Document zQyje0zwMKwOBo6OQ3vvNoer0

MANUFACTURING CHEMISTS ASSOCIATION 1825 CONNECTICUT AVENUE. N.W. WASHINGTON. O.C. 20009 (202) 483-6126 April 17, '. .974 TO: t TECHNICAL TASK GROUP ON VINYL CHLORIDE RESEARCH Subject: Report on Conference with Industrial BIO: TEST Laboratories, April 15, 1974 Gentlemen: As a result of the telephoned information received by MCA from Industrial BIO-TEST personnel last -week, a ^conference at the Northbrook, Illinois offices of IBT was ;set up at which an. oral status report on the chronic in'halation studies with vinyl chloride was presented to MCA, industry and federal agency representatives. Those in attendance, and their affiliations, are shown below: *Z. G. Bell, Jr. A- S. Cummin . J. Fairchild W,, Goode L"E. Gordon L D. Harris M. N. Johnson, M.D ?lynt; Kennedy T L. Keplinger f J. Kociba . L. Kusnetz V. Lassiter E. Rinehart H. M. Smith F. Stara R. Torkelson N. Wheeler M. G. Zwicker ; F. Blewitt WSlc. Clark- D. Johnson PPG Industries, Inc. Borden, Inc. 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 SCC i-oso: tut) Dr. Goode first presented the mortality data and gross observations, and then Dr. Gordon described the pathology observed in the mice. The data, as 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. Dr. Fairchild, of NIOSH, reported that Dr.- David Rail, of IIEW, had appointed a committee to coordinate 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 philosophical and statistical considerations, is expected in the next few weeks. m Dr. Stara expressed the view that the vinyl chloride problem presented industry with a unique opportunity to seek to demonstrate a "no. effect level" of a human carcinogen . i with a sensitive animal model of well-documented validity. ; Dr. Lassiter expressed a guarded judgment that the mouse data reported by IBT would not lead OSHA 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. -4J 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. In an afternoon session of the Research Coordinators,': it was agreed that the exposure of the mice in the present :; A project should be terminated at nine months, but that j exposures of both rats and hamsters should proceed for the,-, r-j initially-planned twelve months. It was further moved, seconded and carried that the rJ chairman appoint a group to begin investigating the cost and availability of facilities of new experiments to be con- .*j\| ducted at lower levels of exposure, with larger groups of animals. He was asked specifically to seek to encourage the National Center for Toxicological Research, at Pine see i-0804 MS & 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 meet ing 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, Kenneth D. Johnson, Ph.D. Secretary Technical Task Group on Vinyl Chloride Research KDJ: mb Tables Attached cc : .Mr. A..W. Barnes D. P. Duffield, M.D. Dr. Tiziano Garlanda Vinyl Chloride Management Contacts TABLE 1 see 1-0806 `JnAh.u/AtoJ 0 1 3-TEST J'tjA}lalcnicA. Sac. mio fro^taQiF * TABLE XX iiObth0ROO^ Hieiois 6006? Summary of Tumors in Vinyl (-Moridc Exposed Mice * " 1 LVr Number Goi -03222 -MCA m. ^ Group, Animal No., Sex T 1 J0^3 Male I l 10 Ft; ma Ic 1119 rVmnlo. 17.00 Female T-H 1347 Female I 309 Female 1689 Male 1382 Female 1351 Female 1?.99 Female r-ia 1538 Female 15 32 Female 156?. Female 1590 Female 1405 Male M9-1 Male 1574 Female 153 l Female 1588 Fornate 1593 Female 1505 Female 1 565 Femalc F-UIQ Male 15-13 Foma lo 1544 Female 1545 remale 1535 Female 1-13 2 Male 1477 Female Histopathologic Findings Date of Death Lutig Live x' AA (sj* IIS (s)" AA (si. Metastatic Skin Tumor US (a) Metastatic Skin Tumor Skin im n\ '4 m EC (para-aural) 3-20-7 ;m 3-24-74 EC k MC+- {Femoral !$ region) 3-30-7,4] ! ijl ! -m Meta static Skin Tumor US (s) A A (s} US US {s) AA (s) IIS (s) AA (s) . AA (s) AA (s) AA {s} AA (s) AA (si AA (sj A A (s) HS (s) US (s) MS (si US (?) US (s) US (s) US (s) AA (s) AA (s) AA (s) AA (sj AA (?) A A (S) AA (s) US (s) US (si US (s) US (si US (?) US (s) IIS MS is) AA (s) AA (si HS (s) AA {s} HS (s) M o l a s 1 a L i c Ski n Tumor? EC( Abdorne n ] 3-5-7i4-igJE 3-18-7.4m] 3-25-7& 4-Z-74| 4-5-74J F.C k MC (Inguinal ul| Region) 4-9-7g * ^jefg 3-6-741 lso? - 3-7.7j^ 3-8-7|| ^1 3-2 2`W 3-22j| EC fc MC (FemoraPjjj region) 3-30 4-3^^ 4-3-JS 4-5-$| 4-5; MC (Axillary region) '''"toB 4-5j^S 4-7M F.C (Para-Aural) MC (Abdomen) EC( Pelvic regton)1tL4^P TABLE. Ill On&uA&Ucd B i O -TEST J^ahytcUmieS, 3nc. 1810 FRONTAGE ROAD NORTHBROOK. ILLINOIS 60062 Summary of Mortality & Tumor Data Among Vinyl Chloride Mice IBT Number 663-03222 (MCA) UlSProup LgEftfl vm:* No. Mortalities with Neoplasms Location ot 'iumors Lung Live r Skin Metastasis--*' Lu 4 (1 Male, 3 Females) WbU` * wrli*4 * awzz.--------- 6 (1 Male, 5 Females) 19 (4 Males, 15 Females) 2(50%) 2(50%) 2(50%) 2 3(50%) 4(66. 1%) 2(33%) . 1 17(89. 5%' 17(89. 5 %) 3(15.8%) .Key to Symbol s If A , V1*,. Alveologcnic Adenoma of 1 unp (AA) ** Hcmangiosarcomn of Liver ( HS) t##* Epidermoid Carcinoma of Skin (EC) Mammary Carcinoma of Skin (MC) Lymphosarcoma of Thymus (*)..'.Multiple tumors of indicated type see 1-0808 -3- Controls Group TE I - 50 ppm Group TE II - 200 ppm Group TE III - 2500 ppm Group TE IV* - 2500 ppm *Rats only, conditions group, special cage for this test 4) There were 2,500 test animals. 5) Inhalation exposures were initiated and terminated as follows: r~" Species Initiated Terminated Mice Rats* Hamsters September 10, September 10, September 10, 1973 1973 1973 June 10, 1974 September 10, September 10, 1974 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 see 1-0309 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 aa.1 pertinent echelons of the research facility briefed on protocol specifications? SCC 1-0810 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? see l-oau -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 see 1-0812 -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 A.ll recorded and/or reported mortality data. see 1-0813 -8- 2.3 Audit Plan IX Team I - 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) SCC 1-0814 -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 (sj 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 SCC 1-0815 -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 SCC 1-0816 -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 see 1-0817 -12- . Random shecks of slide readings against 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 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" as recorded on necropsy sheets versus c omput e r print out s Summaries -prepared under 44 classifications of all tumor data recorded for 17 organs -for all animals in Control and Test Groups T-T, T-II, and T-III see 1-OS1 -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 SCC i-0819 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 Groupj 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 t ised on investigations and observations made at IBT, Decatur during the week of February 20, 1978. The recommendations presented are as follows: see 1-0820 -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 see 1-0821 -16- 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. see 1-0822 -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. JTS;ec Record Subject to Approval March 31, 1978 . T. Seawell Project Manager Vinyl Chloride Research SCC 1-082