Document 2RM0Q9ZXgy4NBjBRZ0XeKapLa

i URL 16180 CHEMICAL MANUFACTURERS ASSOCIATION September 11, 1979 Mr. Fred R. Currant Corporate Counsel Industrial BIO-TEST Laboratories, Inc. 1810 Frontage Road Northbrook, Illinois 60062 Dear Fred: An agreement dated February 1, 1973, was signed between Industrial BIO-TEST Laboratories, Inc, (IBT) and the Chemical Manufacturers Assoc iation (CMA), formerly the Manufacturing Chemists Association, for IBT to conduct a "Chronic Vapor Inhalation Study with Vinyl Chloride". This agreement was extended to include an additional exposure group on May 22, 1973. References to this study in communications received by CMA from IBT bear the study identification of IBT No. 663-03222. The exper imental design incorporated in the protocol appears in Appendix A, which is attached. The Vinyl Chloride Audit Task Group and the pathologist serving as a consultant to CMA have expended in excess of 1,000 hours auditing and studying ways in which data of meaningful value might be salvaged from this research agreement. After their large expenditure of time and money, little or nothing of salvageable value has evolved, and it must be concluded the study has gross, irreparable deficiencies. Little value can evolve from audits of other equally important records and research material, since inadequate pathologic studies and/or observa tions and insufficient numbers of tissues preclude scientifically valid con clusions on tumor incidence and dose-response relationships. Data presented show that there is just cause that IBT (1) reimburse CMA for all costs of administering and auditing the agreement of February 1, 1973, as amended, (2) refund to CMA all funds paid to IBT against this .agreement, and (3) supply funds required in excess of (2) to permit CMA to have the program, as amended, properly conducted at another laboratory. BF:jbf Enclosures 1825 Conneclicut Avenue. NW Vice President and General Counsel APPENDIX A PO* Group Control Tl* T3* T4** Experimental Design for Vinyl Chloride Study Mice KF 100 100 100 100 ioo 100 100 100 -- Number of Animals Rats MF Hamsters MF 100 100 . ioo 100 100 100 100 100 100 100 100 100 100 100 100 100 100* ' * -- Specified Exposure Levels . 50 ppm vinyl chloride 2C0 ppm vinyl chloride 2500 ppm vinyl chloride 2500 ppm vinyl chloride *No food, water, or bedding in cages during exposure **food, water, and boddino to remain in cages during exposure Mil rats of same sex, females; were exposed. c XI CMA INTEROFFICE MEMO July 20, 1979 To: Edmund B. Frost An agreement dated February 1, 1973 was signed between Industrial BIO-TEST Laboratories, Inc. (IBT) and the Chemical Manufacturers Association (CMA), formerly the Manufacturing Chemists Association, for IBT to conduct a "Chronic Vapor Inha lation Study with Vinyl Chloride". This agreement was extended to include an additional exposure group on May 22, 1973. Refer ences to this study in communications received by CMA from IBT bear the study identification of IBT No. 663-03222. The experi mental design incorporated in the protocol appears in Appendix A, which is attached. Calculations and compilations contributing to tissue account ability summaries presented in this communication were based primarily on the tissue inventory conducted by IBT personnel at the request of the Vinyl Chloride Audit Task Group (ATG). Allow me to emphasize that the ATG only partially validated the IBT inventory. The ATG concerned itself initially with histology and histopathology rather than with other phases of this study since they recognized that conclusions relative to tumor incidence and to dose-response relationships would have little scientific validity without adequate histologic and pathologic materials and observa tion records. Therefore, the ATG has confined itself solely to a partial audit of existing tissues, tissue'blocks, slides, and records of gross and histopathologic examinations. The initial audit efforts were concerned with a total organ accountability for each test animal based on necropsy sheets, histopathology sheets, and pertinent laboratory logs. The IBT inventory of all tissues was completed after the transfer of all records and research material to IBT, Decatur, from IBT, Northbrook. The ATG was informed that the inventory includes all tissues, tissue blocks, and slides currently in storage. IBT inventory data are presented in the entry shown in the Tissue Accountability Summary (see Appendix B)'under the caption "Total Tissues Available". In the opinion of the ATG, the technical conduct of this study is grossly deficient as indicated by the following partial list of observations: URL 16182 URL 16183 2- - 1) IBT failed to save most tissues as specified in the protocol. 2) IBT failed to conduct histopathologic examinations of many of the tissues that were saved. 3) Even though all currently available (according to the IBT conducted inventory) tissues were to be examined, the number would still be grossly inadequate to complete the objectives of the study. As an example of observation 2) presented above, of 42 male rats in the top dose level (exposure concentration of 2,500 ppm) surviving at the end of one year exposure period, brains of only nine animals were saved for histopathologic examination. Of these, only four were made into microscopic slides and examined. Hence, 90% of the brains of those animals surviving to the most critical time period were never examined. The overall deficiency is shown dramatically in the Tissue Availability Summary presented as 'Appendix B. The number of tissues per animal should range from 44 to 40 for males and 43 to 39 for females. Tissues from double organs (lung, kidney, testes, etc.) were often arranged on a single slide and this re sults in variations in the manner in which tissues from double organs are counted. Therefore, for purposes of total tissue accountability and relevant percentage computations, the ATG used the smaller of the two figures for each sex when computing data shown in Appendix B. Percentages of total tissues examined by IBT and percentages of total tissues available as presented in the following discussions under specified test animals are all based on the respective protocol tissue requirements shown in Appendix B under the entries entitled "Tissues Required by Protocol". The following examples of observations relevant to Appendix B are summarized under the respective test animals: Rats-Male According to IBT's own inventory, of test Groups II and III, only 26.5% and 27.6% of the tissues required by the protocol are currently available. Of these, only 17.-6% and 9.6%, respectively, of the tissues required by the protocol were examined by IBT pathologist(s). Rats-Female In test Groups II and III only 23% and 25%, respec tively, are available according to IBT's inventory. Of these, only 10% and 8%, respectively, were examined histologically. Thus, for rats, the highest percentage of tissues available is 28%, far below the generally recognized minimum acceptable level of 95% accountability. Mice-Male Again in the crucial test Groups T-II and T-lll the total tissues currently available are 18% and 19%, respectively, and of these tissues only 7% and 5%, re** spectively, were examined by an IBT pathologist(s). Mice-Female In the same above-mentioned test Groups, T-II and T-III, the total tissues available are only 24% and 23%, respectively, and of these, 7% and.5%, respectively, were examined by an IBT pathologist(s). Thus, for the two top levels for this species, the highest percentage of tissues available is 71% below the generally recog nized minimum acceptable level. Hamsters-Male , Only 19%, of the total tissues required by the protocol are available for test Groups T-II and T-III, and of these, only ll% and 8% respectively, were examined. Hamsters-Female URL 16184 In test Groups T-II and T-III only 17% and 12%, respectively, of the total tissues required by the protocol are available. Of these, only 12% and 4%, respectively, were examined. Therefore, for the two highest exposure levels for this test species, the highest percentage of tissues available is 76% below the minimum acceptable level. Controls-All Test Animals The percentages of tissues available as required by the protocol for all control animals (as shown in Appendix B) ranges from a "high" 32% to a low of 10%. Therefore, for the control groups for all test animals the highest percentage of tissues available is 63% below the minimum acceptable level of 95%. I -4- Summary The Vinyl Chloride Audit Task Group and the pathologist serv ing as a consultant to CMA have expended in excess of 1,000 hours auditing and studying ways in which data of meaningful value might be salvaged from this research agreement. After their large expen diture of time and money, little or nothing of salvageable value has evolved, and it must be concluded the study has gross, irrep arable deficiencies. Little value can evolve from audits of other equally important records and research material, since inadequate pathologic studies and/or observations and insufficient numbers of tissues preclude scientifically valid conclusions on tumor incidence and dose-response relationships. JTS:pmt Attachments J. T. Seawell sBisv-wn APPENDIX A Experimental Design for Vinyl Chloride Study Group Control Tl* T2* ' T3* T4** Mice 11 F 100 100 1.00 100 100 100 100 100 -- Number of Animals Rats MK 100 100 100 100 100 100 100 100 ' Hamsters HF 100 100 100 100 100 100 100 100 -- Specified Exposure Levels - 50 ppm vinyl chloride 2C0.ppm vinyl chloride 2500 ppm vinyl chloride 2500 ppm vinyl chloride *No food, water, or bedding in cages during exposure **f"ood, water, and beddino to remain in cages during exposure #AV1 rats of same sex, females were exposed. URL 16186 t APPENDIX B TISSUE ACCOUNTABILITY SUMMARY According to: I. Tissues Required by Protocol II. Tissues Examined by IBT III. Total Tissues Available According to IBT Inventory < .. RATS - HALE Tissues Required by Protocol Total Tissues Examined by IBT Total Tissues Available RATS - FEMALE "ii'K'.'.. ?ouired by Protocol Total Tissues Examined by IBT Total Tissues Available MICE - MALE Tissues Required by Protocol Total Tissues Examined by IBT Total Tissues Available MICE - FEMALE Tissues Required by Protocol Total Tissues Examined by IBT Total Tissues Available HAMSTERS - MALE Tissues Required by Protocol Total Tissues Examined by IBT Total Tissues Available HAMSTERS - FEMALE Tissues Required by Protocol Total Tissues Examined by IBT Total Tissues Available Totals 4,000 590 998 3,900 815 1,263 4,000 262 497 3,900 314 402 4,000 333 5H 3,900 222 372 Per Cent 14.75 24.95 20.89 32.38 6.55 12.42 8.05 10.30 8.32 12.77 5.69 9.53 Grnuo T-l Totals Per Cent 4,000 588 930 14.70 23.25 3, 900 475 853 12.17 21.87 4,000 349 548 8.72 13.70 3,900 295 599 7.56 IS.35 4.000 384 485 9.60 12.12 3,900 217 406 5.56 10.41 GrouD T- 2 Totals Per Cent Grouc T-3 -Totals Per Cent 4.000 706 1,061 17.65 26.52 4.000 386 1,103 9.65 27.57 3,900 395 908 10.12 23.28 3. 900 299 970 7.66 24.87 4,000 284 739 7.10 18.47 4.000 205 766 5.12 19.15 3.900 289 942 7.41 24.15 3. 900 208 910 5.33 23.33 4,000 453 743 11.32 18.57 . 4,000 315 761 7.87 19.02 3.900 485 677 12.43 17.35 3,900 167 454 4.28 11.64 GrouD T-4 Totals Per Cent 3,900 377 856 9.66 .'1.94 e' . 3*'. m9Mtjn t >* r ... -