Document LeZLd98Jjvz0Yaby49rzjE8z

^LJh. ' /- MANUFACTURING CHEMISTS ASSOCIATION 1825 CONNECTICUT AVENUE, N.W. WASHINGTON, D. C. 20009 (202) 483-6126 January 30, 1978 TO: Task Group on Audit of Vinyl Chloride Chronic Inhalation Study Dr. Z. G. Bell, Chairman Dr,, T. Benya Dr. G. K. Hatfield Dr. R. K. Hinderer Dr. C. D. Kary Dr. T. R. Torkelson Dr. W. M. Busey Mr. J. T. Seawell PPG Industries, Inc. Ethyl Corporation Diamond Shamrock Corporation The BFGoodrich Company, Chemical Division Shell Oil Company The Dow Chemical Company Consulting Pathologist, Experimental Pathology Laboratories, Inc. MCA Staff Gentlemen: The audit will begin on Monday, February 20, 1978 at a luncheon meeting at the Sheraton Inn, Decatur. Heretofore, most connecting flights have arrived at Decatur about 11 a.m. and this has enabled a luncheon meeting to begin shortly after 12 m. Acknowledging from the onset the intrinsic, magnitude of the requirements of this audit, e.g., three different animal species, four exposure groups, 600 animals per exposure level, and an initial exposure date of September 10, 1973, strategic planning will be necessary in order to conduct incisive analyses of critical research areas. Therefore, the noon meeting will be the initial stage of an overall planning session which could extend well into the afternoon. In-depth planning will be concerned with the structuring of audit procedures, analyses of the most critical areas to be covered during the first phase of the audit, assignment of missions to the individual audit teams, and analyses of and planning for critical data sampling designed to reflect the most effective spot checks possible of the various exposure levels and animal test groups. Should the initial planning meetings on the afternoon of February 20th be completed prior to the closing time of Industrial BIO-TEST Laboratories (IBT) 9tOTSOT2 BFG09199 2- - then the Task Group will proceed immediately to IBT for its initial work. It is expected that each day of the in-depth audit will be followed by early and late evening meetings concerned with analyses of the findings on a given day, plans for the investi gation of special areas, and modifications of the overall audit procedure should this prove necessary because of interim findings. Enclosed for your review in advance of your audit work are all documents pertinent to the protocol, its modification, and organization of test groups. Hotel space has been reserved for each of you at the Sheraton Inn, Decatur, Illinois (Telephone 217/877-7255) for Monday night (February 20, 1978) through Thursday night (February 23, 1978). Each member of the Task Group is responsible for arranging for guaranteed late arrival (if this be necessary) and for cancel lation of his space should this prove necessary. In the event that your travel arrangements will not permit you to arrive in time for the luncheon meeting, on Monday, then inquire at the Sheraton reservation desk concerning the number of the meeting room. Should the Task Group already have departed for work at IBT, then telephone Mrs. Donna Mundy of IBT at 875-3700 concerning the location of the Group's various audit operations at IBT. Should you have any questions concerning the audit or arrange ments pertinent to its conduct, please contact the Project Manager at the earliest possible time. Sincerely J. T. Seawell Project Manager Vinyl Chloride Research JTS:ec Enclosures cc: Vinyl Chloride Technical Panel BFG09200 1081047 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 PPG Industries, Inc. Ethyl Corporation Diamond Shamrock Corporation The BFGoodrich Company, Chemical Division Shell Oil Company The Dow Chemical Company MCA Staff GUESTS PRESENT 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. 31081048 BFG09201 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? BFG09204 r sors0?s -5- Analysis of the test agent and exposure chamber concentrations and investigations of possibilities of stratified flow in the test chambers. . Test animals - test facilities' 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? BFG09205 N a QO 3 01 u 6- - Histopathology: 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 data. . 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 by 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 BFG09206 es,U8or-r 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. BFG09207 21081054 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 . 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 (both wet tissues and tissue blocks) . Randomization - procedure used . Quarantine - conditions . Replacements Source Documentation Previous Environment . Initial exposure(s) BFG09208 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 & A S C ?t80i'c` BFG09209 -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 BFG09210 -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 o Areas Audited and Work Performed by Audit Team 1 . Inventory of tissues examined microscopically BFG09211 Random shecks of slide readings against recordings on histopathologic summarysheets 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. p. J. Sullivan, Mr. W. J. Koretke, Ms. I. Te Vault and members of the IBT 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" es 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--II, and T-III BFG09212 -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. I. 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, II, III, 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 f'i 1081053 BFG09213 -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. W The recommendations presented are as follows: 1081059 BFG09214 -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 BFG09215 1081060 -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 examinations. 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. JTS:ec Record Subject to Approval March 31, 1978 c. T. Seawell Project Manager Vinyl Chloride Research 1081062 BFG09217