Document QDqaq25D23z2bmNJyBoOpMmE

R&S 112122 BIO-MEDICAL RESEARCH DOCUMENT DESCRIPTION FORM Duplicate.in all cards: 63 68 69 76 \ uuuua59~ year as-1961- File number [Right justify [Numeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 1 20 21_____ r: it \ 40 4160 61 62 - / /CAfA 1--............. ....... 77 78 Sub-Index Code Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 12 61 62 i/ 7~ - 1''C 21 l ' " j- - 7>'' - ; " , V ' r1 /]/ 7?7/. -<r> 't i-r > /''/s.X- --------//?/ . 22 -- 23 ji1 ir,T j. kC* 24 Sojuurce (Journal, Vol., Number, Pages, Date ) 12 / X- ', 61 62 31 32 Brief Summary 61 62 R&S 112123 *t * \ EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. VINYL CHLORIDE PATHOLOGY REPORT Submitted to Manufacturing Chemists Association Washington, D.C. 20009 January 9, 1979 4 Chemical Manufacturers Association VINYL CHLORIDE PROJECT PANEL Washington Hilton Georgetown West March 18, 1980 11:00 a.m. r* , 0000359 R&S 112124 PROPOSED AGENDA 1. Introduction and Purpose of the Meeting 2. Background Information on Industrial BIO-TEST research project and an audit of this study by Experimental Pathology Laboratory 3. Disposition of Busey Report 4. Additional treatment and disposition of Industrial BIO-TEST data and tissues 5. Termination of industrial BIO-TEST Contract and legal claim .6 Other follow-up work EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. VINYL CHLORIDE PATHOLOGY REPORT I. Introduction At the request of the Manufacturing Chemists Association, Experimental Pathology Laboratories, Inc. provided a pathologist (Dr. William Busey) to assist in a partial pathology audit of a chronic inhalation study on vinyl chloride conducted at Industrial Bio-Test Laboratories in Decatur, Illinois. This audit was conducted during the week of February 20, 1978 at the IBT Laboratory in Decatur, Illinois. Dr. Busey participated as a member of the audit team and initially his responsibilities were to audit the histopathological findings. Because of the size of the study (2500 animals), and the number of tissues (31 organs per animal) called for to be examined in the protocol, the members of the audit task force were divided into three teams. Dr. Busey was assigned to audit team No. 1 along with Dr. G.K. Hatfield from Diamond Shamrock Corporation, and Drs. Sullivan and Vlaovic from IBT. The details of the tasks performed by audit team No. 1 are presented in the following section of this report. Prior to the initiation of the audit, EPL was provided with a protocol of the study. The following table depicts the experimental design and group designations: R&S 112125 EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC Experimental Design for Vinyl Chloride Study Group Control Tl* T2* T3* T4** Mice MF 100 100 100 100 100 100 100 100 - Number of Animals Rats MF 100 100 100 100 100 100 100 100 100# Hamsters MF 100 100 100 100 100 100 100 100 -- Specified Exposure Levels+ - 50 ppm vinyl chloride 200 ppm vinyl chloride 2500 ppm vinyl chloride 2500 ppm vinyl chloride +Exposure levels have not been verified by audit team *No food, water, or bedding in cages during exposure **Food, water, and bedding to remain in cages during exposure #A11 rats of same sex, either sex permitted The protocol as amended called for exposure of the above groups six hours per day, five days per week. Mice were to be exposed for nine months, rats and hamsters for twelve months. These groups were originally scheduled to be held for equal additional periods of time (nine or twelve months) but subsequently it was agreed they would be kept for their life time or sacrificed if seriously ill. All animals were to be necropsied either at the time of death or sacrifice and a specified set of tissues was to be preserved in 10% neutral buffered formalin. These tissues were to be examined from all animals in the control, T2 and T3 groups. If exposure related lesions were detected in the organs of the T2 or T3 groups, these same organs from the T1 group were to be examined. BZVZVV -2- EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. II. Audit Tasks Several tasks were assigned to audit team No. 1. These tasks were directed toward: (a) an assessment of the histopathology data developed by the IBT pathologists, (b) an enumeration of the neoplasms diagnosed by IBT, and (c) a verification of the number of tissues examined by IBT microscopically. In addition, EPL was asked to summarize the tissue counts performed by IBT from examination of all of the wet tissue bags, paraffin blocks and microscope slides. This latter task -was subsequently performed at EPL. A. Examination of IBT Histopathology Data from Computer Printouts The recorded diagnoses of the IBT pathologists had been input into a computer which in turn generated a series of printouts listing the findings and separating the neoplastic from the non-neoplastic diagnoses. Working with the IBT printout of the neoplastic diagnoses, summary neoplasm tables were generated by EPL for each of the three species. The number of organs indicated as examined by IBT pathologists was tabulated by the audit team, thus providing a denominator for comparative purposes. These neoplasm summaries are found in Tables I, II, and III. In addition to sunmarizing all of the neoplasms, the audit team extracted all of the diagnoses of angiosarcoma and prepared a separate incidence table for this diagnosis. A summary of the diagnosis of angiosarcoma in any organ, expressed as a percentage of the number of animals examined, is found in Table IV. -3- R&S 112127 R&S 112128 EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. B. Microscopic Examination of Selected Neoplastic and Non-neoplastic Lesions Diagnosed by IBT Pathologists Following examination of the computer printout containing the diagnoses rendered by the IBT pathologists for the various organs examined, selected tissues were examined microscopically. In general, this second microscopic examination correlated well with the original diagnoses and no discrepancies were'noted. The only discrepancies noted were set of slides from apparently two different animals containing the same animal numbers. Since all of the slides were not examined, no assessment of the magnitude of this problem could be made. C. Verification of Number of Tissues Examined Microscopically During the audit selected neoplastic and non-neoplastic lesions were reexamined microscopically, and tissue counts were made from the microscope slides for selected animals. These counts were then checked against the rough pathology reports to assess whether all of the tissues available for microscopic examination were in fact examined. For these selected animals, no discrepancies were noted and the number of tissues available for microscopic examination correlated well with those that were reported. D. Summarization of Counts of Wet Tissue, Paraffin Blocks and Microscope Slides Conducted by IBT PersonniT At the request of the vinyl chloride audit task force, IBT examined all of the wet tissues, paraffin blocks and slides from the animals used in the study. This examination consisted of the identi- -4- R&S 112129 EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC fication and counting of the various tissues that were available for possible microscopic evaluation. These counts were submitted on several individual forms and in order to properly evaluate these data, EPL sunmarized these counts by group, sex, and species. These summaries are presented in Tables V, VI, and VII. III. Summary and Recommendation Inspection of the recorded IBT histopathologic findings clearly indicate that the inhalation exposure of rats, hamsters, and mice to vinyl chloride at 50, 200 and 2500 ppm results in a carcinogenic effect in the liver. This carcinogenic effect was manifest by the development of angiosarcomas, many of which metastasized to regional lymph nodes and the lung. Even though the histopathology is incomplete, the number of angiosarcomas observed clearly indicates the carcinogenicity of vinyl chloride to these three species of laboratory animals. Other neoplasms were observed and reported but because of the paucity of numbers of specific organs examined, conclusive statements about their relationship to vinyl chloride exposure cannot be made. Tumors of Zymbal's gland were seen in all of the exposure groups in the rats and probably are related to the exposure to vinyl chloride. However, only a small number of these organs were examined in each of the control and exposed groups. Malignant tumors of the mammary gland were seen to a greater degree in the exposed female rats; but, here again, the number of mammary glands examined was small and inconsistent. Therefore, conclusive statements -5- EPL experimental pathology LABORATORIES, INC. cannot be made. Four tumors of the central nervous system were seen. One of these occurred in a Group II male and three occurred in Group III males. These are important findings in light of recent epidemiological data in man, but their relationship to the exposure to vinyl chloride in this study is undetermined because of the small number of brains examined,. Primary lung tumors occurred with greater frequency in both sexes of vinyl chloride exposed mice at all concentrations. These primary lung tumors were both benign and malignant and were diagnosed as alveologenic adenomas and carcinomas. Inspection of the IBT pathology reports indicates that approximately 50% of the lungs from the mice were examined microscopically. This number of lungs is sufficient to conclude that the inhalation exposure of vinyl chloride to male and female mice had a carcinogenic effect in the lungs. Primary lung tumors were only seen in the male and female hamsters exposed to 2500 ppm of vinyl chloride. Two bronchiolar carcinomas were seen in the males and one in the females, and one bronchiolar adenoma was seen in the males. Primary lung tumors of the hamster are relatively rare; therefore, the presence of these five neoplasms may be meaningful and related to vinyl chloride exposure. Since microscopic examination of a few selected neoplastic and non-neoplastic lesions diagnosed by the IBT pathologists did not reveal any meaningful discrepancies, it would appear that the histopathology conducted on the tissues from these animals was done accurately. Similar R&S 112130 -6- EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC spotchecks of the number of tissues reported to have been examined did not reveal any significant discrepancies. Inspection of the tissue counts conducted by the IBT personnel of the wet tissue, paraffin blocks and microscope slides indicate that significantly fewer tissues were available for microscopic examination than were called for by the protocol. The reason for this discrepancy became apparent when the necropsy sheets and animal observation books were examined. The tissue from a large number of the animals in this study was not obtained. This discrepancy is unfortunate in light of the fact that the inhalation exposure of these three species of laboratory animals to vinyl chloride might have provided further definition of the pathology produced, the relationship to dose and the variation between species. In conclusion, the results of this investigation revealed some rather severe deficiences in the conduct of thi.s study, primarily with regard to the numbers of tissues that were saved. The pathologic evaluation'of the limited material that was available appears to have been conducted accurately. The available data indicate that vinyl chloride at 50, 200 and 2500 ppm has a carcinogenic effect on the liver of rats, mice and hamsters and a carcinogenic effect on the ZymbaVs gland of the rat. Similarly, there appears to be a carcinogenic effect in the lungs of the mice. These conclusions are based upon the assumption that the concentrations expressed in this report were actually achieved -7- 30 W ro co EPL EXPERIMENTAL PATHOLOGY LABORATORIES, INC. and maintained throughout the course of the study. Any significant excursions in the low level (50 ppm) may negate the conclusion of the carcinogenic effect of vinyl chloride at this level. Because of the serious deficiency in the number of tissues saved from animals in both the control and exposed groups, it is recommended to MCA that no further pathology- work be done on this study. WILLIAM n. BUSEY, KV.M., Ph.D. Pathologist WMB/sfh -8- R&S 112132 R&S 112133 TABLE I RAT - TUMOR SUMMARY DATA ADRENAL (No. Examined) Cortical Carcinoma Cortical Adenoma Medullary Carcinoma BRAIN (No. Examined) Neuroepithelioma CECUM (No. Examined) Lymphosarcoma DUODENUM (No. Examined) Lymphosarcoma HEART (No. Examined) Angiosarcoma KIDNEYS (No. Examined) Lymphosarcoma Nephroblastoma Reticulum Cell Sarcoma Tubular Adenoma Lipoma Metastatic Angiosarcoma LIVER (No. Examined) Angiosarcoma Heptocellular Carcinoma Lymphosarcoma Control Male Control Female T1 Male T1 Female T2 Male T2 Female (11) (26) (8) (9) (19) (7) 11 1 (10) (10) (7) (69) (21) (21) (9) (60) (8) (8) (1) (74) (7) (7)' (6) (52) (18) 1 (17) 1 (16) 1 (64) (4) (4) (4) (59) (70) 2 (70) (72) (73) (75) 1 1 1 3 (77) 11 1 (60) 1 1 1 (62) 17 (68) 1 (69) 35 1 2 (70) 1 (72) 47 EPL Experimental Pathology Laboratories, Inc. -9- R&S 112134 TABLE I RAT - TUMOR SUMMARY DATA . ADRENAL (No. Examined) Cortical Carcinoma Cortical Adenoma Medullary Carcinoma BRAIN (No. Examined) Neuroepithelioma CECUM (No. Examined) Lymphosarcoma DUODENUM (No. Examined) Lymphosarcoma HEART (No. Examined) Angiosarcoma KIDNEYS (No. Examined) Lymphosarcoma Nephroblastoma Reticulum Cell Sarcoma Tubular Adenoma Lipoma Metastatic Angiosarcoma LIVER (No. Examined) Angiosarcoma Heptocellular Carcinoma Lymphosarcoma T3 Male (5) T3 T4 Female Female (5) (6) T4 Male Nnn# 1 (6) (0) (5) 3 (3) (0) (5) (3) (1) (5) (71) (75) (62) (69) 1 (64) 1 (69) (78) 51 (69) 63 (70) 49 EPL Experimental Pathology Laboratories, Inc. -10- TABLE I RAT - TUMOR SUMMARY DATA LIVER (continued) Reticulum Cell Sarcoma Metastatic Adreno-cortical Carcinoma Control Male Control Female T1 Male 3 42 T1 Female 1 1 T2 Male LUNG (No. Examined) Alveologenic Adenoma Bronchogenic Adenocarcinoma Bronchogenic Adenoma Bronchiolar-Alveolar Adenoma Angiosarcoma Lymphosarcoma Reticulum Cell Sarcoma Metastatic Angiosarcoma Metastatic Hepatocellular Carcinoma Metastatic Fibrosarcoma Metastatic Mammary Gland Adenocarcinoma Metastatic Zymbal's Gland Carcinoma Metastatic Adreno-cortical Carcinoma Metastatic Adenocarcinoma N.O.S. (73) 1 2 1 (73) 4 (77) I 1 1 2 9 (58) * 1 7 (71) 1 1 1 2 24 1 12 1 MESENTERY (No. Examined) Metastatic Hepatocellular Carcinoma (2) (3) (12) (ID (31) 1 T2 Female (68) 2 28 1 (43) EP L ExperimenUl Pathology Laboratories, Inc. -11- R&S 112135 TABLE I RAT - TUMOR SUMMARY DATA LIVER (continued) Reticulum Cell Sarcoma Metastatic Adreno-cortical Carcinoma T3 Male T3 T4 Female Female T4 Male 1 LUNG (No. Examined) Alveologenic Adenoma Bronchogenic Adenocarcinoma Bronchogenic Adenoma Bronchiolar-Alveolar Adenoma Angiosarcoma Lymphosarcoma Reticulum Cell Sarcoma Metastatic Angiosarcoma Metastatic Hepatocellular Carcinoma Metastatic Fibrosarcoma Metastatic Mammary Gland Adenocarcinoma Metastatic ZymbaVs Gland Carcinoma Metastatic Adreno-cortical Carcinoma Metastatic Adenocarcinoma N.O.S. (78) 2 1 1 32 (70) 2 37 2 (69) 36 1 MESENTERY (No. Examined) Metastatic Hepatocellular Carcinoma (37) (37) (43) EPL Experimental Pathology Laboratories, Inc. -12- R&S 112136 R&S 112137 TABLE I RAT - TUMOR SUMMARY DATA MESENTERY (continued) Angiosarcoma Reticulum Cell Sarcoma Control Male Control Female T1 Male T1 Female T2 Male T2 Female 2 2 12 1 29 42 PANCREAS (No. Examined) Islet Cell Adenoma (35) 7 (39) 1 (38) 1 (23) (23) (8) PARATHYROID (No. Examined) Adenoma (6) (5) 1 (2) (9) (8) (1) PITUITARY (No. Examined) Chromophobe PLEURA (No. Examined) Angiosarcoma Reticulum Cell Sarcoma Metastatic Angiosarcoma PROSTATE (No. Examined) Adenocarcinoma (9) (18) 8 14 (0) (0) (9) (9) (5) 43 (0) (1) (10) 1 (12) 5 (4) 4 (19) 1 (5) (7) 5 1 SKIN (No. Examined) Fibroma Fibrosarcoma Lipoma Liposarcoma Sarcoma, N.O.S. Reticulum Cell Sarcoma Squamous Cell Carcinoma (19) 7 2 1 1 2 (12) 1 2 1 (12) 5 1 (4) 1 3 1 (17) (4) 1 EPL Experimental Pathology Laboratories, Inc. -13- R& s 112138 TABLE I RAT - TUMOR SUMMARY DATA MESENTERY (continued) Angiosarcoma Reticulum Cell Sarcoma PANCREAS (No. Examined) Islet Cell Adenoma PARATHYROID (No. Examined) Adenoma PITUITARY (No. Examined) Chromophobe PLEURA (No. Examined) Angiosarcoma Reticulum Cell Sarcoma Metastatic Angiosarcoma PROSTATE (No. Examined) Adenocarcinoma SKIN (No. Examined) Fibroma Fibrosarcoma Lipoma Liposarcoma Sarcoma, N.O.S. Reticulum Cell Sarcoma Squamous Cell Carcinoma T3 Male T3 Female T4 Female T4 Male None 38 41 42 (4) (2) (4) (3) (2) (0) (4) (0) (4) 2 (4) (5) (4) 3 44 1 1 (3) 3 (3) (1) (3) 1 1 11 EPL Experimental Pathology Laboratories, Inc. -14- j R&S 112139 TABLE I RAT - TUMOR SUMMARY DATA Control Male Control Female T1 Male MAMMARY GLAND (No. Examined) Fibroadenoma Adenoma Adenocarcinoma (1) 1 ZYMBAL'S GLAND (No. Examined, Carcinoma 0) SPLEEN (No. Examined) Angiosarcoma Lymphosarcoma Reticulum Cell Sarcoma (65) 2 SKELETAL MUSCLE (No. Exam.) Metastatic Angioma STOMACH (No. Examined) Lymphosarcoma (9) (9) (62) 75 23 5 (4) 4 (16) (7) 2 (69) 2 (66) 1 1 2 (15) (6) (20) (8) TESTIS (No. Examined) Interstitial Cell Tumor Angioma (54) (64) 2 THYMUS (No. Examined) Lymphosarcoma (1) (0) (0) THYROID (No. Examined) Lymphosarcoma C-Cell Adenoma (11) 1 (22) (12) T1 T2 Female Male T2 Female (52) 45 8 24 (3) 4 (19) 10 7 8 (7) (17) 1 (54) (62) (6) 2 (65) 1 1 (7) (14) (3) (7) (18) 1 (41) 1 (0) (2) 2 (ID (16) 1 (4) (4) (4) 4 EPL Experimental Pathology Laboratories, Inc. -15- R&S 112140 TABLE I RAT - TUMOR SUMMARY DATA T3 Male MAMMARY GLAND (No. Examined) Fibroadenoma Adenoma Adenocarcinoma 1 T3 Female T4 T4 Female Male ___ Clone-- 35 12 8 14 ZYMBAL'S GLAND (`No. Examined] Carcinoma (8) 9 SPLEEN (No. Examined) Angiosarcoma Lymphosarcoma Reticulum Cell Sarcoma (71) 1 SKELETAL MUSCLE (No. Exam.) Metastatic Angioma (1) (5) 4 (67) (0) 4 (0) (0) STOMACH (No. Examined) Lymphosarcoma (3) (0) (0) TESTIS (No. Examined) Interstitial Cell Tumor Angioma (5) THYMUS (No. Examined) Lymphosarcoma (0) (1) (0) THYROID (No. Examined) Lymphosarcoma C-Cell Adenoma (3) (2) (0) EPL Experimental Pathology Laboratories, Inc. W R&S 112141 TABLE I RAT - TUMOR SUMMARY DATA THYROID (continued) Follicular Adenoma Follicular Adenocarcinoma Control Male Control Female T1 Tl Male Female T2 Male T2 Female 1 1 TRACHEA (No. Examined) Lymphosarcoma (14) (27) (17) (15) (23) (9) 1 UTERUS (No. Examined) Reticulum Cell Sarcoma (36) 1 (35) * (11) LYMPH NODE (No. Examined) Fibrosarcoma (12) (21) (8) (7) (17) 1 (5) Total Number Neoplasms 44 141 58 134 123 155 No. Animals with Angiosarcomas S)0 PM) o NR) 2 T) 2 %) 2.4 0 12 7 3 0 12 13 33 62 0 00 0 4 0 13 20 40 69 0 15.7 26.7 52.6 84.1 Total No. Primary Angiosarcomas No. Primary Angiosarcomas per Rat 2 0.0125 0 12 29 69 96 0 0.145 0.387 0.908 1.170 Sacrificed PM=Died During Study T=Total NR=Newly Read EPl Experimental Pathology Laboratories, Inc. -17- R&S 112142 TABLE I RAT - TUMOR SUMMARY DATA THYROID (continued) Follicular Adenoma Follicular Adenocarcinoma T3 Male T3 Female T4 Female T4 Male None TRACHEA (No. Examined) Lymphosarcoma (4) (3) (0) UTERUS (No. Examined) Reticulum Cell Sarcoma (2) (0) LYMPH NODE (No. Examined) (3) (0) (0) Fibrosarcoma Total Number Neoplasms 148 168 161 No. Animals with Angiosarcomas S) 10 PM) 41 NR) 2 T) 53 %) 63.9 8 50 8 64 79.0 5 53 3 61 81.3 Total No. Primary Angiosarcomas No. Primary Angiosarcomas per Rat 93 110 96 1.069 1.358 1.28 S=Sacrificed PM=*Died During Study T=Total NR=Newly Read EPL Experimental Pathology Laboratories, Inc. TABLE II MICE - TUMOR SUMMARY DATA R&S 112143 HEART (No. Examined) Lymphosarcoma Angiosarcoma KIDNEY (No. Examined) Angiosarcoma Lymphosarcoma Reticulum Cell Sarcoma Metastatic Angiosarcoma Control Male (50) 2 Control Female (45) (52) 3 2 (45) 2 LIVER (No. Examined) Angiosarcoma Hepatocellular Carcinoma Lymphosarcoma Reticulum Cell Sarcoma Metastatic Mammary Carcinoma Hepatocellular Adenoma Metastatic Squamous Cell Carcinoma (52) 3 1 1 (45) 3 1 LUNG (No. Examined) Alveologenic Adenoma Alveologenic Carcinoma Lymphosarcoma Reticulum Cell Sarcoma Metastatic Mammary Carcinoms Metastatic Angiosarcoma Metastatic Squamous Cell Carcinoma (51) 8 1 3 2. (45) 2 2 PL Experimental Pathology Laboratories, Inc. T1 Male (56) 1 T1 Female (58) (58) 3 2 1 (59) 18 1 2 1 (62) 7 2 1 (62) 28 1 (58) 68 4 2 1 1 (62) 34 6 2 7 1 2 TABLE II MICE - TUMOR SUMMARY DATA HEART (No. Examined) Lymphosarcoma Angiosarcoma KIDNEY (No. Examined) Angiosarcoma Lymphosarcoma Reticulum Cell Sarcoma Metastatic Angiosarcoma T2 Male (64) T2 Female (59) 1 (69) 1 1 (62) 1 1 LIVER (No. Examined) Angiosarcoma Hepatocellular Carcinoma Lymphosarcoma Reticulum Cell Sarcoma Metastatic Mammary Carcinoma Hepatocellular Adenoma Metastatic Squamous Cell Carcinoma (70) 71 1 1 (64) 60 1 LUNG (No. Examined) Alveologenic Adenoma Alveologenic Carcinoma Lymphosarcoma Reticulum Cell Sarcoma Metastatic Mammary Carcinoma Metastatic Angiosarcoma Metastatic Squamous Cell Carcinoma (70) 66 1 1 1 (64) 53 3 4 1 EPL Experimental Pathology Laboratories, Inc. -20- T3 Male (46) T3 Female (40) (50) 2 2- (51) 52 (48) 1 (50) 61 1 1 1 | (51) 92 10 2 4 (50) 61 8 1 6 5 4 R&S 112144 TABLE II MICE - TUMOR SUMMARY DATA LYMPH NODE (No. Examined) Lymphosarcoma Angiosarcoma Reticulum Cell Sarcoma Control Male (3) 1 Control Female (2) 2 1 MESENTERY (No. Examined) Angiosarcoma Lymphosarcoma Reticulum Cell Sarcoma Fibrosarcoma (2) (2) 1 1 1 OVARY (No. Examined) Angiosarcoma (10) 1* PANCREAS (No. Examined) Angiosarcoma Lymphosarcoma (4) 1 SALIVARY GLAND (No. Examined) Angiosarcoma (0) (14) (o) SKELETAL MUSCLE (No. Examined Lymphosarcoma (0) (0) SKIN (No. Examined) Lymphosarcoma Fibrosarcoma Squamous Cell Carcinoma (0) (3) 1 ' Diagnosed angioma epl Experimental Pathology Laboratories, Inc. -21- T1 Male (2) Tl Female (2) 1 (10) 7 2 1 (ID 1 (27) 29 1 1 (5) 1 (5) 1 (7) (1) (6) (2) . -- (3) (4). 1 1 1 e 0e --J *4 to 07 i TABLE II MICE - TUMOR SUMMARY DATA LYMPH NODE (No. Examined) Lymphosarcoma Angiosarcoma Reticulum Cell Sarcoma T2 Male (0) T2 Female (2) MESENTERY (No. Examined) Angiosarcoma Lymphosarcoma Reticulum Cell Sarcoma Fibrosarcoma (12) 11 1 (10) 10 OVARY (No. Examined) Angiosarcoma (4) 1 PANCREAS (No. Examined) Angiosarcoma Lymphosarcoma (3) (4) - SALIVARY GLAND (No. Examined) Angiosarcoma (1) (1) 1 SKELETAL MUSCLE (No. Examined ) Lymphosarcoma (1) 1 (2) SKIN (No. Examined) Lymphosarcoma Fibrosarcoma Squamous Cell Carcinoma 0) (2) 2 T3 Male (0) T3 Female (1) 1 (6) 10 (7) 8 0) 0) 0) i (2) (0) (0) (0) (1) 0) 1 R&S 112146 EPL Experimental Pathology Laboratories, Inc. -22- TABLE II MICE - TUMOR SUMMARY DATA R&S 112147 MAMMARY GLAND (No. Examined) Adenosquamous Carcinoma Adenocarcinoma Control Male (0) Control Female (1) 1 SPLEEN (No. Examined) Angiosarcoma Lymphosarcoma Reticulum Cell Sarcoma Metastatic Angiosarcoma Metastatic Mammary Carcinoma (46) " 2 1 (41) 3 1 T1 Male 0) 1 T1 Female (24) 9 19 (57) 2 1 . (62) 3 2 STOMACH (No. Examined) Adenocarcinoma Lymphosarcoma Reticulum Cell Sarcoma (8) (17) 1 1 (6) (2) 1 URINARY BLADDER (No. Examined! Lymphosarcoma (6) 1 (8) (5) 0) UTERUS (No. Examined) Sarcoma, N.O.S. 04) 1 (5) Total Neoplasms 31 19 120 145 No. Animals with Angiosarcoma: S) 0 PM) 0 T) 0 %) o Total No. Primary Angiosarcoma s 0 No. Primary Anaiosarcomas/Mou: e -0- 0 0 1 2.2 1 .02 4 0 20 33.3 30 0.5 3 0 40 61.5 69 1.06 EPL S=Sacrificed, PM=Died During Study, T=Total Experimental Pathology Laboratories, Inc. TABLE II MICE - TUMOR SUMMARY DATA R&S 112148 MAMMARY GLAND (No. Examined) Adenosquamous Carcinoma Adenocarcinoma T2 Male (0) T2 Female (9) 6 5 T3 Male (3) 1 2 T3 Female (7) 8 8 SPLEEN (No. Examined) Angiosarcoma Lymphosarcoma Reticulum Cell Sarcoma Metastatic Angiosarcoma Metastatic Mammary Carcinoma (68) 3 1 1 1 (63) 1 1 (47) . (50) 2 1 1 STOMACH (No. Examined) Adenocarcinoma Lymphosarcoma Reticulum Cell Sarcoma (0) (2) (0) O) URINARY BLADDER (No. Examined Lymphosarcoma UTERUS (No. Examined) Sarcoma, N.O.S. (0) 0) (2) (0) (0) (0) Total Neoplasms 152 136 160 127 No. Animals with Angiosarcoma ; S) 3 0 9 12 PM) 0 0 00 T) 74 65 51 63 %) 96.1 91.5 89.5 88.7 Total No. Primary Angiosarcom as No. Primary Anqiosarcomas/Mou se 85 75 l.io _____ 64 71 1.12 _____ UL_ S=Sacrificed, PM*Died During Study, T=Total EPL Experimental Pathology Laboratories, Inc. -24- A TABLE III HAMSTERS - TUMOR SUMMARY DATA R&S 112149 ADRENAL (No. Examined) Cortical Adenoma Cortical Carcinoma Control Male Control Female (9) (4) HEART (No. Examined) Lymphosarcoma (45) (32) KIDNEYS (No. Examined) Angiosarcoma Reticulum Cell Sarcoma Tubular Adenoma Metastatic Mammary Adenocarcinoma (53) (36) LIVER (No. Examined) Angiosarcoma Lymphosarcoma Metastatic Granulosa Cell Metastatic Mammary Adenocarcinoma (50) (33). - LUNG (No. Examined) Alveolar Adenoma Angiosarcoma Bronchiolar Carcinoma Bronchiolar Adenoma Metastatic Angiosarcoma Metastatic Melanosarcoma Metastatic Adenocarcinoma (49) - (32) EPL Experimental Pathology Laboratories, Inc. -25- T1 Male (12) 1 (41) T1 Female (4) (30) (43) 1 1 (33) 1 (44) 5 (30) 2 - (42) (29) . 1 R&S 112150 TABLE III HAMSTERS - TUMOR SUMMARY DATA ADRENAL (No. Examined) Cortical Adenoma Cortical Carcinoma HEART (No. Examined) Lymphosarcoma KIDNEYS (No. Examined) Angiosarcoma Reticulum Cell Sarcoma Tubular Adenoma Metastatic Mammary Adenocarcinoma LIVER (No. Examined) Angiosarcoma Lymphosarcoma Metastatic Granulosa Cell Metastatic Mammary Adenocarcinoma LUNG (No. Examined) Alveolar Adenoma Angiosarcoma Bronchiolar Carcinoma Bronchiolar Adenoma Metastatic Angiosarcoma Metastatic Melanosarcoma Metastatic Adenocarcinoma T2 Male T2 Female (is) 1 (11) 1 (35) (51) (40) 2 (57) 1 (36) 1 (52) 11 . .1 (36) ..1 (49) 12 1. .1 EPL Experimental Path logy Laboratories, Inc. -26- T3 Male T3 Female (5) (2) 1 (45) 1 (50) (23) (24) (48) 38 1 (26) 18 . (44) 1 2 2 1 7 (26) 1 4 # TABLE III HAMSTERS - TUMOR SUMMARY DATA R&S 112151 LUNG (Continued) Metastatic Mammary Adeno carcinoma Metastatic Uterine Adeno carcinoma Control Male Control Female MESENTERY (No. Examined) Angiosarcoma Melanosarcoma Adenocarcinoma, N.O.S. (0) (0) ESOPHAGUS (No. Examined) Papilloma (7) (2) OVARIES (No. Examined) Granulosa Cell, Malignant Thecal Cell PANCREAS (No. Examined) Islet Cell Adenoma (14). (16) 1 (4) PLEURA (No. Examined) Metastatic Angiosarcoma (0) (0) SKELETAL MUSCLE (No. Examined > Lymphosarcoma (3) (3) SKIN (No. Examined) Angiosarcoma (5) (2) PL Experimental Pathology Laboratories, Inc. T1 Male T1 Female - (5) 1 1' (3) 1 (7) (3) (20) . 1 (0) (13) 1 (11) (0) (7) (2) (7) (4) 4 TABLE III HAMSTERS - TUMOR SUMMARY DATA LUNG (Continued) Metastatic Mammary Adenocarcinoma Metastatic Uterine Adenocarcinoma T2 Male T2 Female 2 1 MESENTERY (No. Examined) Angiosarcoma Melanosarcoma Adenocarcinoma, N.O.S. ESOPHAGUS (No. Examined) Papilloma (ID 2 (14) (3) 3 1 (9) 1 OVARIES (No. Examined) Granulosa Cell, Malignant Thecal Cell (16) 1 1 PANCREAS (No. Examined) Islet Cell Adenoma PLEURA (No. Examined) Metastatic Angiosarcoma (16) .. 1 (0) (12) (0) SKELETAL MUSCLE (No. Examined 1 (16) Lymphosarcoma (5) SKIN (No. Examined) Angiosarcoma (16) (12) 2 EPL Experimental Path 1 gy Laboratories, Inc. -28- T3 Male T3 Female (8) (4) 74 (4) (3) (2) # (4) (3) 1 - (1) () 1 - (5) (3) 1 (7) (3) M R&S 112152 TABLE III HAMSTERS - TUMOR SUMMARY DATA SKIN (Continued) Fibroma Fibrosarcoma Melanosarcoma Metastatic Uterine Adenocarcinoma Control Male Control Female MAMMARY GLAND (No. Examined) Adenocarcinoma Adenoma (0) (2) SPLEEN (No. Examined) Angiosarcoma Metastatic Mammary Adenocarcinoma Lymphosarcoma (40) (31) STOMACH (No. Examined) Papi11oma THYMUS (No. Examined) Lymphosarcoma (3) (3) 1 (0) (0) UTERUS (No. Examined) Adenocarcinoma Angiosarcoma Papilloma (22) 1* T1 Male T1 Female .1 1 (0) (4) (36) 3 (26) 2 (8) (3) 3 (0) (0) (15) * Diagnosed as angioma. Experimental Path logy Laboratories, Inc. R&S 112153 i R&S 112154 TABLE III HAMSTERS - TUMOR SUMMARY DATA SKIN (Continued) Fibroma Fibrosarcoma Melanosarcoma Metastatic Uterine Adenocarcinoma T2 Male MAMMARY GLAND (No. Examined) Adenocarcinoma Adenoma (0) SPLEEN (No. Examined) Angiosarcoma Metastatic Mammary Adenocarcinoma Lymphosarcoma (34) 5 STOMACH (No. Examined) Papilloma THYMUS (No. Examined) Lymphosarcoma (16) 1 (2) UTERUS (No. Examined) Adenocarcinoma Angiosarcoma Papilloma T2 Female 1 2 (12) 3 1 (47) 11 1 (14) 10 (3) (33) 2 1 1 -- EPL Experimental Pathol gy Laboratories, Inc. -30- T3 Male T3 Female -- (0) (3) 1 (41) 8 (22) 9 1 (7) (4) 22 (2) (0) 1 (4) 1 t i TABLE III HAMSTERS - TUMOR SUMMARY DATA Control Male Control Female Total Neoplasms 22 No. Animals with Angiosarcomas S) PM) T) X) 0 0 0 0 Total No. Primary Angiosarcomi s No. Primary Angiosarcomas/ Hamster 0 0 1 0 1 2.7 1 0.027 T1 Male T1 Female 18 9 2 5 7 15.21 1 3 4 12.9 95 1.28 1.25 R&S 112155 S=Sacrificed PM=Died During Study T=Total EPL Experimental Pathology Laboratories, Inc. -31- TABLE III HAMSTERS - TUMOR SUMMARY DATA Total Neoplasms T2 Male 17 T2 Female 61 No. Animals with Angiosarcoma S) 3 PM) s T) 8 %) 21.6 2 15 17 26.98 Total No. Primary Angiosarcom is No. Primary Angiosarcomas/ Hamster 12 1.50 25 1.47 T3 Male 75 T3 Female 41 8 31 39 75.0 4 16 . 20 64.5 55 1.40 32 1.60 - i R&S 112156 S=Sacrificed PM=Died During Study T=Total - EPL Experimental Pathology Laboratories, Inc. -32- * # TABLE IV PERCENTAGE OF ANIMALS WITH PRIMARY ANGIOSARCOMAS RATS Male Female MICE Male Female HAMSTERS Male Female Untreated Control 2.4 0 0 2.2 0 2.7 T1 IS.7 26.7 33.3 61.5 15.2 12.9 Allowed feed and bedding during exposure T2 52.6 84.1 T3 63.9 79.0 96.1 91.5 ' 89.5 88.7 21.6 27.0 75.0 64.5 T4* 81.3 R&S 112157 -33- R&S 112158 TABLE V TISSUE COUNTS - MALE RATS Number of Animals ADRENAL BONE BRAIN EPIDIDYMIS ESOPHAGUS EXT. & MID. EAR EYES HEART KIDNEYS LIVER LUNG & BRONCHI MUSCLE OVARIES PANCREAS Untreated T-l Control 81 82 T-2 75 18 15 22 18 15 23 19 15 23 79 79 73 59 69 63 10 6 19 19 15 . 22 81 80 74 81 80 73 81 80 . 74 81 81 74 19 17 23 1 69 65 65 T-3 86 22 24 23 81 73 0 24 86 86 86 86 22 71 EPL Experimental Pathology Laboratories, Inc. -34- 4 R&S 112159 TABLE V TISSUE COUNTS - MALE RATS PITUITARY PROSTATE SALIVARY GLAND SEMINAL VESICLE SKIN SPINAL CORD SPLEEN STOMACH TESTIS THYMUS THYROID TISSUE MASS TRACHEA URINARY BLADDER UTERUS Untreated Control T-l T-2 T-3 14 13 16 21 11 15 23 8 17 15 23 22 8 5 14 0 24 14 25 22- 17 13 21 20 81 78 73 85 19 15 25 20 78 79 73 81 4 318 26 27 30 36 21 24 37 62 49 48 49 52 18 15 25 20 1 EPL Experimental Pathology Laboratories, Inc. -35- R&S 112160 AORTA OPTIC NERVE INTESTINES LYMPH NODE PERIPHERAL NERVE STERNUM TONGUE NOSE DIAPHRAGM FAT UNKNOWN ZYMBAL'S GLAND SKULL TABLE V TISSUE COUNTS - MALE RATS Untreated Control T-l T-2 T-3 18 13 19 17 16 13 15 20 21 15 24 23 32 32 38 54 18 13 21 16 . 15 14 23 8 18 15 22 22 9 12 23 16 . 1 002 1 000 40 47 39 35 0 000 0 13 22 0 - EPL Experimental Pathology Laboratories, Inc. TABLE V TISSUE COUNTS - FEMALE RATS R&S 112161 Number of Animals ADRENAL BONE BRAIN EPIDIDYMIS ESOPHAGUS EXT. & MID. EAR EYES HEART KIDNEYS LIVER LUNG & BRONCHI MUSCLE OVARIES PANCREAS Untreated Control T-l 92 76 30 12 28 13 28 14 T-2 79 10 10 10 60 18 28 79. 78 . 77 78 30 72 69 54 7 13 65 65 65. . 63 15 62 56 71 5 11 73 74 75 74 12 71 67 T-3 T-4 79 15 16 17 75 3 18 78 77 79 78 11 69 61 74 9 10 11 67 1 11 73 72 72 73 10 67 50 EPL Experimental Pathology Laboratories, Inc. 37- R&S 112162 TABLE V TISSUE COUNTS - FEMALE RATS PITUITARY PROSTATE SALIVARY GLAND SEMINAL VESICLE SKIN SPINAL CORD SPLEEN STOMACH TESTIS THYMUS THYROID TISSUE MASS TRACHEA URINARY BLADDER UTERUS Untreated Control T-l 24 9 T-2 11 T-3 12 T-4 .8 33 12 13 17 10 58 29 19 26 13 8 78 64 74 34 14 11 - 2 31 60 55 28 75 12 21 29 61 . 69 47 56 14. 11 64 71 13 14 79 12 3 32 67 19 13 73 12 9 70 13 2 22 67 44 14 66 EPL Experimental Pathology Laboratories, Inc. -38- 1 AORTA OPTIC NERVE INTESTINES LYMPH NODE PERIPHERAL NERVE STERNUM TONGUE NOSE DIAPHRAGM FAT UNKNOWN ZYMBAL'S GLAND SKULL TABLE V TISSUE COUNTS - FEMALE RATS Untreated Control T-l T-2 T-3 27 9 9 15 T-4 5 26 10 7 15 9 31 17 10 15 13 41 28 38 62 51 21 8 7 9 . 9 26 10 9 5 5 24 11 11 10 9 16 13 10 8 6 0 0 00 0 0 0 00 0 65 59 48 38 53 7 .1 0 0 0 14 9 10 10 8 R&S 112163 EPL Experimental Pathol gy Laboratories, Inc. -39- R&S 112164 TABLE VI TISSUE COUNTS - MALE MICE Number of Animals ADRENAL BONE BRAIN EPIDIDYMIS ESOPHAGUS EXT. & MID. EAR EYES GALL BLADDER HEART KIDNEYS LIVER LUNG MUSCLE NASAL CAVITY Untreated Control T-l 61 61 14 27 6 13 5 13 56 57 23 10 67 86 60 60 61 60 60 61 60 61 6 13 00 T-2 T-3 82 71 51 52 7 16 3 14 81 66 ' 13 22 16 2 13 5 16 82 71 82 70 82 71 82 71 7 13 1 12 EPl Experimental Pathology Laboratories, Inc. -40- ________ A R&S 112165 TABLE VI TISSUE COUNTS MALE MICE OVARIES PANCREAS PITUITARY PROSTATE SALIVARY GLAND SEMINAL VESICLE SKIN SPINAL CORD SPLEEN STOMACH TESTIS THYMUS THYROID TISSUE MASS TRACHEA Untreated T-l Control T-2 T-3 26 17 36 69 0 0 3 12 8 800 3 9 5 14 6 500 7 11 10 13 2 9 4 12 60 58 79 71 51 60 82 67 52 57 81 64 0 000 0 311 4 4 19 12 12 8 9 22 EPL Experimental Pathology Laboratories, Inc. -41- R&S 112166 TABLE VI TISSUE COUNTS r MALE MICE URINARY BLADDER UTERUS AORTA INTESTINES LYMPH NODE PERIPHERAL NERVE STERNUM TONGUE SKULL UNKNOWN OPTIC NERVE FEET LEGS LIMBS ZYMBAL'S GLAND Untreated Control T-l T-2 T-3 46 47 77 65 2 111 53 59 82 70 11 6 33 33 0 515 0 700 2 1 3 11 3 649 3 11 20 10 6 700 0 000 0 000 0 010 0 006 EPL Experimental Pathology Laboratories, Inc. ---------- A. TABLE VI TISSUE COUNTS - FEMALE MICE Number of Animals ADRENAL BONE BRAIN EPIDIDYMIS ESOPHAGUS EXT. & MID. EAR EYES GALL BLADDER HEART KIDNEYS LIVER LUNG MUSCLE NASAL CAVITY Untreated Control T-l T-2 T-3 45 76 77 72 20 29 77 64 6 9 9 16 2 6 8 13 7 2 48 39 0 2 3 .3 I 5 8 14 16 , . 6 38 19 43 75 75 71 44 75 77 72 44 76 77 72 44 75 76 72 9 . 11 5 14 . 0 0 5 12 EPL Experimental Pathology Laboratories, Inc. -43- - R&S 112167 R&S 112168 TABLE VI TISSUE COUNTS - FEMALE MICE OVARIES PANCREAS PITUITARY PROSTATE SALIVARY GLAND SEMINAL VESICLE SKIN SPINAL CORD SPLEEN STOMACH TESTIS THYMUS THYROID TISSUE MASS TRACHEA Untreated Control T-l T-2 T-3 28 53 68 64 20 10 71 69 1 1 5 10 0 2 8 15 . 3 18 11 19 3 3. 8 13 43 75 75 71 44 74 76 70 0 022 4 165 3 52 21 27 12 . 3 37 33 EPL Experimental Pathology Laboratories, Inc. -44- t 0 TABLE VI TISSUE COUNTS - FEMALE MICE URINARY BLADDER Untreated Control T-l T-2 T-3 23 30 64 60 UTERUS 38 48 75 69 AORTA 1 045 INTESTINES 43 73 74 72 LYMPH NODE 11 2 53 50 ' PERIPHERAL NERVE 0 2 18 STERNUM TONGUE 2 310 1 088 SKULL 1 10 5 8 UNKNOWN 3 45 19 19 OPTIC NERVE 1 570 FEET LEGS 1 00 1 0 200 LIMBS 0 000 ZYMBAL'S GLAND --_______________ ____________________________________ 0 008 EPL Experimental Pathology Laboratories, Inc. -45- 2169 U cn R&S 112170 TABLE VII TISSUE COUNTS - MALE HAMSTERS Total Number of Animals ADRENAL BONE BRAIN EPIDIDYMIS ESOPHAGUS EXT. & MID. EAR EYES GALL BLADDER HEART KIDNEYS LIVER LUNG & BRONCHI MUSCLE NASAL CAVITY (NOSE) Untreated Control T-l T-2 T-3 57 45 46 61 13 12 21 9 5 7 17 9 5 7 17 9 56 41 45 56 . 10 9 17 11 2 7 15 4 4 7 17 9 24 26 25 21 57 45 46 61 57 45 46 61 57 45 46 61 57 45 46 61 3 8 19 9 2 EPL Experimental Pathol gy Laboratories, Inc. -46- # TABLE VII TISSUE COUNTS - MALE HAMSTERS OVARIES PANCREAS PITUITARY PROSTATE RIB (JUNCTION) SALIVARY GLAND SEMINAL VESICLE SKIN SPINAL CORD SPLEEN STOMACH TESTIS THYMUS THYROID TISSUE MASS Untreated Control T-l T-2 T-3 24 28 27 21 0 570 13 12 20 11 1 3 8 17 8 7 10 19 11 5 6 17 8 4 8 16 4 52 41 43 59 10 14 . 31 41 - 55 41 44 54 1 221 6 . 9 11 4 - 3 274 EPL Experimental Pathology Laboratories, Inc. -47- LVZW </> R&S 112172 TABLE VII TISSUE COUNTS - MALE HAMSTERS TRACHEA URINARY BLADDER UTERUS AORTA OPTIC NERVE INTESTINES LYMPH NODE PERIPHERAL NERVE STERNUM TONGUE SKULL UNKNOWN PAPILLARY PROJECTION FEET CYST Untreated Control T-l 18 17 12 19 T-2 23 30 T-3 30 36 22 20 10 4 2 59 16 13 32 46 3 7 15 2 1 371 4 3 15 7 3 6 16 8 1 .5 15 2 13 14 10 16 236 12 PL Expcrimcntal Pathology Laboratories, Inc. -48- TABLE VII TISSUE COUNTS - FEMALE HAMSTERS R&S 112173 Total Number of Animals ADRENAL BONE BRAIN EPIDIDYMIS ESOPHAGUS EXT. & MID. EAR EYES GALL BLADDER HEART KIDNEYS LIVER LUNG & BRONCHI MUSCLE NASAL CAVITY (NOSE) Untreated Control T-I T-2 T-3 35 36 61 31 6 779 3 587 3 588 7 6 10 8 I 583 4 577 8 14 23 12 35 . 36 60 31 35 36 60 31 35 36 60 31 35 36 59 31 3 474 EPL Experimental Pathology Laboratories, Inc, -49- OVARIES PANCREAS PITUITARY PROSTATE RIB (JUNCTION) SALIVARY GLAND SEMINAL VESICLE SKIN SPINAL CORD SPLEEN STOMACH TESTIS THYMUS THYROID , TISSUE MASS TABLE VII TISSUE COUNTS - FEMALE HAMSTERS Untreated Control T-l T-2 T-3 18 22 34 18 17 20 27 13 0 221 3 5 12 5 3 3 12 5 3. 4 7 4 34 34 57 30 15 14 3Q 26 4 021 3 372 3 343 R&S 112174 EPL Experimental Pathology Laboratories, Inc. -50- TABLE VII TISSUE COUNTS - FEMALE HAMSTERS TRACHEA URINARY BLADDER UTERUS AORTA OPTIC NERVE INTESTINES LYMPH NODE PERIPHERAL NERVE STERNUM TONGUE SKULL UNKNOWN PAPILLARY PROJECTION FEET CYST Untreated Control T-l 12 14 T-2 18 16 12 21 32 34 50 2 6 20 3 26 18 18 30 3 38 2 33 2 47 2 36 2 43 3 2 20 1 . 13 T-3 19 22 28 6 28 3 1 4 4 3 6 2 1 R&S 112175 EPL Experimental Pathology Laboratories, Inc. -51- R&S 112176 Manufacturing Chemists Association Record of Meetings TASK GROUP FOR AUDIT OF VINYL CHLORIDE CHRONIC INHALATION STUDY Industrial BIO-TEST Laboratories, Inc. Sheraton Inn Decatur, Illinois Decatur, Illinois February 19-24, 1978 Dr. Bell presided and convened the meetings with the following in attendance at the respective meetings described below: Industrial BIO-TEST Laboratories Meeting MEMBERS PRESENT Z. G. Bell, Chairman T. J. Benya G. K. Hatfield R. K. Hinderer C. D. Kary T. R. Torkelson J. T. Seawell GUESTS PRESENT PPG Industries, Inc. Ethyl Corporation Diamond Shamrock Corporation The BFGoodrich Company, Chemical Division Shell Oil Company The Dow Chemical Company MCA Staff W. M. Busey P. Churukian J. W. Goode W. J. Koretke D. C. Lindberg J. H. Mennear R. Rhudy R. J. Roman D. J. Sullivan I. Te Vault M. Vlaovic Experimental Pathology Laboratories, Inc. Industrial BIO-TEST Laboratories, Inc. Industrial BIO-TEST Laboratories, inc. Industrial BIO-TEST Laboratories, inc. Industrial BIO-TEST Laboratories, inc. Industrial BIO-TEST Laboratories, inc. Industrial BIO-TEST Laboratories, inc. industrial BIO-TEST Laboratories, Inc. Industrial BIO-TEST Laboratories, Inc. Industrial BIO-TEST Laboratories, Inc. Industrial BIO-TEST Laboratories, inc. Meetings of the Task Group for Audit of Vinyl Chloride (VC) Chronic Inhalation Study at the Sheraton inn______ Dr. Zeb G. Bell, Chairman, and Mr. J. T. Seawell, Project Manager, began work .on the development of basic and contingent audit design plans on Sunday, February 19, 1978. Dr. Bell, Dr. C. D. Kary, and Mr. Seawell conducted a general assessment review of all material available for the audit in the adminis trative offices and laboratories of Industrial BIO-TEST Laboratories, Inc. (IBT), Decatur, during the morning of February 20, 1978. Dr. Bell opened the initial meeting of the entire Task Group at 1:35 p.m., February 20, 1978 at the Sheraton Inn with only Members Present (see Members Present roster listed above). Additional meetings of the Audit Task Group were held as follows February 20, February 21, February 22, 1978 1978 1978 7:10 p.m. 6:2h,.>p.m. 9:45 p.m. - 10:30 p.m. - 9:30 p.m. - 12:15 a.m. All other meetings were held at IBT with IBT management, project supervisors, specialists in necropsy and histopathology, and laboratory technicians present (see Guests Present listed above) 1.0 Background Information Audit plans were designed with due recognition of and consideration given to the following factors which dictated conditions under which the audit was conducted: 1) Initial exposures of test animals began on September 10, 1973. 2) The test protocol involved three different animal species, i.e.: Mice: CDI Swiss Charles River Rats: COBS Charles River Hamsters: COBS Golden Syrian 3) There were three different exposure levels for the mice and hamsters and four exposure groups of rats. The exposure levels were as follows: -3- R&S 112178 Controls Group TE I - 50 ppm Group TE II - 200 ppm Group TE III - 2500 ppm Group TE IV* - 2500 ppm Rats only, special cage conditions for this test group. 4) There were 2,500 test animals. 5) Inhalation exposures were initiated and terminated as follows: Species initiated Terminated Mice Rats* Hamsters September 10, 1973 September 10, 1973 September 10, 1973 June 10, 1974 September 10, 1974 September 10, 1974 6) The last interim report on this research project issued on September 23, 1975. No additional data or reports subsequent to this date were available to the Task Group. 7) On Monday morning, February 20, 1978 it was learned that final shipments of VC test documents, organ and tissue evidence from IBT, Northbrook to IBT, Decatur were com pleted on Friday, February 17, 1978. There were available to the Audit Task Group, only gross inventories of the shipment components. 8) No summaries or detailed inventories were available on the: a. Status of necropsy sheets or reports b. Status of histopathology readings c. Wet tissues inventoried or catalogued -4- d. Tissue blocks inventoried by designated animal numbers e. Histologic slides available and inventoried by animal numbers 2,0 Audit Designs and Contingency Plan Developed by Task Group Chairman and Project Manager 2.1 Introductory Comments It is to be emphasized that the intrinsic magnitude of test data and research evidence from 2/500 test animals (in the form of wet tissues, tissue blocks, and histopathologic slides) dictated that audit plans be comprehensive .and well designed prior to the initiation of work by any of the audit teams. This being accomplished, then the teams could proceed rapidly and effectively within their respective audit parameters, complete their work within the limited time frame allowed, and have a limited time in which to summarize their findings. Since no data pertinent to items 7) and 8) (see above) were available prior to the audit design work conducted on February 19, 1978, the Chairman and the Project Manager developed two basic plans by which the in-depth audit could be conducted. The third audit design developed on February 19, 1978 was a contingency plan which was based on- an estimate of conditions prior to and immediately following shipment on February 17, 1978 of documents and research evidence from IBT, Northbrook to IBT, Decatur. 2.2 Audit Plan I This plan was designed to incorporate criteria estab lished by the Food and Drug Administration in their proposed Good Laboratory practices (GLP) document. Among the more important GLP criteria which guided the audit, designs were the following: . Was the research being conducted in strict conformity with the protocol and were all pertinent echelons of the research facility briefed on protocol specifications? R&S 112179 -5- . Analysis of the test agent and exposure chamber concentrations and investigations of possibilities of stratified flow in the test chambers. . Test animals - test facilities1 procedures for quarantined, randomization, identifi cation, and environment. Possible deviations from these procedures - Execution of Study: . Frequency of observations of animals for possible abnormalities. . Clinical laboratory test conducted. . Recording of clinical observations in bound laboratory notebooks with appropriate signatures and initials of investigators. . Nature of test conducted on animals found dead. Necropsies (Gross Pathology): . Were necropsies performed on all animals? . Examination of animals found dead and subject to postmortem autolysis. Supervision of examination by Board Certified Pathologist. . Organs described and weighed. . Descriptive data on all lesions observed. . What wet tissues and tissue blocks were preserved and were these clearly identi fied or labeled and recorded? . Where are wet tissues and histopathologic slides stored and under what storage conditions? R&S 112180 R&S 112181 6- - Histopatholoqy: Who examined what tissues and when were they examined in relation to completion of gross pathology? . Records of all tumors or other unusual findings noted on gross examination. . Were these findings studied microscop ically? Data, Records, and Reports: . The overall laboratory plan for the collection of da-ta. . Were all animals involved in the study accurately accounted for? If any errors were observed, what could be their potential impact on the scientific integrity of the study? Audit Teams and Parameters to be covered bv Each Team Plan I provided for in-depth analyses of case histories of selected animals within given exposure groups. The audit teams were structured as follows: Team 1 - Pathology Audit Parameters . Tissue preparation . Slide - preparation . Slides - storage and retrievability . Uncut material or wet tissues examination of storage of preserved and prepared tissue R&S 112182 -7- . Pathology - examination of prepared slides . Number of tissues being prepared . Organs selected for histopathologic study Team 2 - General Laboratory Audit Audit Parameters . Body weights . Organ weights . Analytical chemical data . Clinical chemical data . Hematological data - blood parameters . Clinical observations . Air flow in exposure chambers . Records of concentrations of test chemical in exposure chambers . Cross checks of necropsy sheets with behavioral sheets Team 3 - Audit and Review of Mortality Data and __Reported Lesions Audit Parameters All recorded and/or reported mortality data. -8- R&S 112183 2.3 Audit Plan II Team 1 - Good Laboratory Practices Audit Parameters Animal Data . Data on Shipment Source Shipping date and date of receipt at test facility Number shipped - by sex How many shipped per case Batch numbers . Historic background data - sires, dams . Ages at mating . Numbers in each litter i Individual or gross weights at time of shipment Animal Preparatory and Test Data Identification of individual animals procedure used and tie-in with identification of tissues (bpth wet tissues and tissue blocks) - . Randomization - procedure used . Quarantine - conditions . Replacements Source Documentation Previous Environment Initial exposure(s) -9- . Individual weights) ____ weight change data Organ weight ) relevant to both Exposure Chamber Data . Concentrations of test chemical . Computer printouts . Detailed records of down-times and reasons for, duration of . Checks for stratified flow in chamber(s) . Number of full exposure days Criteria used to determine a full exposure day Team 2 - Research Procedures up to and *Including Necropsy Audit Parameters . Laboratory Notebooks - Type System of recording entries Tie-in with computer entries and printouts . Types of observations recorded . Mortality incidences . Mortality curves . Records of postmortem autolysis . Clinical observations Mortality Curves Versus Calendar Incidences Comparative summations of: Animals found dead versus day of week Animals sacrificed versus day of week Records of all tissues saved R&S 112184 -10- . Necropsy Sheets What tissues were actually saved - check for individual animals or conduct random checks within given exposure groups Tissues saved versus protocol requirements Recorded tissue masses Time to first tumor observations Behavioral reactions Detailed examinations and analyses of histopathology sheets Team 3 - Histopathology Audit Parameters . Residual tissues . Wet tissue preparation . Wet tissue preservation . Preservative used for eyes . Cataloguing of missing tissues . Inventory of "good" tissues and check of source animal (animal number) Complete this inventory as soon as possible to enable Board Certified Pathologist to conduct confirmatory observations or readings . Number of tissues prepared . Type of examinations of pathologic slides . Organs selected for histopathologic study R&S 112185 R&S 112186 -11- Possible Target Organs and Organs of Major Concern, e.g., Brain Heart Kidneys Liver Lungs Mammary Gland Spleen Stomach . Tissue Blocks Preparation procedure Preservation Inventory records - by test animal number 2.4 Audit Plan III This plan was designed on the basis of findings evolving from the general assessment and review of research documents and materials conducted on February 20, 1978. The results of the general assessment survey conducted during the morning of February 20, 1978 showed clearly that Plan III would have to be used. Detailed audits based on the original necropsy/histopathology sheets for each control and test animal would have to be conducted and the tissues histopathologically read and/or retained for each test animal would have to be recorded on master audit sheets showing each of the possible 38 organs of each test animal from which tissues reportedly had either been taken, or for which histologic slides had been prepared, or from which wet tissues had been preserved. The organization of this audit plan is as follows: Team 1- Histopathology Audit Team 1, Members Dr. w. M. Busey Dr. G. K. Hatfield Drs. D. J. Sullivan and M. Vlaovic and members of the IBT histopathology and necropsy staffs Areas Audited and Work Performed by Audit Team 1 . Inventory of tissues examined microscopically R&S 112187 -12- . Random shecks of slide readings aga'inst recordings on histopathologic summary sheets . Verification of slide readings . Verification of selected tumor diagnosis . Tabulation of angiosarcomas . Summary prepared of all tumor diagnoses Audit Team 2, Members Dr. T. J. Benya Dr. R. K. Hinderer Dr. D. J. Sullivan, Mr. W. J. Koretke, Ms. I. Te Vault and members of the XBT staff Areas Audited and Work Performed by Audit Team 2, Test Animal - Mice . Review of all research entries under "Gross Pathological Observations" . Review of all recorded data under "Histological Observations" . Preparation of summaries of all gross pathological observations and histological observations recorded on a possible total of 38 organs . Verification cross checks of "Days on Test" as recorded on necropsy sheets versus computer printouts . Summaries prepared under 44 classifications of all tumor data recorded for 17 organs for all animals in Control and Test Groups T-I, T--XI, and T-III -13- Audit Team 3, Members Dr. Z. G. Bell Dr. C. D. Kary Dr. D. J. Sullivan, Dr. M. Vlaovic, Mr. w. J. Koretke, Ms. X. Te Vault, and members of IBT staff Areas Audited and Work Performed by Audit Team 3. Test Animals - Hamsters The areas audited and investigations conducted by Audit Team 3 are covered by the descriptive work titles shown under this comparable section under Audit Team 2. Audit Team 4. Members Dr. T. R. Torkelson Mr. J. T. Seawell Dr. D. J. Sullivan, Dr. M. Vlaovic, Mr. W. J. Koretke, Ms. I. Te Vault, and members of IBT staff Areas Audited and Work Performed by Audit Team 4. Test Animals - Rats The areas audited and the investigations performed by Audit Team 4 are covered by the descriptive work titles shown under this comparable section under Audit Team 2. How ever, Audit Team 4 reviewed all research entries under "Gross Pathological Observations" and "Histological Observations" for Controls, Test Group i, li. Hi, and IV. The fourth test group for this species of test animal was included in this exposure series to enable comparison with animals subjected to comparable test conditions in the laboratories of Dr. Cesare Maltoni. Test Group 4 audited gross and histopathological data for 900 test animals, 38 organs per animal, or a total of 34,200 organ R&S 112188 -14- data summaries. Teams 2 and 3 audited gross and histopathological data for 800 test animals, 38 organs per animal, or a total of 30,400 possible organ entries. Audit Team 4, as did the other teams, gave special consideration to the following organ tissues of possible specific importance with respect to VC exposure: Brain Kidney Liver Lung Lymph Nodes Mammary Gland Spleen Stomach Zymbal Gland 3.0 Combined Meeting of the Members of the Task Group for the Audit of vinyl chloride Chronic Inhalation Study and. the Executive Staff of IBT, Decatur, for the Purpose of Reviewing Findings and Presenting the Recommendations of the Audit Task Group Dr. T. R. Torkelson presented a thoroughgoing history of the project to date to include work leading up to the acceptance of the protocol by the Technical Panel, a summary of conditions pertinent to the initial exposures, and a chronological recapit ulation of dates on which research findings have been made available to the Research Coordinators, and ultimately the Technical Panel. Dr. Z. G. Bell presented a review of the findings reported in the 23-month status report, and observations evolving from the studies made by the four audit teams of necropsy sheets and histopathologic findings reported to date. The VC Audit Task Group recommended to the IBT Executive Staff that the following course of action be taken. It was emphasized that these recommendations are based on investigations and observations made at IBT, Decatur during the week of February 20, 1978. The recommendations presented are as follows: R&S 112189 r &S 112190 -15- 3.1 Phase I - An Inventory of All Wet Tissues, Tissues in Blocks, and Histologic Slides The Task Group was unanimous in its recommendation that IBT complete the following at the earliest possible time: 1. A complete inventory is to be made of: A. All wet tissues in preservative in plastic containers are to be inven toried by opening each container and specifically identifying all tissues present. B. All tissues in blocks with specific identification of each tissue therein. C. All histologic slides with a complete identification and listing of each tissue for each animal. D. A histopathology sheet is to be used for recording all entries evolving from inventories under A., B., C. above. E. Summary sheets similar to those developed by the Audit Task Group, i.e., 50 animals per sheet/38 organs per animal, are to be used when pre paring data summaries. 2. Arrange in order all animals as to the days on test at death by: A. Species B. Group C. Exposure level D. Sex E. Animal numbers -16- R&S 112191 All animals for which there are no wet tissues, tissue blocks or slides are to be excluded. 3. Data obtained in 1. and 2. (of section 3.1) above are to be sent to MCA for immediate distribution to the Vinyl Chloride Audit Task Group. 4. A meeting is to be arranged in the Chicago area within 4-6 weeks to be attended by the Chief Pathologist of IBT, any other IBT executive concerned with this study, and the members of the Vinyl Chloride Audit Task Group for the purpose of discussing the results of the inventory and reaching a decision . concerning the next course of action. 5. If the inventory reveals that adequate data are available to enable the inves tigations of target organs and suspicious lesions recommended by the consulting pathologist. Dr. W. M. Busey, then IBT is to draft a report which will be forwarded to MCA. 6. The Audit Task Group will comment on the IBT draft report. 3.2 Phase 2 - Alternative Recommendations on IBT Action in the Event that Data Evolving from the Inventory are Insufficient for the Resolution of a Consensus on Effects_________________________ In the event that data evolving from the inventories cited above are not sufficient to resolve a consensus on effects, then tissues will be worked-up for specific target organs in low and high exposure levels. If this proves inadequate, then tissues for exposure groups T-I and T-II animals will be histologically examined and reported to the members of the Vinyl Chloride Audit Task Group. -17- Item 2 - At this stage, the IBT pathologist and members of the Audit Task Group will proceed according to Phase 1, Step 4 (of section 3.1) described above. 3.3 Procedure to Govern Reading of Histologic Slides Only one pathologist should be assigned tissue exam inations. By no means should different pathologists histolog ically examine animal tissues from the same species. Further, IBT should use a consistent code of findings when summarizing histopathologic data. 4.0 Concluding Comment by Dr. John H. Mennear, Technical Director, IBT, Decatur Dr. Mennear stated that he fully recognized the importance of this study and concluded by saying that he wanted to get it com pleted as promptly as possible. R&S 112192 JTS :ec Record Subject to Approval March 31, 1978 -J. T. Seawell Project Manager Vinyl Chloride Research R&S 112193 MANUFACTURING CHEMISTS ASSOCIATION 1825 CONNECTICUT AVENUE. N.W., WASHINGTON. D.C. 20009 - TELEPHONE' (20Z) 32B-4200 TELEX: 80617 (MCA W5H) January IX, 1979 To; Vinyl Chloride Audit Task Group (ATG) / 2. G. Bell, Jr. - PPG Industries, Inc. T. J. Benya - Ethyl Corporation W. M. Busey - Experimental Pathology Laboratories, Inc. G. K. Hatfield - Diamond Shamrock Corporation R. K. Hinderer - The BFGoodrich Company, Chemical Division C. D. Kary - Shell Oil Company T. R. Torkelson - The Dow Chemical Company Subj ect: ATG Report Members: Enclosed are copies of the following documents: 1. Appendix index 2. Retyped draft of ATG report 3. Appendixes If another meeting of the ATG is held, it will be at the call of the Chairman. Sincerely, LCHrpmt Enclosures Lucille C. Henschel Acting Project Manager vinyl Chloride Research THE WRITER'S DIRECT DIAL NUMBER IS (202) 328- 4250 R&S 112194 Appendix 1 Report by Dr. William M. Busey, Experimental Pathology Laboratories, Inc. Appendix 2 Protocols - February 1, 1973 - May 22, 1973 - September 7, 1973 - January 30, 1975 - August 2, 1973 - August 3, 1973 Appendix 3 Site Visits - June 15, 1973 letter - August 6, 1973 letter - August 10, 1973 letter - April 17, 1974 letter (necessity of this questioned) - February 19-24 Record of Meeting * DRAFT Final Report of Audit Task Group on LIFETIME INHALATION STUDY ON VINYL CHLORIDE at Industrial BIO-TEST Laboratories, Inc. Introduction In 197tL 31 vinyl chloride (VC) producers and users through the coordination of the MCA, contracted with the Industrial BIOTEST Laboratories (IBT) to conduct a long-term carcinogenic study in rats, mice and hamsters. Because of the absence of a final report and subsequent questions on other studies by IBT, an Audit Task Group (ATG) was established by the Technical Panel on VC Research on January 12, 1978. The group, including technical representatives of the companies and William M. Busey, D.V.M., Ph.D. of the Experimental Pathology Laboratories, Inc. (EPL), who was retained as an independent consultant, have conducted a partial audit of the histopathologic recorcfe. The findings and recommenda tions from this audit are presented in this report, including Dr. William M. Busey*s Vinyl Chloride Pathology Report, January 9, 1979. (Appendix 1) History Based on available information, a protocol for a lifetime study was designed which included exposure of male and female rats, mice i and hamsters to either 0, 50, 200 or 2500 ppm. (see Appendix 2) The contract for this study was let in February 1973 and exposures started on September 15, 1973. Reports of site visits conducted during the study are in Appendix 3. -2- Interim reports were periodically received by MCA and have been transmitted to the Technical Panel. Since no final report was received, an ATG was formed by the Technical Panel to determine the feasibility of obtaining a valid document. This was further prompted by inadequacies in other studies performed by 1ST. V*-. ' 't Procedure *i -. ` . mt mt "y The ATG recognized several questions that would have to be. answered properly if this study was to be considered of adequate t technical quality to be useful. However, after inspection of the ' } available IBT records, it seemed more appropriate to the ATG to i, first conduct a partial audit to assess the quantity and quality of the ' autopsy and histopathological data. Depending upon whether t* adequate tissues, blocks and slides were available or not, it would be possible to determine the usefulness of extending the audit to . ' animal records, exposure records, source of animals, and other equally i* * important questions. If it was found that adequate autopsy material Jt 1 <. . t was not available, nothing would be gained by several months effort i r- to conduct a complete audit. Therefore, this partial audit of pathology records was conducted. With the cooperation of remaining IBT personnel at the Decatur location, the ATG and its consultant, Dr. William M. Busey, divided Sbb(Appendix 3) itself into three teams/ The activities of the first team were - * N i described in Dr. Busey's report of January 9, 1979. The other two teams examined the autopsy records to determine the disposition of r I R&S 112196 the experimental animals and the number that had been sacrificed $ and saved for histological examination. The totals are included in Tables 1, II and III of the January 9, 1979 report. In addition, the ATG examined a small sample of the wet tissues to determine if the number of organs required by the protocol had been taken at autopsy. The findings suggested that the number of organs was deficient and ' IBT was requested to do a complete inventory of tissues, blocks . and slides. This was subsequently done and the totals of available tissues are presented in Tables V, VI, and VII of the January 9, ,t 1979 report. The ATG estimates that the full group has spent more than 800 '* *1 hours in completing this partial audit, in addition to several weeks by MCA staff and IBT personnel. Conclusions and Recommendations The ATG concludes that the conduct of the study by IBT is scientifically unacceptable and makes the following recommendations: Jf ; 1. That Dr. William Busey's report be accepted by the Technical.. Panel as the final report of this study. 2. That as recommended by Dr. Busey "no further pathology work be done on this study". 3'. That IBT be instructed that no further work be done on this study and that all materials and records of this study be retained by IBT indefinitely according to conformity with the Good Laboratory Practice Regulations, as published in the Federal Register. December 22, 1978. -4- 4. That IBT be instructed that this project is considered closed and that no further funds will be available from MCA. 5. If the report of the ATG is accepted by the Technical 30 99 (/> Panel that it be transmitted to the appropriate government agencies. NO CO 00 IK. t .V (VC.1f3 1, !V( PROTOCOL MANUFACTURING CHEMISTS' ASSOCIATION, INC. CHRONIC VAPOR INHALATION TOXICITY STUDY WITH VINYL CHLORIDE Outline of Investigation A. Type and Length*: 12-month vapor inhalation in White Mice 12-month vapor inhalation in Albino Rats 12-month vapor inhalation in Hamsters B. Number of Animals; t C. Exposure Schedule: 800 Mice 800 Rats 800 Hamsters Seven Hours per Day Five Days per Week D. Test Materials; Vinyl Chloride (Ethylene derived) E. Organization; See Table I F. Dose Levels; See Table I R&S 112199 *Aftcr exposure, animals will be maintained for observation and sacrifice at end of two-year period (18 months for mice). -1- QQZZll SSH I TABLE I Chronic Vapor Inhalation Toxicity Study Organization of Groups Test Material Group ________________________Number of Animals_____________ Mice______________ _______Rats_________ _____ Hamsters Kales Females Males Females Males Females None Control 100 100 100 100 100 ` . ICO Vir.yl Chloride- TZ-I Ithy 1 cr.e derived) Lov/ level 50 ppm TE-II Intermediate level 500 ppm TZ-III High level 5000 ppm 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 ICO ICO ICO -2- R&S 112201 II. Chamber Par nine; Up r i-. Each group of animals will be exposed in a specially constructed plexiglas inhalation chamber having a capacity of approximately 6.0 M^, allowing animal loading of less than 2% when the animals reach maturity. Flow rate through the cham ber will be at least 0.60 M^/min. providing a theoretical air. change every ten minutes. The chamber supply air will be filtered and maintained at 40% to 60% relative humidity and 70 to 75F. Ill. Animal Parameters A. Clinical Observations All animals will be observed daily for lesions and v behavioral changes attributable to the test material. The time of appearance and location of all tumors that occur among both control and test animals will be recorded. Mor tality records will be kept on all groups of animals. All animals which die during the study will be nccropsicd and * t their tissues processed in accordance with the methods given in the Anatomic Pathology Section. Care will be exercised to minimize loss of tissues through cannibalism or autolysis. Animals in a moribund state will be sacrificed _i_n extremi.s when death is imminent. -3- R&S 112202 13 Dody Weights Individual body weights will be recorded once before exposure and after 1, 2, 3, and 4 weeks of testing. There after, mean group body weights will bo determined monthly up to the 12-month point of the study. C. Clinical Pathology Hemoglobin, hematocrit, total erythrocyte and total leukocyte counts will be performed at 18 and 24 months on 3Q (15 male and 15 female) rats of the control and each test group. Differential leukocyte counts will be performed on all animals having high total leukocyte counts. ' D. Anatomic Pathology 1. Methods of Sacrifice Upon completion of the study, all survivors will be sacrificed by exsanguination,following carbon dioxide anesthesia. 2. Gross Pathology Complete necropsies will be performed on all ani mals which die or are sacrificed and all macroscopic lesions will be recorded. The lungs will be inflated with formalin < fixative. 3. Histopathology Representative specimens of the following organs -4- R&S 112203 and tissues will be ta?ccn from all animals at time of sacrifice and fixed in 10.0% neutral buffered formalin; Adrenal Glands All Gross Lesions Done (femur, tarsal and metatarsal, including long bones of all four limbs) Done Marrow (sternal) Drain Both Ears (external auditory canal with ceruminal (Zymbal's) glands) Esophagus Eye Gonads (testes and ovaries) Kidneys Large Intestine (caecum and colon) Liver Lungs Lymph Nodes (tracheobronchial, cervical and mesenteric) Optic Nerve _ Pancreas Parathyroid Gland Pituitary Gland Prostate Salivary Gland Seminal Vesicles Skin Small Intestine (duodenum, jejunum and ileum) Spleen S tomaeh Thymus Thyroid Gland Trachoo Urinary Bladder Uterus The above tissues, from animals of the control, TE-II, and TE-III will be processed by conventional methods, embedded in paraplast, sectioned (4-6p) , stained with hema toxylin and eosin, and evaluated by light microscopy. If -5- drug-related lesions arc detected in tissues from the high or intermediate dose (TE-II or TE-III) animals, affected tissues from the TE-I group animals will be processed and examined in the same manner as the above. Only major organs (liver, kidney, spleen, heart, lungs) and neoplasms from animals which die and arc found in an advanced state of autolysis will be processed for histo pathologic evaluation. IV. Reports Quarterly summaries of mortalities, clinical observations, clinicopathologic and anatomopathologic findings will be pre pared. Upon completion of the study, a .complete report will be prepared and issued. R&S 112204 February 1, 1973 I -6- JAMES n. CARNES vir:r rnrr.ini nr SLCCI. I AMY-1 m-.AUJUUI MANUFACTURING CHEMISTS ASSOCIATION 103b CONNECTICUT AVLNIJE, N.W. WASHINGTON, D. C. 30009 (303) 403-6126 Way !;, 1*73 Dr. J. C. Calnndra, President lufin*--trial BXO-T*'.:?T Laboratories, 7.010 Frontage ttond Uorthbroox, Illinois 60002 Inc. Dear Dr. Cnlanelra* Dy this letter, the agreement dated February 1, 1973, between Industrial PIO-TEST Laboratories, Inc. (DIO-TEST) and the Manufacturing Chemists' Association (MCA) for bJO-VUST to conduct a "Chronic vapor Inhala tion iitudy with vinyl Chloride" is extended to include an additional exposure group as described in the fol lowing pa r." 'j ilt. r-ii. This experimental group ii> to consist of 100 rats of the same sc::, to bo exposed to vinyl chloride vapors at a concentration of 5,000 ppm v/v. Food, water, and bedding are to be present in the cages in which the animals are exposed during the entire exposure period. Otherwise, experimental procedures, including exposure conditions, their documentation and control, and the handling, observation and necropsies of aninals shall conform to those deecrilied in the Protocol incorporated by reference in the subject agreement, and hereby so incorporated in this agreement extension. The cost for this additional exposure group will be $15,000, payable in threa equal installments, the firat and second payable on the first day of the 7th and 16th months, respectively, of the study period covered by the basic agreement, and the third upon receipt of the final report from BIO-TEST. R&S 112205 R&S 112206 Mr. 0. C. c.il.-uu'ira ;*:iy ia, 1* '71! Pago Two Plauf.o indicate your .iccoptancc by signing the enclosed copy of thin latter in the space provided and returning to us. Sincerely, Accepted for: Industrial EIO-TE3T Laboratories, Inc. Signed . 'fir. O Title President Date May 22, 1973 1 i * ALBERT C. CLARK VICE PnESIDENT technical oidectoh oepV*. t\, MANUFACTURING CHEMISTS ASSOCIATION 182S CONNECTICUT AVENUE. N. W. WACIIINC, TON, U C 70000 (707) 403-GI2G August 31, 1973 R&S 112207 Dr. C. C. Calandra, President Industrial DIO-TEST Laboratories, 1810 Frontage Road Northbrook, Illinois 60062 Inc. Dear Dr. Calandra: By this letter, the agreement dated Felrruary 1, 1073 between Industrial BIO-TEST Laboratories, Inc. (BIO-TEST) and the Manufacturing Chemist?* Association (MCA), and the agreement extension thereto dated May 14, i*'>73, are amended by. the revision of the concentrations of vinyl chloride monomer vapors to which experimental animals are to be exposed under the terms of the referenced agreements. The exposure levels, as revised by fhis amendment, are to be as specified in Table I (Revised) attached hereto. For purposes of brevity, the animal test group to which the May 14 extension relates has been designated "TE-IV." The revised exposure levels shall apply to the animal exposures beginning September 4, lv73, at which time all exposure tests will be restarted with new animals. All other elements of the test protocol .will continue to be governed by the referenced prior agreements. There will be no change in cost to MCA by the implementation of the terms of this amendment. i Dr. J. C. Calandra August 31, 1973 Page Two Please indicate your acceptance of thin amendment by signing the enclosed copy of this letter in the space provided, and returning to me. Sincerely, l(U> Accepted for: industrial BIO-TEST Laboratories, Inc. ^0- A' Signed Title Assistant to the President Date September 7, 1973 R&S 112208 TABLE I (Revised Auguat 31, 1973) Chronic Vapor Inhalation Toxicity Study Organisation of Groups Test Material Hone GrouD Control Mice Males Females Kucher of Animis ______ Rats_________ Ka les Fe *:alen _____ Y a ry -1 n r r Ka les V o r n ' " i 100 ICO 100 100 100 loo Vinyl Chloride TE-I* (Ethylene derived) Low level 50 ppm - TE-II* Intermediate level 200 ppm TE-II1* High level 2,-50 0 ppm TE-IV** High leval 2,500 ppn 100 100 100 -- 100 100 ICO ---- 100 100 100 100 100 100 100f} 100 ICO 100 100 mo ___ ICC */ * Ho food, water, or bedding in cages during exposure ** Food, water, and bedding to re:; a in in cagoa during exposure # All rats of same se:c, either sex permitted 6023 U S9U JAN J01975 THE DOW CHEMICAL COMPANY January 27, 1975 BENNETT BUILDING 2030 DOW CENTER MIOLANO, MICHIGAN 4*640 R&S 112211 Mr. Milton Freifeld Manufacturing Chemists' Assoc. 1825 Connecticut Ave, N.W. Washington, D.C. 20009 Dear Mr. Freifeld: The attached table was compiled from information received ov.cr the telephone January 20, 1975. Dr. Keplinger of Industrial Dio Test wanted to know if the committee wished to sacrifice the surviving control mice and the 13 female rats exposed to 200 ppm. After talking to as many of you as I could get ahold of, I found, that the majority preferred to keep the rats as long as possible and to main tain the mice at least for 18 months. I informed Keplinger of this decision and he will keep these animals until notified otherwise. Therefore, about March 1 I will be contacting you again on the disposition of the surviving control mice. Since Maltoni has kept his animals for their entire life and since you may be considering more studies at a later date, there appears to be reason to keep these animals for lenger than the original protocol called for. Note that it was necessary to sacrifice several moribund hamsters, mice and rats on January 20. All exposed mice are now gone as well as all the top dose of rats and virtually all the top dose hamsters. There is no apparent explanation for the reversal in mortality of the groups of female hamsters. It's just one of those things. Sincerely yours. Theodore R. Torkelson Corporate Medical Department kjf end ec:. Distribution List Attached cc: Vinyl Chloride Research Coordinators Dr. Zeb G. Bell, Jr. PPG Industries,-Inc. One Gateway Center Pittsburgh, PA 15222 Dr. Walter D. Harris UNIROYAL, Inc. Oxford Management 6 Research Center Middlebury, Conn. 06743 M. N. Johnson, M.D. The B.r. Goodrich Company Medical Center 500 South Main St. Akron, Ohio 44318 Mr. H. ti. Kusnetz Shell Oil Company P.0. Box 2463 Houston, TX 77001 Dr. W. Mayo Smith Air Products 6 Chemicals P.0. Box 538 Allentown, PA 18104 Dr. William Rinehart Cthyl Corporation Medical Department 451 Florida Avenue Baton Rouge, LA 70801 Mr. R. N, Wheeler Union Carbide Corp. Chemicals Plastics Div. P.0. Box 8004 S. Charleston, W. VA 25303 M. L. Keplinger Industrial BioTest Laboratories, Inc 1810 Trontage Road Northbrook, ILL 60062 J, Goode Industrial BioTest Laboratories, 1810 frontage Road Northbrook, ILL 60062 Inc INFORMATION COPY MuAhud Bio -TEST JoMomMv>:a, %c,, DECATUR RESEARCH 1800 CAST rERSHlNG f?0 A D DECATUR, ILLINOIS 62526 August 2, 1973 ABCA CODE 2t? TELEPHONE Q77P*ft4 H. Slatin Manufacturing Chemists Association H826 Connecticut Avenue, N.W. 3JF?t'Washinglon, D. C. 4 *'!!*'?! ..;'a 20009 Dear Dr. Slatin: JsDue to problems which have occurred in the early stages of the .k&bi.vinyl chloride inhalation project, II3T 663-0322?., we respect fully request that we be allowed to restart the study. rJ our opinion, two major problems make this request necessary: $Re*S(a) The design on the animal feeding system is not working satis factorily. This caused considerable weight loss in the hamsters $$|Sand they have been terminated. The rats ami mice have not had .^normal weight gains and the feeder system must lie redesigned. jL(b) Some of the changes deemed necessary by the MCA committee fon their last visit to the laboratory, have been made? hut others p?jtare delayed due to shipping dates on equipment. ' [la our opinion, to continue such an important project with animals Ewhich. have been stressed and in which sampling and air handling ^equipment would ho changed in the near future, would compromise data and leave Dio-Test open to eventual criticism. SWe feel that all equipment changes can be made by September 1, V&Kfe.l973, at which time the study would he restarted with new groups Tof animals. ,<am sure that a favorable decision on this matter will allow llio-.Tcst '.conduct a study which will be. better received by the scientific immunity. Sincerely, (u JtlctcLc_ f Jfohn W. Goode, I3h. I). '--'Manaficr Decatur Research Laboratories > cn yr*- jv* IT' L9*^ ko'l p' ir- .**4*1* i i ,1 4 I ,J1 ^v- ;f*:*W*}t'* r *4r a clark ^.-iCt NSSIDENT AjMUt. OIWCTOA ^.I'Oiwwii'XON COPY manufacturing chemists association 182b CONNECTICUT AVENUE, N W. WASHINGTON, D C JOCli i*0?) 483-ul26 August 3, 1973 3ohn W. Goode, Ph.D., Manager ^-iecatur Research Laboratories iustrial Dio-Test Laboratories, 10 East Pershing Road atur, Illinois 62526 Inc. ta^r.Dr. Goode: Thank yoxi for the courtesies extended to Mr. Harry Slatin ,*|d the representatives of our member companies. Dr. T. R. M*k Ison, Dr. Z. G. Bell, Dr. W. D. Harris, and Mr. II. L. jinetz in their visit to your laboratories August 2, 1973. $0 We were all sorry to hear, as you told th^m n-d vein: .fitter of August 2, 1973, indicates, that the current st-.-rt on ft*.vinyl chloride inhalation project, IBT-663-03222, is such 'iat you recommend a restart of the study on September 1, 1973. Jfcderstand from discussions at the time of the visit that SWiotal cost of this study to MCA will remain as originally t.rKeed. % MCA and its member representatives concur with you that a start of the study is desirable and advise you to proceed. f4 ?. vv'It .is appreciated that the changes you have made in your ,'sical setup, as well as those you contemplate will help the (ly appreciably. *" i .If there are any other problems, please advise us. Sincerely, im-mm /\%A* *V` _v". .. *i R&S 112216 \ it ii- i lit I t i !i 1t jl '* ! 1, R&S 112217 June 15, 1973 7,eb Bell Walter Harris ( Russ Maycock Maurey Johnson , Bill Rinehart ' R. N. Wheeler , ' ' cc: John Goode / Ken Johnson Howard Kusnetz r /1` Moreno Keplinger VISIT TO INDUSTRIAL BIO-TEST LABORATORIES, DECATUR, ILLINOIS On June 7, 1973, Ken Johnson (MCA), Howard Kuznetz (Shell), and myself, visited the Decatur Research Laboratories of Industrial Bio-Test Laboratories, Inc. The purpose of the visit was to observe the equipment and facilities and to discuss the program to be sponsored by MCA. Vie were accompanied in our visit by Ken Schadeberg, John Goode and Moreno Keplinger of Industrial Bio-Test. Following a brief introduction* we were shown the inhalation facilities in a large room on the lowest floor of a rela tively now building in Decatur. We had expected the exposure to be underway, but to our disappointment found out that, although many of the animals were on hand, the experiments were not ready to begin. We were assured exposures would be underway in 10-14 days, but after viewing the incompleted facilities, we expressed concern for this possibility. One month appeared more reasonable before exposure could start. As described, the inhalation facility is new and this will be the maiden voyage for much of the equipment. Therefore, wc had many questions about the adequacy of the equipment and whether it will be shaken down before tiic experiment gets underway. A number of comments were made, including the following: 11 Because of the shape of the chambers, the large number of animals per chamber, and the fact that the cages were attached to tlie walls and separated by trays, there was possibility of channeling of air tiix-ough the chamber. It was suggested that R&S 112218 *> * n Vinyl Chloride Res. Coordinators June 15, 1973 an air distribution plenum, and/or a circulating fan, and certainly a plenum vent system be considered to assure dis tribution of air throughout the chamber. It was pointed out .'I that it would be necessary to verify the adequacy of the air distribution by a suitable analytical method. ; There were floor drains in the bottom of each chamber and there was concern that these drains' holes might become unplugged and that contaminated air could back up into the chambers from a common floor drain. It was suggested that a more positive seal such as a screw cap be considered. It was also suggested that draft gauges with alarms be included tj to assure closure of the chambers and operation of the pumps so that the animals do not die of asphyxia. , Because it was considered necessary to do very frequent J sampling during the first part of the experiment and routine monitoring later (twice/day per chamber), it was recommended that a multi-point continuous analyzer be considered in order to reduce the cost. This analyzer could also be used to verify the distribution of air throughout the chambers. An electron capture detector on a gas chromatograph was suggested. The orifice meters used to control the air flow into the chambers were connected by rather long, flexible hoses. It was suggested that, these be shortened to decrease the likeli/ hood of leaks. Air was supplied through a common duct, which ' had its inlet inside the room. It was therefore considered possible that during wash-dowq procedures there could bo feedback into other chambers and that cross contamination should be carefully guarded against. 7 The matter of daily records \*as discussed. It was recommended that a daily log of meter readings, exposure times, flow meter readings be kept, and that calibrations of equipment become part of the experimental record. In this regard, if flow meters (rotometers) are used, they should be glass and not plastic. s. There appeared to be unusually small hoses from the chambers to the common exhaust. These were obviously connected in a temporary manner with tape, but it was assumed that this was merely to check out the operation oC the chambers and that they would have more permanent attachments. Iixhaust from all chambers went into a common duct, which was recognized as another possible source of cross contamination. Because of the possibility of injury and death of the experi mental animals or explosion if the concentration increased to the flammable range due to failure of an air pump, it was suggested that an alarm system be included in the setup to assure movement of air through the chambers. ,, O ' vinyl Chloride Res. Coordinators June 15, 1973 In regard to records, it was pointed out that it would be necessary to account for the fate of every animal and that they should be coded in such a way as to prevent mix-ups, which could occur .in the somewhat crowded conditions. Pathological examination will be done by technicians who will make gross observations, photograph any unusual growths, and save tissues from all animals, including abnormal growths. It was stressed that all abnormal growths must be examined microscopically since this is the ultimate purpose of the s tudy. Everything appeared to be in order on shipment and delivery * of samples and there was understanding what would be done to assure'a supply on hand at all times. One major concern was the possible number of company contacts who might approach Industrial Bio-Test for information. It was felt undesirable to allow 20 companies to be asking for information. It was determined that no information would be given by Bio-Test to anyone except Ken Johnson unless Bio-Test was specifically authorized to do so by Ken Johnson. This was considered necessary so that well-intentioned but unauthorized people from the various supporting companies would not be 'putting Industrial Bio-Test in the embarrassing situation "of having to refuse to give information to their clients. In summary, we are seriously concerned about the newness of the equipment and the fact that it has not been demon strated in previous experiments to provide good air distri bution. We are seriously concerned about the possibility of cross-contamination bet\/ecn chambers because of common inlets, outlets, and floor drains. We are concerned about the adequacy of the analysis and about the keeping of records. Because of the excellent reputation of Industrial Bio-Test, we.feel they will correct many of these problems, but it is our recommendation that the committee work very closely with them so that the,experimental results are not jeopardized by technical errors. Bio-Test's personnel wore impressed with the importance of the situation, and we think we have their complete understanding. Sincerely yours. T. R. Torkclson Registration Section Ag-Orgnnics Department la i R&S 112219 R&S 112220 INDUSTRIES To: R. E. Widing INTER-OFFICE CORRESPONDENCE August b, if?! F ,0m: Zeb G. Bell, Jr. tucai>u>1; if East Sub |CC t: Indus trial Biotest L-jbor.i tory Vi r.i t, Decatur, Illinois As a member of the KCA-VCM Technical Cncnlinutorr- TnsA Group, chv undersigned visited the Industrial Siotest Laboratory faeilicv in Decatur, Illinois, where the MCA inflation studv on VCH is being performed. There were some problem.: in the cost chamber deciur reported by Dr. T. TorVelson I Dew) cr. his lust visit, there. This visit revealed that these condition;, have b< *'n or an being rectified; We (MCA) have been advised thioujh c.-.u attached letter that : c'te early problems have developed resulting in their recommendation that the study be re-started. This -:onsii tutes a lurcher delay in getting this program "off else ground", however, it it a very wise move since the experiment may neve heu to be terminated at a later date because of these factors anyway. Industrial Biotest Laboratory has acted in good faith, in complying with our recommendations, but they rave liad some unfortunate '...".con trollable circumstances develop that prompted them to suggest a re-start.. I see that we have no other choice than to concur. Zeb G. Bell, Jr. / --- ZGBtrmp Attachment ce: J. A. Clapperton L. B. Grant, M.D. d. L. MacMilla-n ,H. ^la tin (MCA) v/Th R. Torkelson (Dow) * MANUFACTURING CHEMISTS ASSOCIATION 192b CONNECTICUT AVENUE. N.W. WASHINGTON, D C. 20009 (202) 483-6126 August 10, 1973 R&S 112221 Memorandum TO: A. C. Clark FROM: H. L. Slatin SUBJECT: Visit August 2, 1973 Industrial BIO-TEST Laboratories, Inc. Decatur, Illinois At the meeting of the Technical Task Group on Vinyl Chloride Research, July 11, 1973, considerable concern was expressed over certain aspects of the ani mal studies being performed by Industrial BIO-TEST Laboratories (IBL). To assure that discrepancies in the facilities and program noted during the visit to IBL by Drs. TorkeIson and Johnson have been corrected, it was agreed to schedule a follow-up visit after the tests had been started. This will summarize discussions and observations during the conference on August 2, 1973, which I attended for Dr. K. D. Johnson. In attendance: For MCA IBL Dr. T. R. TorkeIson Dr. Z. G. Bell, Jr. Dr. W. D. Harris Mr. H. L. Kusnetz Mr. H. L. Slatin Dr. J. W. Goode Mr. Ken Schadeberg Mr. Dennis Lindberg The difficulty Industrial BIO-TEST was having with the animals was discussed. The animals were received during a period of an air strike of Ozark, the only sched uled airline into Decatur. It was necessary to truck the animals from Northbrook, Illinois using temporary cages and an irregular schedule. It was felt this was an unusual stress to the animals, particularly the hamsters. ' r ,w--r- . i -2 R&S 112222 n The protocol required that food be taken away from the animals while they are exposed to inhalation of the mixture of vinyl chloride. In order to do this, special food racks were provided by IBL, which did not allow the animals, particularly the smaller ones, to eat the food. Consequently, they lost weight and some died. Industrial BIO-TEST felt it would be better to scrap these experiments and start anew. September 1, 1973 was suggested as the new starting date. By this date, IBL could effect the following additional improvements: construct a new air exhaust system; install a new gas chromatography unit to automatically and regularly monitor the vinyl chloride concentration in each of the different inhalation chambers; and provide a new feeding device which would allow the animals to get at the food. The starting delay means that we will not have test data for one year available until September 1974. The one year (12 month) data could be presented at the annual fall meeting of the Industrial Hygiene Foundation as the first part of the 24-month test period. Dr. Torkelson felt that the key part of the experi ment is the one wherein the food would be in the chamber at all times. This part had not been initiated to date, but will be an integral part of the experiment as it is restarted. It was indicated that restarting the study would involve no additional cost to the MCA sponsoring group. All in attendance favored the restart. It was also requested that Industrial BIO-TEST obtain from Charles River, at the start of the experiment, information on all of the animals as to their background and the number of multiparous litters from which they came. In any case, if everything was not ready by September 1, 1973, but the animals were, the experiment would start anyway. Dr. Goode noted that the high dose of 5,000 ppm v/v was a feasible testing dose. He also stated there are 13 different points from which the chambers are sampled. The Baffle plates and funnels do not affect the homogeneity R&S 112223 'n -3- of the-VCM/air mixtures. It took about 35 minutes for the chambers to reach equilibrium, which remained steady thereafter. The chambers have a complete air change every ten minutes. The current animals will be used to check out the feeding part of the experiment. Industrial BIO-TEST agreed to make suitable arrange ments for a possible leak and/or rupture of one or more containers of vinyl chloride. Changes will also be made to the air exhaust system so that the air intake will be at a point up and away from the air exhaust. Subsequent to the meeting, committee members M. N. Johnson, M. D., Dr. W. E. Rinehart, and Mr. R. N. Wheeler were contacted by phone and all concurred with the decision to restart the testing procedure September 1. HLS :mb H. L. Slatin * i TABLE I Mouse Mortality Data DATE Controls FM February 10, 1974 28 GROUP TI TII FM FM 6 26 24 Till FM 78 April 12, 1974 5 11 9 31 13 7 13 18 R&S 112224 30 g ^ !)n$uAlAMjM BlO -TEST J'rilk*IfiMyiueA. J)flC- IVJ inio rRONTAcvr ROAO TABLE II IO Ilf'DTIinROO^ HIIMOIS A00A7 m Summary of Tumors in Vinyl f'hloridc Exposed Mice I13T Number 60-3 -UJ222-MCA Group, Animal No. . Sex T-I 1023 Male 1110 Female 1119 Female 1200 Female Histopathologic Findings Date of Death Lung Liver Skin A A (sj* IIS (s)** AA (s). Metastatic Skin Tumor HS ( s) Metastatic Skin Tumor EC (para-aural) 3-20- 3-24-74 EC MC+ (Femoral region) 3-30-74 T-II 1347 Female 1309 Female 1889 Male 1382 Female 1350 Female 1299 Female T-m 1538 Female 1532 Female 1562 Female 1598 Female 1405 Male 1494 Male 1574 Female 1531 F emale 1588 Female 1593 Female 1505 Female 1565 Female 1409 Male 1543 Female 1544 Female 1546 Female 1535 Female 1432 Male 1477 Female Metastatic Skin Tumor HS (s) AA (s) HS HS (s) AA (s) HS (s) AA (s) AA (s) AA (s) AA (s) AA (s) AA (s) AA (s) AA (s) HS (s) HS (s) IIS (s) HS (s) * HS (s) HS (s) HS (s) 'AA (s) AA (s) AA (s) AA (s) AA (s) AA (S) AA (s) HS (s) HS (s) IIS (s) HS (s) IIS (s) HS (s) HS HS (s) AA (s) HS (s) AA (s) A A (s) HS (s) Metastatic Skin Tumor? EC( Abdomen) 3-5-74 3-18-74 3-25-74 4-2-74 4-5-74 EC te MC. (Inguinal Region) 4-9-74 LS< 3-6-74 3-7-74 3-8-74 2-25-74 3-22-74 3-22-74 EC k MC (Femoral region) 3-23-74 3-25-74 3-30-74 4-3-74 4-3-74 4-5-74 4-5-74 4-5-74 MC (Axillary region) 4-5-74 4-7-74 4-8-74 EC (Para- Aural) MC ( Abdomen) EC( Pelvic region) 4-9-' Group T-I T-II T-UI TABLE III 9nduL6t/iUil BIO -TEST JlaJxyiaJjMizd', 9nc. 1810 FRONTAGE ROAD NORTHBROOK, ILLINOIS 60062 jj B ^ Summary of Mortality 8t Tumor Data Among Vinyl Chloride Mice IBT Number 663-03222 (MCA) ro 01 No. Mortalities with Neoplasms - Location ot Tumors Lung Liver Skin Metastasis-> Lu; 4 (1 Male, 3 Females) 2(50%) 2(50%) 2(50%) 2 6 (1 Male, 5 Females) 3(50%) 4(66. 7%) 2(33%) 1 19 (4 Males, 15 Females) 17(89.5%) 17(89. 5 %) 3(15. 8%) Key to Symbols * Alveologcnic Adenoma of Lung (AA) Hemangiosarcoma of Liver ( HS) *** Epidermoid Carcinoma of Skin (EC) + Mammary Carcinoma of Skin (MC) (3 Lymphosarcoma of Thymus ( (s) Multiple tumors of indicated type MANUFACTURING CHEMISTS ASSOCIATION 1825 CONNECTICUT AVENUE. N. W. WASHINGTON, 0 C. 20003 (202) 483-6t26 April 17, 1974 To: TECHNICAL TASK GROUP ON VINYL CHLORIDE RESEARCH Subject: Report on Conference with Industrial BIOTEST Laboratories, April 15, 1974 Gentlemen: As a result of the telephoned information received F by MCA from Industrial BIO-TEST personnel last week, a . conference at the Northbrook, Illinois offices of IBT was se^ UP at which an oral status report on the chronic inhalation studies with vinyl chloride was presented to MCA, ^..industry and federal agency representatives. Those in attendance, and their affiliations, are << shown below: M' 2. g. Bell, Jr. s. Cummin 1*E. J* Fairchild ?VJ. W. Goode .^ `D. E. Gordon u. Harris !'m. n. Johnson, M.D. Flynt Kennedy L. Keplinger ^R. J. Kociba Kusnetz Lassiter Rinehart Smith Star a &T. R. Torkelson ER. N. Wheeler |b* M. G. Zwicker SR. F. Blewitt fA. C. Clark . D. Johnson PPG Industries, Inc. Borden, Tnc. NIOSH Industrial BIO-TEST Laboratories Industrial BIO-TEST Laboratories UNIROYAL, Inc. The B. F. Goodrich Company Continental Oil Company Industrial BIO-TEST Laboratories The Dow Chemical Company Shell Oil Company OSHA Ethyl Corporation Air Products & Chemicals, Inc. U. S. Environmental Protection Agency The Dow Chemical Company Union Carbide Corporation B. F. Goodrich Chemical Company MCA MCA MCA R&S 112227 ;i * Dr. Goode first presented the mortality data and gross observations, and then Dr* Gordon described the pathology observed in the mice. The data, ns presented, are shown in the attached tables. There are apparent discrepancies between the total mortality data and the detailed listing of recent deaths. These will be re solved. No test-related pathology has yet been noted in any animals other than mice. ,, jjj, -t . -"TJ.tl.. tfi'W Dr. Fairchild, of NIOSH, reported that Dr. David Rail, of HEW, had appointed a committee to coordinate ..** i ** yV* '; *' \ - departmental toxicology and related programs, and that under this committee there has been named a subcommittee to develop a "white paper" on guidelines for research to determine "socially acceptable" levels of risk. A report from this subcommittee, which will cover both philosophicaland statistical considerations, is expected in the next few weeks. j` wr MM Dr. Stara expressed the view that the vinyl chloride "liPS: problem presented industry with a unique opportunity to seek to demonstrate a "no effect level" of n human carcinogen with a sensitive animal model of well-documented validity. Dr. Lassiter expressed a guarded judgment that the mouse data reported by IBT would not load OSIIA to modify the emergency temporary standard, but that it might well cause OSHA to accelerate the rule-making process for the development of a permanent standard. Dr. Lassiter also reported briefly on the retrospective) morbidity and mortality studies being conducted by NIOSH/CDC at nine or ten locations (six companies) around the country. ' * No epidemiological data were presented. ; ^,.T. '! 'r tJ gfr-vfijWr' In an afternoon session of the Research Coordinators, -t-:1' 1 it was agreed that the exposure of the mice in the present i , ;. V ;-v project should be terminated at nine months, but that t i#S exposures of both rats and hamsters should proceed for the^ feT'.s initially-planned twelve months. It was further moved, seconded and carried that the chairman appoint a group to begin investigating the cost and availability of facilities of new experiments to be con ducted at lower levels of exposure, with larger groups cf animals. He was asked specifically to seek to encourage the National Center for Toxicological Research, at Pine A'; -`A* R&S 112228 -3- Bluff, Arkansas, to offer to undertake such a program. Details of the test protocol are to be left open until after the Rail committee makes its report available. The Research Coordinators asked MCA to call a meeting of the Technical Task Group on Vinyl Chloride Research as soon as the report of Tabershaw-cooper Associates on their epidemiological study reaches them. A copy of the MCA news release reporting the Industrial BIO-TEST mouse data has been sent to you in this morning's mail. Sincerely, R&S 112229 KDJ;mb Kenneth D. Johnson, Ph.D. Secretary Technical Task Group on Vinyl Chloride Research Tables Attached cc : . .Mr. A. W. Barnes D. P. Duffield, M.D. Dr. Tiziano Garlanda Vinyl Chloride Management Contacts