinomas) and bone (osteoch ndromas) of Wistar rats that had been exposed to 30, 000 ppm of VC vapor for 4 hours a day, 5 days a week, for 10 months. This was probably the earliest report of a carcinogenic effect of VC in experimental animals. His study was originally designed in an attempt to develop an animal model for acroosteolytis, a bone disease that was reported in the early 1960's among VCM and PVC workers. ucc 001089 SruJLtit/Ual B I O T E S T Ja&&u2loA4&&; Z In view of Dr. Viola's findings, inhalation studies in rats were subsequently initiated in Bologna, Italy, by Dr. Cesare Maltoni in which vapor concentrations of 50 to 10,000 ppm were, investigated. Early in 1973, it was disclosed that angiosarcomas of the liver and tumors in other organs. (Zymbal's gland tumor of the ear canal and Nephroblastomas of the kidney) had been seen in these animals. At that time, liver tumors had not been reported in rats at exposures of 50 ppm of VC. In view of these findings by Drs. Viola and Maltoni, a vapor in halation study with VCM in mice, rats and hamsters was started in September of 1973 at Industrial BIO-TEST Laboratories, at the voluntary request of the Manufacturing Chemists Association (MCA) which represents a group of 31 companies in the United States involved in the production of VCM or PVC. The study was designed, by this group, as a life-span study in each of these species to complement Dr. Maltoni's study. The exposures selected were 50, 200 and 2, 500 ppm of VC vapor with exposures 7 hours a day, 5 days a week. Two hundred of each species and each exposure, level were used, for a total of 600 animals per exposure level. Preliminary tumor data from animals on this study were reported at the end of the first 8 months when liver angiosarcomas appeared in mice that had died at the 50 ppm and higher levels. This preliminary data was presented on April 15, 1974, to representatives of the Environmental Protection Agency (EPA), Occupational Safety and Health Administration (OSHA) and the National Institute of Occupational Safety and Health (NIOSH). UCC 001090 Jnduii'uaL B I O - T E S T JtaiwKdo'deA, 9nc. 3 Meanwhile, the first 3 fatal cases of liver angiosarcomas among vinyl chloride workers in the United States had been reported in January of 1974. With the identification of this rare tumor in humans and experimental animals, there rapidly resulted a national interest in this problem. Dr. Louis Thomas, at the National Cancer Institute in Bethesda, Maryland, and Dr. Hans Popper, who was at that time a Fogarty Scholar at the National Institute of Health, were asked to review all the angiosarcoma cases among workers in the vinyl chloride industry. In September of 1974, I met with Drs. Thomas and Popper to review slides from both the human and mouse angiosarcoma cases. At that time. Dr. Thomas had tumor material from 14 or 15 industrial workers. Slides of human angiosarcoma cases of unknown etiology from Dr. Godfrey Kent at Northw stern Memorial Hospital in Chicago were subsequently reviewed. Slide #1. Gaseous Vinyl Chloride-Induced Hepatic Angiosarcomas in - 15 workers in Polymerization Plants - Rodent Experiments Does Similar Morphologic Evaluation in Man and Mice Enforce Causal Relation and Permit Differentiation From Angiosarcomas of Unknown Etiology? Within 8 Months of Exposure - Hepatic Angiosarcomas Seen in - 2/200 Mice at 50 ppm - 11/200 Mice at 200 ppm - 28/200 Mice at 2, 500 ppm The purpose, then of this presentation is to present some of the comparative. UCC 001091 JntjLktf/tial B I O - T E S T Jtai&uUo'Uei, ^nc- 4 early developmental and morphologic features of the human and rodent angiosarcomas that have been studied thus far. In this slide, preliminary tumor data at 8 months from our mouse study revealed an exposure-related relationship in the incidence of grossly visible liver tumors that were later verified histologically as angiosarcomas. The first hepatic angiosarcoma appeared at 6 months in I animal at the 2, 500 ppm level that had died. The gross appearance of these tumors in man and animals was similar. The livers were frequently enlarged and contained solitary to multiple dark red circumscribed or nodular foci. The tumor foci in mice varied in size from 1 mm to 3 cm in diameter and the cut surface contained blood-filled cystic spaces associated with necrotic foci. The tumors usually extended up to and involved the capsular surface of the liver. In most of the animals with liver tumors, there was blood present in the peritoneal cavity that resulted from hemorrhages at the capsular surface of these tumors. Internal hemor rhage was one of the major causes of death in these animals. Slide #2. This is a section of human liver in which there was an angiosarcoma in another portion. The earliest lesion that Drs. Thomas and Popper have been able to detect, and have reported, is this irregular focal sinu soidal dilatation without necrosis of hepatocytes. ucc 001092 Stidmiiial BIO-TEST JaAo'iaAyu&i' Stic. Slide #3. 5 This is just a higher magnification of the previous field to show a few enlarged sinusoidal lining cells. Slide #4. In the human cases, there is a characteristic, progressive portal tract and capsular fibrosis present throughout the liver that can be seen in this Aniline Blue-stained section in which collagen and reticulin fibers stain blue. This feature has not been observed in liver sections from our VC-exposed animals. However, the liver of rodents (rats, mice, hamsters) normally contain less connective tissue within the portal tracts and lobules when compared to the liver of man. Slide #5. This is the earliest lesion in the mouse which again is focal sinusoidal dilatation. Slide #6. At higher magnification, some of the lining cells appear to be slightly increased in size. There is also focal hypertrophy of hepatocytes in these areas. Slide #7. There is also a focal hypertrophy'of hepatocytes in areas without sinusoidal dilatation and some of these hepatocytes are binucleated. ucc 001093 JtuludiAial B I O - T E S T ^aioAalMiei, !)hc. 6 Slide #8. The next stage in progression of both the mouse and human Lesions is the formation of small to large blood-filled cavities or areas of peliosis. This section is from a mouse. The larger lesions are usually located just beneath the capsule and, microscopically, they are frequently early or advanced lesions of angiosarcoma. Slide #9. At higher magnification of such a peliotic focus, the neoplastic process can be seen extending up to the capsule. Rupture of the capsule at these sites may result in fatal internal hemorrhage. In addition to fresh blood, these peliotic foci contain large fibrin thrombi which are not present in this field. Slide #10. A slightly higher magnification of the angiosarcoma reveals papillary projections of liver cords extending into the peliotic space which are en veloped by neoplastic lining cells. In some areas of these tumors, there is slight widening of the Space of Disse. However, this feature is not as prominent nor as frequent as seen in man. There is also hypertrophy of the entrapped hepatocytes which later undergo necrosis. Slide #11, In other areas of the tumor, there are solid sheets of neoplastic cells that have replaced the liver cords. Slide #12. This is the counterpart of the above liver angiosarcoma in man wh re we again see a papillary projection of liver cells extending into a bloodfilled space that is covered by neoplastic lining cells. There is a prominent separation of the Space of Disse which contains a non-neoplastic prolifera tion of different types of cells including macrophages, lipocytes and fibro blasts. ucc 001094 9ndt*ibual BIO*TEST J.abyutiiyUe&, Httc, 7 Slide #13. This is another firea of the same tumor to show the presence of intracannicular bile thrombi in hepatocytes due to stasis of bile flow. Slide #14. This Aniline Blue-stained section shows an increase in perisinusoidal connective tissue. Eventually, with destruction of the entrapped hepato cytes, there is extensive fibrosis in the area of the angiosarcoma. Now, I would like to briefly show you a series of slides of the developmental lesion and angiosarcoma in rats. Slide #15. Again, this is the initial lesion, an irregular focal sinusoidal dilata tion without necrosis of hepatocytes. This lesion seems to occur more frequently in the subcapsular region of the liver lobes. Slide #16. At higher magnification, there is hypertrophy of a few endothelial cells and some nuclei contain mitotic figures. Slide #17. We now see hyperplasia and hypertrophy of the lining cells which have enveloped most of the liver cords. Some of these cells are clearly neoplastic. ucc 001095 JtuhtitruaJ. BIO-TEST , Jt-'.c. 8 Slide #18. The hepatocytes in the immediate vicinity of the tumor have now been replaced by these sarcomatous lining cells. Slide #19. A few large pleomorphic tumor cells can be seen in the lumen of one vessel as well as in and along the margin of the tumor. Slide #20. In this trichrome-stained section, there is an absence of collagenous connective tissue in the stroma of the tumor. Slide #21. In this section, tumor cells can be seen within a portal tract vessel adjacent to a bile duct. Last Slide. Common Features of Human and Mouse Angiosarcomas Support Etiology and Epidemiology: 1. Multiple, Focal, Sinusoidal Dilatation 2. Blood-filled Sinusoidal Cysts (Peliosis) 3. Proliferated Hepatocytes Enveloped by Sarcoma Cells 4. Progression to Papillary Pattern 5. Vasoformative and Anaplastic Nodules are Rare Dissimilarities: in Mice and Rats 1. Less Fibrosis (in Tumor and Parenchyma) 2. Often Uniform Sarcoma Cells vs. Multipotential Cells in Widened Tissue Space of Disse in Man ucc 001096 Httduibual BIO-TEST JaA&tafo'ti&i, 9*tc. 9 In summary, there are a number of common features between the human, mouse and rat lesions from exposure to vinyl chloride. These common or similar features are: multiple, focal areas of sinusoidal dilatation. We do not believe that these are angiosarcomas at this stage. We have no way of knowing at just what step, histologically, the angiosarcomas start and then progressively develop into a clinically important tumor. The second point of similarity is that of the pcliotic lesions (blood-filled sinusoidal cysts). Then, there is, at the early stage of angiosarcoma, focal to multifocal hyper trophy and proliferations of hepatocytes, enveloped by sarcoma cells. This progresses to a papillary pattern and, finally, there may be solid anaplastic areas within the angiosarcoma. There are a couple of points of difference: in the mice and rats, we see very little or no increase in connective tissue in the neoplastic and unaffected portions of the liver when compared with man. Finally, there seems to be a somewhat more uniform population of tumor cells in the animal tumors than in the human. In man, there is- a possibility of not only the endothelial lining cells but some of the other cells in the tissue space of Disse being involved in the neoplastic process. Thank you. ucc 001097 Viil. t'J, Nn :t. I!)7.r, ANNUAL MKKTISf; AUSTKAUTS tion was (he same. The earliest lesion was local dilation placenta with nitro-hhie tetra/oliiim solution, an oxida of sinusoids in which the lining cells were increased in tion-reduction indicator which yields purple iormn/an number, piled up. and exhibited hvperchromatic and pigment at sites of dehydrogenase activity. Areas of bizarre nuclei. Subsequently, sarcomatous lining cells dehydrogenase deficiency had a white to yellow-white enveloped plates of hepntoeytes which were hypertrophic appearance and were readily differentiated from adja and hyperplastic. They become cords surrounded by cent purple-stained tissue in which formazan pigment proliferated lining cells of different types- in papillary was deposited. Succinic acid dehydrogenase activity arrangement associated with blood-filled cavities re was present in the placentas from uncomplicated preg sulting from sinusoidal ectasia. Eventually, nodules of nancies. whereas placentas from complicated preg anaplastic sarcomatous cells with vascular spaces de nancies showed slight to marked decrease in formazan veloped with hemorrhage and necrosis. This charac pigment. In these placentas, addition of substrate did teristic evolution common to animal and man indicates not enhance the intensity of formazan pigmentation. a specific and identifiable effect of vinyl chloride or its Placentas of infants with low Apgar scores and placentas metabolites upon hepatic mesenchymal and epithelial associated with neonatal morbidity and mortality con cells. It enforces the causal relation of vinyl chloride ex sistently demonstrated reduced enzyme activity. The posure to angiosarcoma formation, but also assists in the clinical diagnosis of uteroplacental insufficiency was exclusion of vinyl chloride as the cause of some angiosar also associated with absence or marked decrease of suc comas of different appearance. cinic acid dehydrogenase activity. (Supported by Pro fessional Stall Association. The Los Angeles County- Ultrastructural Changes in Pulmonary Bleomycin University of Southern California Medical Center. Proj Toxicity ect 2-155-0-0.) F. Gyokkey, I. Daskai, and P. Gyokkky. Veterans Ad ministration Hospital 'and Baylor College of Medi Acquisition of Columnar (Barrett Type) Epithelium cine. Houston. Texas 770111. in the Distal Esophagus after Partial Esophago- Ultrastructural studies of the nuclei of type I and type gastrectomy II pulmonary epithelial cells and of alveolar septal cells Stanley R. Hamilton ano -John J. Yardi.ey. De from patients with diffuse pulmonary fibrosis following partment of Pathology. The -Johns Hopkins University- bleomycin treatment revealed that the drug had a dif School ol Medicine and Hospital. Baltimore. Mary ferential effect on the fine morphology of these cells. land 21205. The most striking alterations were observed in the The origin of the columnar cells in the columnar epi type I alveolar cells: their number was markedly de thelium-lined distal esophagus (Barrett esophagus) is creased. with formation of nucleolar fibrillar centers and unknown. It has been proposed, however, that the co a large increase in nuclear bodies. These nuclear bodies lumnar epithelium may be: (1) congenital, resulting from ranged in size from 0.3 to 0.7 in diameter and were incomplete replacement of embryonic columnar epithe of three main varieties: membranous, beaded, and gran lium; or (2) acquired, being a response to chronic gas ular. Some nuclei contained up to 12 nuclear bodies. tric reflux. There was an abundance of nuclear bodies in all of the We have studied at autopsy a 74-year-old male who type 1 cells, which contained nucleoli with well defined had undergone partial esophagogastreciomv for squa fibrillar centers. The nuclei of type It alveolar cells mous carcinoma of the distal esophagus 6 years earlier. (granular pneumonocytes) contained compact nucleoli The body of the stomach, with lundic mucosa at the with ill defined fibrillar centers and few. if any, nuclear mnrgin. had been anastomosed to the remaining normal bodices. When present, the nuclear bodies were of the esophagus. Postoperativelv there was persistent gastric membranous variety. The nuclei of the alveolar cells reflux. Following death from cardiopulmonary disease, were similar in appearance to those of type I cells but a mild stricture and a 0.5- to 1-cm. circumferential zone did not contain nuclear bodies of the granular variety. of tan mucosa was found in the distal esophagus just We postulate that the above described ultrastructural above the suture line. There was no tumor in the area changes, in particular the appearance of fibrillar centers of resection. The circumferential zone resembled mu and nucleolus-derived nuclear bodies, were induced by cosa of a Barrett esophagus, being composed of co bleomycin. lumnar. goblet, and endocrine cells. The columnar cells of the. surface and glands showed periodic acid-Schiff A Macroscopic Method for Evaluating Succinic Acid (PAS)-posilive and Alcian Blue (AB)-negativc mucin. Dehydrogenase in the Placenta Scattered goblet cells stained with both PAS and AM. T. D. Hall, B. A. Woodling, N. E. Warner, S. B. Numerous argyrophil cells and scattered argentaffin Furukawa, and H. W. Puffer Department of Pathol cells were demonstrated. ogy'. University of Southern California School of Med Findings in this case strongly indicated that the co icine. Los Angeles, California. lumnar epithelium in the distal esophagus was acquired, 5 A histochemicn! assay for succinic acid dehydrogenase perhaps stimulated by gastric reflux. It haa been sug described for evaluating respiratory enzyme in myocar gested that Barrett epithelium may arise from cardiac dium (Nachlas, M. M., and Schnitka. T. K. Am. J. Pathol. 42: 379; 1 !X:i) was adapted and mintilied for the study of 106 plneentns from normal and complicated pregnancies. The method entails incubation of the mucosa. This case also indicated, therefore, that the presence of cardiac mucosa is not necessary for forma tion of columnar epithelium-lined esophagus, although its origin remained unclear. Metaplasia of squamous ucc 001099 ik': News Release Chemical Industries Association Limited, Alembic House, 93 Albert Embankment, London SE1 7TU CIA/1932/2/ER WMcM/JC 20 February, 1975 VINYL CHLORIDE - FIRST COMPREHENSIVE GUIDE TO ANALYTICAL METHODS The first comprehensive guide to analytical methods recommended for measuring the levels of vinyl chloride in air, and residual vinyl chloride in polymers, has been published today by the Chemical Industries Association's Vinyl Chloride Comnlttee, which is Che focus of the joint effort in the vinyl chloride occupational health field by the British Chemical Industry Safety Council, The British Plastics Federation, the UK vinyl chloride producers/ polymerlsers and Che Chemical Industries Association. The 110-page book, entitled "The Determination of Vinyl Chloride A Plant Manual" has been compiled by specialists from Che four UK vinyl chloride producers/polymerlsers and is one part of these companies' massive contribution to the CIA Vinyl Chloride Comaittee's work on industrial hygiene in factories where vinyl chloride is handled. This manual, which includes 17 diagrams, presents the best analytical methods currently available for ensuring that vinyl chloride production and polymerisation plants, and polyvinyl chloride processing plants, are operated in accordance with official hygiene standards. Its format is specifically designed for plant control. Analytical techniques are summarised and listed for each area of application: (a) Vinyl Chloride Monomer Plants (b) Vinyl Chloride Polymerisation Plants (c) PVC Conversion Plants (d) Environments outside factories. ucc 001100 2- - The ten analytical methods specified cover the c ntr 1 of personal exposure, works atmospheres, external atmospheres, liquid effluents and polymeric products, using both infra-red and gas-liquid chromatographic techniques. Complete instructions for the conduct of each, method are given, together with appraisals of their range, sensitivity and accuracy. It is intended both to supplement the loose-leaf manual and to up-date various sections, as further developments result from the work of the CIA group. This manual is thought to be unique and is likely to be of worldwide Interest, Copies are available, post free, from the Publications Department, Chemical Industries Association Ltd., Alembic House, 93, Albert Embankment, London, SE1 7T0, England, at the price of 20,%er copy. * NJ>. Sales are only made on a prepaid basis, i.e. cheques must accompany orders. UCC 001101