Document n9XVKB7yYbpm8eJmR5x1QRyZ2

, --,T . 'j*; J. -.. 'ST. ^ ''' **f** '-.x ,v . x ><* January 11, 1979 To: Vinyl Chloride Audit Task Group (ATG) G. Dali, Tr, - TPG Industries, Inc. T. J. Benya - Ethyl Corporation VT. M. 2usey - S:perircental Pathology Laboratories, Inc, G. K. Hatfield - Diamond Shamrock Corporation p. Hindo'-or - The BFGoodrich Company, Chemical Dlv C. D. Kary - Shall Oil Company T. R. Torkelson - The Dow Chemical Company Subject: ATG Report Members: Enclosed are copies of the following documentst 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, LCHipnt Encloeur Lncills C# Hanachel Acting Project Manager Vinyl Chloride Research 4250 CMA 004516 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 CMA 004517 DRAFT Final Report of Audit Task Group on LIFETIME INHALATION STUDY ON VINYL CHLORIDE at Industrial BIO-TEST Laboratories, Inc. Introduction In 197^, 31 vinyl chloride (VC) producers and users through the coordination of the MCA, contracted with the Industrial BIO TEST 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 records. The findings and recommenda tions from this audit are presented in this report, including Dr. William M. Busey* s Vinyl Chlorids, Pathology _Report. January 9,^ 197SU (Appendix 1) History Based on available information, a protocol for a lifetime study '*i was designed which included exposure of male and female rats, mice ^' 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 start d on September 15, 1973. Reports of site visits conducted during the study are in Appendix 3. CMA 004518 / 2- - Interim reports were periodically received by MCA and have been transmitted to the Technical Panel. Since no final report ' r?> r. * , 1* \ -)V was received, an ATG was formed by the Technical Panel to determine the feasibility of obtaining a valid document. This was further u prompted by inadequacies in other studies performe<3H3yr jg&T. , - v/. 90" , 0-t procedure : ': ' j::' ^Louisiana. V f. The ATG recognized several quVeCs-a't-ilo;-"n51s;' U =arisb, that would have to be t-.y v t answered properly if this study was to be considered of adequate technical quality to be useful. However, after inspection of the available IBT records, it seemed more appropriate to the ATG to first conduct a partial audit to assess the quantity and quality of the I j i..,v* Vv ".r Vi 'i'V-irf .,>r>' j .?v.C .,r< ,.** ` autopsy and histopathological data. Depending upon whether adequate tissues, blocks and slides were available or not, it would j ". 1 be possible to determine the usefulness of extending the audit to V~ animal records, exposure records, source of animals, and other equally-, *'!? important questions. If it was found that adequate autopsy material . i . was not available, nothing would be gained by several months effort -'<V 'f to conduct a complete audit. Therefore, this partial audit of r pathology records was conducted. .V;.^ !i` With the cooperation of remaining IBT personnel at the Decatur 1 .^ ,. j, location, the ATG and its consultant. Dr. William M. Busey, divided \. tf See (Appendix 3) m. itself into three teams/ The activities of the first team wer ' w, . , AK . ( described in Dr. Busey's report of January 9, 1979. The other two teams examined the autopsy records to determine the disposition of CMA 004519 4 * .*' -3the experimental animals and the number that had been sacrificed \ -*f \ *\ and saved for histological examination. The totals are included in Tables I, 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 `i# VSK ; j. tissues are presented in Tables V, VI, and VII of the January 9, v r* l+fyy' 1979 report. The ATG estimates that the full group has spent more than 800 - r '' h J ,4` **'< * hours in completing this partial audit, in addition to several weeks . vrV by MCA staff and IBT personnel. Conclusions and Recommendations jSfr**I#* sa1i5e0\onoootj2^?!< W* i; The ATG concludes that the conduct* ie study by IBT is i' scientifically unacceptable and makes the following recommendations: ;v (S* 1. That Dr. William Buseyrs report be accepted by the Technical"1$ _P_a__n_e_ l _a_s the final _r_e_p__o_r_t of this study. 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 .* I' * study and that all materials and records of this study be : 4 retained by IBT indefinitely according to conformity with the Good Laboratory Practice Regulations, as publish d in the Fed ral Register, D cember 22, 1978. qo4520 -4- AW r' considered closed y* and that no further funds will be available from MCA. 5. If the report of the ATG is accepted by the Technical *V*' ' Panel that it be transmitted to the appropriate government ik agencies *5 \>i *vft A, liU * i*v CMA 004521 `l n PROTOCOL MANUFACTURING CHEMISTS' ASSOCIATION, INC. CHRONIC VAPOR INHALATION TOXICITY STUDY WITH VINYL CHLORIDE I. 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; 800 Mice 800 Rats 800 Hamsters C Exposure Schedule; Seven Hours per Day Five Days per Week ..s D Test Materials: Vinyl Chloride (Ethylene derived) E Organization: if See Table I F Dose Levels: See Table I After exposure, animals will be maintained for observation and sacrifice at end of two-year period (18 months for mice). 4 CMA 004522 TABLE I Chronic Vapor Inhalation Toxicity Study Organization of Groups Test Material Group Mice_______ Males Females Number of Animals _______ Rats ____ Males Females Hamsters Males Females None Control 100 100 100 100 100 100 Vinyl Chloride TE-I Ethylene derived) Low level 50 ppm TE-I I Intermediate level 500 ppm TE-III High level 5000 ppm 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 ICO 100 ` iJ 'j Ji- * *'i Jvdui/ivj linJur in jtoss. v. Conoco, Inc.. No. 90-4837 14th Judicial District Court t Caloasieu Parish,, Louisiana o o in utoi -2- II. Chamber Parameters Each group of animals will bo exposed in a specially constructed plexiglas inhalation chamber having a capacity of 3 approximately 6.0 M , allowing animal loading of less than 2% when the animals reach maturity. Flow rate through the cham- 3 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. III. Aniniiimmaail Pccaij.racumuceutcejlrsa A. Clinical Observations All animals will be observed daily for lesions and 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 nccropsied and 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 in extremis when death is imminent. -3- CMA 004524 B. Body 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 be 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 30 (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 S\1 1. Methods of Sacrifice Sieu c&ica 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. Ilistopatholoov Representative specimens of the following organs -4- CMA 004525 and tissues will be taken Irom all animals at Lime of uacrilice and fixed in 10.0% neutral buffered formalin: Adrenal Glands All Gross Lesions Bone (femur, tarsal and metatarsal, including long bones of all four limbs) Bone Marrow (sternal) Brain 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 Stomach Thymus Thyroid Gland Tracheo 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 , stained with hema toxylin and eosin, and evaluated by light microscopy. If -5- CMA 004526 drug-related lesions are 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 are 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. -6- * CMA 004527 V JAMES R. CARNES V:!,P M ' GItif'ir SECfti l^nic-TniASuni.H -j MAM! JFACTi i; MMG C! 0/1137 3 AGSO NATION in?: coNtJftr.ncur /..venue. n.vv. V./.'aii.nt.mM, u.c. rno<H (W>;*) 4B3-GI2G t'.iV 1 >73 !.<r. J . 0 . c:; I.i;i, : roi''; r-n b IV. div: tri.nl PL1 Ln].i*r i boric r., I3?/J !'rri\t. Pori'l llochii1. , '( J J.i jV;i. n i>Our?. Tty;, Pear Or. cahiv'u.n r .- . -. ; \ T Ml ubjecti_ P.C3S V. j; 4-CCJ. jtol'i S-Stri=t Cour 1C4athlcasilem farlBh. Louisa W'!-' P'lf;-!:, the nyr-'-, r.<\ d vV* i rc.bruv.ry 1, ?.`.''7!5f ' t'./r 0,1 `I n-.P ' Min 1 VilO-i'P:; i' f d r-I.ori rn, In j. (n:c<*) it:*-' p 'M-n*.,c:turiry c V ri,?tr' Ar.coc.iai'J.on (j .t'.'i) \:>y L.'.O- 1 to ceiv.'-uan n 'i> v . n .1 e vipnr .1. nb 3 3 a - Mon vi i.h bh.lr*.ri<b:" M r:-tended to include nn ; v(; i-.jon.il n;:o- <j? cun or. f'. "erriJ /ri in the fpl* m ji ;i. Mile :> . xlr.ouL.il orrup ii- La cunriot of TO Cl r.^to oi` the ::,u.'.o r ? . to ho c* uor r*! !:{* v;;yl ch?ojri-:'o v spors at ,i cr.nrontroMen of t.ono y-.., v/v. Peed, inV.r, nnd bedding are to be pvt. .nut in the jc:..\r :j In which th0 !jniri.-.Xa are c;;ro.:t:d Purina the H-tiro ';*nv. /uro peril od. Otliro-.-i <!(JI cnporir/.ontal prccr-Ver1- r, r.y.tzZiMinn -<pofe:tire coivJi.hi.ono, LVdr riocunrintnticn nr*.-* ecritrol, and tl i> himUinn, obnorvuI.ion m'l oi. nniiIn oh till con.Com to ttioni tV-rcrijvH in hh- p/otcro). incorpoirn tod !:y i*c for once in the ?:;ibjcct and hereby so incorporated in this acmnwent cjitenrion. The coat i:or this aridi.hiep O. CM-oruro croup will be $10,000, M-iyablo in throe v:nMJ. hii-i.ntc, the Cirafc and ccicvnui piy.iiilo on the ii.r:;h *."-y of tho 7l;h and 10th r*.ontlirt, i.\ :;prcU.voly, of Ui;: iv-'y period covered Iry th" b.'wij.o ii.tr-*' `pent, nnd tho third upon receipt of tha innt report iron JJlO-TCdT. CMA 004528 s IK-. J. f-* an.)) a f'.y M, 1'-7'? PJ.r .:].<(! In iic: i ho yonr arc ir>tr. nee ny ri'miner the enclosed nnjiy oJC letter in ,lhn .'-earn provider) and XTturninn lo in. Sir.coirol v, ./ i> /;) (J Accepted for: Industrie1 ClO-TnjT LaboraLoricr., Inc. ' - - r j. AiJ 7^9 "Order ltt SuMeft to 90- 4834 Koss v J ^H2^^rlct Cou*t" . l0a& P-i*- WUl8l" Siyncd __ \\ . d. d Title Pro si He nt ias.z Date May 22, 1973 CMft. 004529 ALBERT C. CLARK VICE PRESIDENT TECHNICAL OlfiECTOR oe.pt MANUFACTURING CHEMISTS ASSOCIATION 182b CONNECTICUT AVENUE. N W WASHINGTON, D C 70000 (702) 183-G12G Augunt 31, 1973 r:x Dr. J. C. Calandra, President Industrial 1310-TEST Laboratories, 1810 Frontage Road Northbrook, Illinois 60062 Calcasieu Pariah^ L'-t Court Louisiana Inc. Dear Dr. Calandra: By this letter, the agreement dated February 1, 1073 between Industrial BIO-TEST Laboratories, Inc. (BIO-TEST) and the Manufacturing Chemists1 Association (MCA), and the agreement extension thereto dated May 14, Ir-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 this 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, 1973, 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. t CMA 004530 Dr. J. C. Calandra August 31, 1973 Page rwo Please indicate your acceptance of this amendment by signing the enclosed copy of this letter in the space provided, and returning to me. Sincerely, UO Accepted for: Industrial BIO-TEST Laboratories, Inc .... .. ' " . ^O'i Sub^GtConoC. . -o'0 ` ur* ss&tb Parish* Calcasieu Signed 1/ Titlo Assistant to the President Date September 7, 1973 CMA 004531 TABLE I (Revised'August 31, 1973) Chronic Vapor Inhalation Tonicity Study Organisation of Groups Test Katerial Hone GrouD Centro! -- Mice Kt Ipi r o'-t a 1 es Ku'seer of An i.mis Pats Ka los Fn ->a 1 e r. ^ n'` ~ > n y r Mi los i'o 'n ' ~ 1 100 ICO 100 100 100 1G3 CMA 0 0 4 5 3 2 Vinyl Chloride TE-I* (Ethylene derived) Low level 50 ppm 100 100 TE-JI* Intermediate level 200 ppm 100 100 TE--III* High level 2,503 ppm 100 100 TE-IV** Eigh level 2,500 ppm -- -- * Ho food, water, or bedding in cages during exposure ** I'ooJ, water, and bedding to regain in cages during exposure # All rats of same sex, either sex perr.itted 100 LOO 100 100 100 100 r>' t 1, r-><,'> ' `` t - ' I" ^ i. - . 100 100 mo -- ICO 10 0 ICO ) JAN JO 1975 7^ THE DOW CHEMICAL COMPANY January 27, 1975 BENNETT BUILDING 2030 DOW CENTER midland. Michigan 4bmo Mr. Milton Freifeld Manufacturing Chemists' Assoc 1825 Connecticute Ave, N.W. Washington, D.C. 20009 Dear Mr. Freifeld: C.~lcr-V';U iff 0 , s'* 43,.3S^3'1,* 3t Coff**, ^ _uisiatia . The attached table was compiled from information received over the telephone January 20, 1975. Dr. Keplinger of Industrial Bio 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 longer 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 cc: Distribution List Attached. CMA 004533 cc: Vinyl Chloride Research Coordinators: Dr. Zcb G. Bell, Jr. PPG Industries, Inc. One Gateway Center Pittsburgh, PA 15222 Dr. Walter D. Harris UN IROYAL, Inc. Oxford Management Research Center Middlebury, Conn. 06749 M. N. Johnson, M.D, The B.F. Goodrich Company Medical Center 500 South Main St. Akron, Ohio 44318 Mr. H. L, 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 -- - a . Dr. William Rinehart Ethyl 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, Inc. 1810 Frontage Road Northbrook, ILL 60062 CMA 004534 AIIIMALS AT IT' A3 Ot >0, 1975 r<-3)i 03 CMA 0 0 4 5 3 5 :cn~rat.\on Lorxci (25CO d: 230 Mal< iters era; 16 0(3) 26 41 17 50 22 Mi r1 ra 1 Female j j \ o! 0 i1 0 0| 0(7) 0(2) IS" 54* Male 0(4) 511 69 75 Rats Ferale 0 13* 55 77 t ) Ir.dicates r.or se as kest at least nick ar.i-als sacrificed Tais date'ch 10. !-i1 ^c-*n : 1 u with T:oi 0(7) -- k i -i ! INFORMATION COPY r CWTAl sciences twees iCNces MuMii&l BIO-TEST loPsiolfi'vrj,,, DECATUR RESEARCH 1800 Cast PERSHING POAO 0 ECaTU P , I l LI NOI S 62526 August: 2, 197 3 arca cooC i\7 tUCPHOIIE 87?-054 ^ * Dr. H. Slatin Manufacturing Chemists Association 1826 Connecticut Avenue, N. W. Washington, D. C. t 20009 Dear Dr. Slatin: ' r* -s ,, -r- 't j i > Due to problems which have occurred in the early stages of the yinyl chloride inhalation project, IBT 663-03222, we respect fully request that we be allowed to restart the study. ii In our opinion, two major problems make this request necessary; (a) The design on the animal feeding system is not working satis`actorily. This caused considerable weight loss in the hamsters and they have been terminated. The rats and mice have not had normal weight gains and the feeder system must be redesigned. (b) Some of the changes deemed necessary hy the MCA committee on their last visit to the laboratory, have been made hut others re delayed due to shipping dates on equipment. In our opinion, to continue such an important project with animals Which have been stressed and in which sampling and air handling Equipment would he changed in the near future, would compromise fhe data and leave Bio-Test open to eventual crilicism. We feel that all equipment changes can he made hy September 1, 1973, at which time the study would be restarted with new groups of animals. CMA 004536 .am sure that a favorable decision on this matter will allow Iiio-Tcst conduct a study which will be better received by the scientific ommunity. Sincerely, 1i1, /.dm / /john W. Goode, Ph.I). ^' Manager Decatur Research Laboratories i, J. t: T` r r CMA 004537 uSStr C. CLARK msioENT . director INFORMATION COPY MANUFACTURING CHEMISTS ASSOCIATION 182b CONNECTICUT AVENUE. N.W. WASHINGTON, 0 C 20009 (202) 483-6126 August 3, 1973 ohn W. Goode, Ph.D., Manager :atur Research Laboratories dustriaJ Bio-Test Laboratories, 00 East Pershing Road atur, Illinois 62526 inc. Dr. Goode: cor-:.' lolrj T nV . C5" Thank you for the courtesies extended to Mr. Harry Slatin the representatives of our member companies, Dr. T. R. kelson. Dr. Z. G. Bell, Dr. w. D. Harris, and Mr. H. L. etz in their visit to your laboratories August 2, 1973. We v,Tere all sorry to hear, as you told tt^m and yom; ter of August 2, 1973, indicates, that the current s-nrt on vinyl chloride inhalation project, IBT-663-03222, is such t you recommend a restart of the study on September 1, 1973. .understand from discussions at the time of the visit that total cost of this study to MCA will remain as originally eed. MCA and its member representatives concur with you that a rt of the study is desirable and advise you to proceed. It is appreciated that the changes you have made in your sical setup, as well as those you contemplate will help the appreciably. .If there are any other problems, please advise us. Sincerely, CMA 004538 June 15, 1973 " ' - 4-037 Zeb Dell Walter Harris i Russ Maycock M'aurey Johnson Bill Rinehart-' R. N. Wheeler . ' cc: Joh, n Good,e '/ i ' / ^ y/-/ Ken Johnson Howard Kusnetz Moreno Keplinger t,d - - . ,,~:uu * / '* f 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. We 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 new 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, we had many questions about the adequacy of the equipment and whether it will be shaken down before the experiment gets underway. A number of comments wore made, including the following: j' Because of the shape of the chambers, the large number of animals per chamber, and the fact that the cages were attached to the walls and separated by trays, there was possibility of channeling of air through the chamber. 'It was suggested that CMA 004539 F 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 ,7- 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. r , Because it was considered necessary to do very frequent / 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-down procedures.there could be feedback into other chambers and that cross contamination should be carefully guarded against. C- h CD JJ M ^^ c rfWd-* O<Ly>, 5o cj ,,w-t t^-q_ F-o* <D 52,^5 +.OHH= doH-j M^ ^sr. lt3i '-]'r.* ^! 3 r. c, ,4 `"l ^ '!* ?Pi OCAIl r-"-l- 2ma- o3;! vo co,! T' .?- cl+) - ! 9 Ta7J &. -. --e ta h,u tr i / The matter of daily records was 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. r. 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 of the chambers and that they would have more permanent attachments. Exhaust 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. CMA 004540 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 study. 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-Tost 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 between 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 were impressed with the importance of the situation, and we think we have their complete understanding. la CMA 004541 n INDUSTRIES To: R. E. Witling INTER-OFFICE CORRESPONDENCE Date1: From: Location: August. G, ir?i Z<C b G. Beil, Jr. I'J LdSt ubiect. industrial Biotust Laboratory Vir.it, Decatur, Illinois As ri member of the KCA-VCM Technical Coerdi nn tors Task Group, the undersigned visitco the Indus trial Siotest Laboratory facilitv in Decatur, Illinois, where cite MCA inhalation study on VCM is being performed. There were some problem.; in the test chamber desiur reported by Dr. T. TorKelson (Dow) cn his last visit there. This visit revealed that these condition: have been or are being rectiiied. We (MCA) have been advised thiough tr.e attached letter that so me early problems have developed resulting in their recommendation that the study be re-started. This constitutes a further delay in getting this program "off the ground", however, it is a very wise move since the experiment may neve hau to be terminated at a later date because of these factors anyway. Industrial Biotest Laboratory has acted in goed faith in complying n with our recommendations, but they rave had some unfortunate uncon * i 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. ZGB:rmp / --^ w Attachment cc: J. a. Clapperton L. B. Grant, M.D. J. L. MacMillan ,H.-latin (MCA) JT..R. Torkelson (Dow) as*0 <g^ * UH . .i to CMA 004542 MANUFACTURING CHEMISTS ASSOCIATION 1826 CONNECTICUT AVENUE, N. W WASHINGTON, D C. 20009 (202) 483*6126 August 10, 1973 Memorandum TO: A. C. Clark FROM: H. L. Slatin c?------- - c,-*, - n ;;b Court louiuiar.a 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. Torkelson 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: MCA IBL Dr. T. R. Torkelson 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. CMA 004543 * 2- - .. cC0O0- p c3 <D o o C73 1-4 f--> 1'- , oM o H G* fO * _j_h b -Ui> oA A O~J A - o` r ! -H rj P-* c ^ o 6! O *H PC rjj i *C/Mr--jf r* CQ cc/:ii, oa 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 18 different points from which the chambers are sampled. The Baffle plates and funnels do not affect the homogeneity CMA 004544 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 CMA 004545 MANUFACTURING CHEMISTS ASSOCIATION 1825 CONNECTICUT AVENUE, N.W. WASHINGTON. D C. 20009 (202) 483*6126 CL0J; ? - 7 Sul if-c: t ' P: v ' T iL-L ' '' in . , - .137 ; L-'b lourt , Lcm: 3 i.ana 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 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. Cummin Fairchild Goode Gordon Harris Johnson, M.D Kennedy Keplinger Kociba Kusnetz Lassiter Rinehart Smith Stara Torkelson Wheeler G. Zwicker Blewitt Clark 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 Corppration B. F. Goodrich Chemical Company MCA MCA MCA CMA 004546 2- - 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 HEW, 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. 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 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. Dr. Lassiter also reported briefly on the retrospectiv morbidity and mortality studies being conducted by NIOSH/CDC v; 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 >: project should be terminated at nine months, but that exposures of both rats and hamsters should proceed for the^ initially-planned twelve months. , It was further moved, seconded and carried that the chairman appoint a group to begin investigating the cost andi availability of facilities of new experiments to be con- ..^ 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 jr.-i' .A& CMA 004547 S u b je ct "to P ro te c tiv e O rder in Koss v . Conoco, I n c . , Mo. 90-4837. 14th J u d ic ia l D is tric t Court Calcasieu P arish, Louisiana -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 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 CMA 004548 TABLE : Mouse Mortality Data DATE Controls FM February 10, 1974 28 GROUP TI TI I FM FM 6 26 24 Till FM 78 April 12, 1974 5 11 9 31 13 7 13 18 CMA 004549 `huCjiA/:<nl 0 1 J-rEST A'fourA, i'nc into rrco^,A^,r 1,0 i k'D mnoO'i*' iiiiMOin agoi*'? Summary of Tumors in Vim ' ' Mun.le Kvposed Mice IL51' Number 6i> j - 0 3 22 2-M C A TABLE II Animal No. , Sex Histopathologic Findings Date of Death T I ! y13 Male 1 ! 1 0 } t mnlti ) 1 1 V F('ma in 1200 Female Lung Liver A A (?)* HS (?)- A A (s), Metastatic Sic in Tumor HS (a) Metastatic Skin Tumor Skin ,$ EC (para-aural) 3-20-7 3-24-74J EC h MC + (Femoral region) 3-30-744 T -a 134 7 Female 1 309 Female IF9? Male13R2 Female 1 3 50 Female 12 99 Female t- m 15 36 Female 15 32 Female 1562 Female 1598 Female 1405 Male 1494 Male 1574 Female 1531 Jr'emalo F emale Foma In 1505 F emale 1 5 ( 5 F emale M09 Main 1543 Fema le l 5 4 4 Foma In 1546 Female 1535 Female M32 Male 1477 Female Meta static Skin Tumor HS (s) AA (s) HS HS (?) A A (?) HS (s) AA (s) ^ C55 CD jp U' 05 O Tj Ou * 3 O iHn -P ^ -4 3 2 03 *** f-4 . i H * p - r=* +O> opj 3 f3 n M 5M fo5Uh , ou SB Fi i Ol -P5 SO 20 O! 4a^1. 3 > r2j m Wmooj 1"3 & S H % <L*J> A A (?) AA (s) AA (?) AA (?) A A (?) A A (?) A A (s) HS (s) IIS (?) IIS (?) as (?) as (?) ns (?) HS (s) A A (s) A A (?) A A (?) A A (?) A A (?) A A (S) AA (s) IIS (?) as (s) IIS (?) HS (?) ns (?) HS (?) ns as (s) AA (?) as (s) A A (s) A A (?) as (s) Metastatic Skin Tutno r ? EC( Abdomen) 3-5-741 3-18-7$ 3-25-74 4-2-74] 4-5-74] EC Rt MC (Inguinal Region) 4-9-74 LS<X> 3-6- 3-7-74 3-8-7] 2-25^ 3-22- 3-22? EC Rt MC (Femoral region) 3-23- 3-25* 3-30-i 4-3* 4-3* 4-5-1 4-54-5* MC (Axillary region) 4-5^ 4-7j 4-8? EC (Fara-Aural) j MC ( Abdomen) '< EC (Pelvic region) i CMA 004550 -74 Croup )-74 Mf m gn .-74J Pi pii TABLE III SaSuASual BIO -TEST Jlali&bat^yu^, Sac, 1010 FRONTAGE ROAD NORTHBROOK, ILLINOIS 60062 Summary of Mortality Si Tumor Data Among Vinyl Chloride Mice IBT Number 663-03222 (MCA) No. Mortalities with Neoplasms Location ai I umors Lung Live r Skin Metastasis-*! 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%) 9-74] [Key to Symbols ; i_ ; Alveologcnic Adenoma of I ung (AA) Hcmangiosarcoma of Liver (IIS) Epidermoid Carcinoma of Skin (EC) . Mammary Carcinoma of Skin (MC) -Z3: I, , Lymphosarcoma of Thymus I,' Multiple tumors of indicated type ' LO../J CMA 004551 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. Ta 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 q QT]'FlX)Si^rCl A.L suwsot to' . order in? Boss_v. 14th Judicial Court T.,,i0i!ina CMA 004552 -2- 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 l.*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 February February 20, 1978 21, 1978 22, 1978 7:10 p.m. - 10:30 p.m. 6:2b,p.m. - 9:30 p.m. 9:45 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: CMA 004553 -3- 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, 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 catalogued CONFIDENTIAL Subject to Protective Order In Ross v. Conoco, Ino.^llo. 90-4837 14th Judicial District Court Calcasieu Parish, Louisiana CMA 004554 -4- d. Tissue blocks inventoried bydesignated 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? CMA 004555 -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? a n a 01 CO CMA 004556 -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 CMA 004557 -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. TftIenCcti''eSo1o-^' BOBS V. J",410lpaiisu Calcasieu Parisn.i Court CMA 004558 -8- 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 itest 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) t* i h Sf o ''7/ca . n I o -m t? g* o ) / O 0/5! R/-P H/q w h / o / r* ote/;/ / o coC2>9////h-3n'-i ^ 03) 1-t3> > 's -CJ Oftj -Q <""f CO / <-f O CMA 004559 -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 CMA 004560 -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 C CO 1 .- ci <V) O , lO -O5 a v-4 .0 \ Wet tissue preservation Preservative used for eyes Cataloguing of missing tissues Inventory of "good" tissues and check of source animal (animal number) - - A\ r' .CrOt -j cy >'3c. :* : r-* CJ C/i l\ 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 CMA 0456l -11- Possible Target Organs and Organs of Major Concern, e.g., Brain Heart Kidneys Liver Lungs Mammary Gland Spleen Stomach Tissue Blocks Preparation procedure calcate'L':'" 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 CMA 004562 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 croas checks of "Days on Test" as recorded on necropsy sheets versus computer printouts . Summaries prepared upder 44 classifications of all tumor data recorded for 17 organs .for all animals in Control and Test Groups T-l, T-II, 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. 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 c: g ;1 . ' -wi >--> ''-w ,^_wy ^ y e:l+> . ^ ^ j -3 * l^ * -'*- -"!/imn -y ay j y di -y ^ I 0-> ' -tcocy y ^^ o a tot*-#Ao rc-ii O/ ry c.' 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, in, 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 CMA 004564 r tr.' -14- data summaries. Teams 2 and 3 audited gross and histopathologica1 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. 2. 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: CMA 004565 -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 CONFIDENTIAL Subject to Protective Order in Boss v. Conoco, Inc., No. 90-4837 14th Judicial District Court Calcasieu Parish, Louisiana 004566 L, ,.t Coart L o u is ia n a -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. C '7.OD - - ' IK3 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. CMA 004567 -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 o. T. Seawell Project Manager Vinyl Chloride Research 0 Oil? I DENT IAL cubi0ct to Protective Urder in Holst'. nonooo, 90-4837 14th Judicial District Cour Calcasieu Parish,, Louisiana CMA 004568 Manufacturing Chemists Association Record of Meeting AUDIT TASK GROUP (ATG) OF VINYL CHLORIDE TECHNICAL PANEL Experimental Pathology Laboratories, Inc. Herndon, Virginia January 8-9, 1979 Dr. Torkelson presided and convened the meeting with the following in attendance: MEMBERS PRESENT T. R. Torkelson, Acting Chairman T. J. Benya G. K. Hatfield R. K. Hinderer C. D. Kary The Dow Chemical Company Ethyl Corporation Diamond Shamrock Corporation The BFGoodrich Company, Chemical Division Shell Oil Company L. C. Henschel MCA Staff Experimental Pathology Laboratories, Inc. PPG Industries, Inc. 1. Dr. w. M. Busev's Pathology Report The Audit Task Group (ATG) reviewed and accepted Dr. W. M. Busey' Vinyl Chloride Pathology Report. CMA 004569 2 2 ATG Report A draft of the report of the ATG was written and a cental: ivlist of appendixes was prepared. The following items were to L included: Dr. W. M. Busey's Pathology Report - Protocols Reports on Site Visits 3. The ATG wishes to express their appreciation for Dr. W. M. Busey' generous hospitality during this meeting. 4. The meeting adjourned at 12:30 p.m. <^u-ci //-e. C. litMilsJ) Lucille C. Henschel Acting Project Manager Vinyl Chloride Research LCH:pmt Record of Meeting Subject to Approval January 16, 1979 ft &MA QobStf*