Document gYG3mLNapeVeb2knomNjrBOG

CHEMICAL MANUFACTURERS ASSOCIATION August 8, 1980 -'/>* ro0-' Mr. Fred Current, President Industrial Bio-Test Laboratories, 1810 Frontage Road Northbrook, IL 60062 Inc. Dear Fred: S0- 'I <\0> XV I was out of the office for the last couple of weeks and so apologize* for not' forwarding to you the information you requested during our*meeting on July 16, 1980. The total cost- to conduct the study at IBT and the estimated interest are summarized below: $169,825 20,147 4,000 9,908 29,759; 15,000 103,680 $352,319 Payments to IBT Payments to Experimental Pathology Labs Payments.to Bob .WestAssociates. CMA-administrative expenses from 1973 to 1977 CMA administrative__expenses from 1978 to present .'. Estimated expenses incurred by Panel members during various audits and related activities from 1978 to present Estimated interest from 1976 to present TOTAL Please do not hesitate to call me if yon need additional information. I look; forward to a mutually agreeable settlement of this issnev*. i Thank, you. Sincerely. ^% Basmukh C. Shah, Ph.D. . Director, Special Projects cc: Dr. Ted Torkelson*;.. Dr. Zeb Bell . Mr. Roger Lockheed ' CMA 001315 Formerly Manufacturing Chemists Association--Serving the Chemical Industry Since 1872. 1825 Connecticut Avenue. NW Washington, OC 20009 Telephone 202/328-4200 Telex 89617 (CMA WSH) MANUFACTURING CHEMISTS ASSOCIATION 1825 CONNECTICUT AVENUE. N.W., WASHINGTON, D.C. 20009 TELEPHONE; (2021 328-4200 TELEX 89617 (MCA WSH) January 11, 1979 To: Vinyl Chloride Audit Task Group (ATG) / Z. G. Bell, Jr. - PPG Industries, Inc. T. J. Benya - Ethyl Corporation W. M. Busey - Experimental Pathology Laboratories, Inc. G. K. Hatfield - Diamond Shamrock Corporation R. K. Hinderer - The BFGoodrich Company, Chemical Division C. D. Kary - Shell Oil Company T. R. Torkelson - The Dow Chemical Company Subject: ATG Report Members: Enclosed are copies of the following documents: 1. Appendix index 2. Retyped draft of ATG report 3. Appendixes If another meeting of the ATG is held, it will be at the call of the Chairman. Sincerely, LCH: pint Enclosures SuV ^ w Tl Lucille C. Henschel Acting Project Manager Vinyl Chloride Research 4250 THE WRITER'S DIRECT DIAL NUMBER IS (202) 328- CMA 001316 U 3 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; C. Exposure Schedule: 000 Mice 000 Rats 000 Hamsters Seven Hours per Day Five Days per Week D. Test Materials: Vinyl Chloride (Ethylene derived) E. Organization: See Table I F. Dose Levels: See Table I i *Aftcr exposure, animals will be maintained for observation and sacrifice at end of two-year period (10 months for mice). 3-0.s'*' -1- 001322 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 c`**` Research on January 12, 1978. The group, including technical 'J1 t, 5? (h < 5.S <5 ^ representatives of the companies and William M. Busey, D.V.M., tA Js' 0b ,2 3 fH ^Ph.D.-of the Experimental Pathology Laboratories, Inc. (EPL) , who t ^H c~|-a> Safe'S waa retained as an independent consultant, have conducted a partial O . . teJ $-4 -Si*1' audit of the histopathologic recordfe. The findings and recommenda- oi!i>3 5 ^ tions from this audit are presented in this report, including QO . JC .' .2U> Dr. William M. Busey's Vinyl Chloride Pathology Report, January 9, 1979. (Appendix 1) History ' `4. ^ ,V. Based on available information, a protocol for a lifetime study 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 started on September 15, 1973. Reports of site visits conducted V"-. **(>' during the study are in Appendix 3. CMA 001318 co::?ir: --t/\T. 'I Subject Boss y. Cor- J Order in' 1 "o. 90=4632 -2-.y. 1r4tih Ju4 lie- ' '-^-~-.^icntrrCou-rrt. ..Calcasieu Parish, Louisiana Interim reports were periodically received by MCA and have been transmitted to the Technical Panel. Since no final report was received, an ATG was formed by the Technical Panel to determine the feasibility of obtaining a valid document. This was further prompted by inadequacies in other studies performed by IBT. Procedure `, The ATG recognized several questions that would have to be. 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 autopsy and histopathological data. Depending upon whether adequate tissues, blocks and slides were available or not, it would be possible to determine the usefulness of extending the audit to . \. animal records, exposure records, source of animals, and other equally *, < important questions. If it was found that adequate autopsy material was not available, nothing would be gained by several months effort to conduct a complete audit. Therefore, this partial audit of pathology records was conducted. , r V iV-' With the cooperation of remaining IBT personnel at the Decatur location, the ATG and its consultant, Dr. William M. Busey, divided Ssh(Appendix 3) itself into three teams/ The activities of the first team were described in Dr. Busey's report of January 9, 1979. The other two* * teams examined the autopsy records to determine the disposition of CMA 001319 the experimental animals and the number that had been sacrificed 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 autopsj The findings suggested that the number of organs was deficient and IBT was requested to do a complete inventory of tissues, blocks . and slides. This was subsequently done and the totals of available tissues are presented in Tables V, VI, and VII of the January 9, 1979 report. The ATG estimates that the full group has spent more than 800 hours in completing this partial audit, in addition to several weeks by MCA staff and IBT personnel. Conclusions and Recommendations The ATG concludes that the conduct of the study by IBT is scientifically unacceptable and makes the following recommendations: 1. That Dr.'William Busey's report be accepted by the Technical.. Panel as the final report of this study. 2. That as recommended by Dr. Busey "no further pathology work be done on this study". 3'. That IBT be instructed that no further work be done on this study and that all materials and records of this study be retained by IBT indefinitely according to conformity with the Good Laboratory Practice Regulations, as published in the Federal Register, December 22, 1978. CMA 001320 -44. That IBT be instructed that this project is considered closed and that no further funds will be available from MCA. 5. If the report of the ATG is accepted by the Technical Panel that it be transmitted to the appropriate government agencies. Vi CMA 001321 ty' ^ I. I 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: \ C. Exposure Schedule; 000 Mice 000 Rats 000 Hamsters Seven Hours per Day Five Days per Week D. Test Materials: E. Organization: Vinyl Chloride (Ethylene derived) * See Table I F. Dose Levels: See Table I i *Aftcr exposure, animals will be maintained for observation and sacrifice at end of two-year period (IB months for mice). CMA 001322 TABLE I Chronic Vapor Inhalation Toxicity Study Organization of Groups Test Material Group Mice Kales Females Number of Animals Rats Hales Females Hansters Kales Females None Control 100 100 100 100 100 ' ICO Vinyl Chloride- TE-I Ethylene derived) Low level 50 ppm TE-II Intermediate level 500 ppm TE-III High level 5000 ppn 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 ICO ICO ICO 001323 n .CONFIDENT nt. Subject to Protectivo~0rdar in 14th Judicial District Court Calcasieu Parish, Louisian* -2- t XI . Chamber Par runt; Lor:.'. Each group of animals will be exposed in a specially constructed ploxiglas inhalation chamber having a capacity of approximately 6.0 allowing animal loading of less titan 2% when the animals reach maturity. Flow rate through the eham- ber will be at least 0.60 M /min. providing a theoretical air. change every ten minutes. The chamber supply air will_.be filtered and maintained at 40% to 60% relative humidity and 70 to 75F. Ill. Animal parameters A. Clinical Observations All animals will be observed daily for lesions and \ 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 necropsicd and ,1 their tissues processed in accordance with the methods given J 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 j_n extremi s when- death is imminent. to r,oco-'./rr0:-.' ' ^ -3- CMA 001324 13, Dody Weigh Ur; Individual body weights will be recorded once before exposure and after 1, 2, 3, and 4 weeks of testing. There after, mean group body weights will bo determined monthly up to the 12-month point of the study. C, Clinical Pathology Hemoglobin, hematocrit, total erythrocyte and. total leukocyte counts will be performed at 10 and 24 months on 3Q (15 male and 15 female) rats of the control and each test group. Differential leukocyte counts will be performed on all animals having high total leukocyte counts. D. Anatomic Pathology 1. Methods of Sacrifice Upon completion of the study, all survivors will be sacrificed by exsanguination^following carbon dioxide anesthesia. 2. Gross Pathology Complete necropsies will be performed on all ani mals which die or are sacrificed and all macroscopic lesions will be recorded. The lungs will be inflated with formalin fixative. 3. Ilistopathology Representative specimens of the following organs CONFIDENTIAL Subject to Protective Order in Poss v. ConocoInc., No. 90-4837. 14th Judicial District Court Calcasieu Parish,, Louisiana CMA 001325 and tissues will be taken Iren all animuJe .it time of sacrifice' and fixed in 10.0% neutral buffered formalin: Adrenal Glands All Gross Lesions Done (femur, tarsal and metatarsal, including long bones of all four limbs) Bone Marrow (sternal) Drain Both Ears (external auditory canal with ceruminal (Zymbal's) glands) Esophagus Eye Gonads (testes and ovaries) Kidneys Large Intestine (caecum and colon) Liver Lungs Lymph Nodes (tracheobronchial, cervical and mesenteric) Optic Nerve Pancreas Parathyroid Gland Pituitary Gland Prostate Salivary Gland Seminal Vesicles Skin Small Intestine (duodenum, jejunum and ileum) Spleen Stomach * Thymus Thyroid Gland Trachco Urinary Bladder Uterus The above tissues, from animals of the 'control, TE-II, and TE-III will be processed by conventional methods, embedded in paraplast, sectioned (4-6^) , stained with hema toxylin and eosin, and evaluated by light microscopy. If COTJI'IDE^rm. Gt to Protective Order in 9-lw l Judicial District casieu Parish, U 5- CMA 001326 Aukfe- drug-related lesions arc detected in tissues from the high or intermediate dose (TE-II or TE-III) animals, affected tissues from the TE-I group animals will be processed and examined in the same manner as the above. Only major organs (liver, kidney, spleen, heart, lungs) and neoplasms from animals which die and arc found in an advanced state of autolysis will be processed for"histo pathologic evaluation. IV. Reports Quarterly summaries of mortalities, clinical observations, clinicopathologic and anatomopathologic findings will be pre pared. Upon completion of the study, a .complete report will be prepared and issued. i February 1, 19^3 COITFIDSITTXAIj Jcr to Protsctiva Ordar inv. Conoco, Ir.o,, No. 90-4837 14th Judicial District Court Calcasisu Parish,, Louisiana K* -6- CMA 001327 JAI/.OS n. CARNES vu:l HI iLGiiLiAiir-mi AGum.H MANUFACTURING CHEMISTS ASSOCIATION 102b cqnn::cticut avlnue. n w. Washington, o.c, 20000 (?oy) 4H3-G12S Kay 1-1, 1/73 Dr. 0 . c. c a lu n dra, Pr as ident trial BIO -V-:jt La boratorie: 10! 0 J'rontn.go Uend dor th orcob, 111 inois 00002 Dear Dr. Ca land ra t By this letter. the agrci 1073, hatv.'ii:en I nduotri a 1 I'.IQ-TI (no- ami the nan ulacturin! (bC>.) for ~10- 'i BIT to conduce a tioii :v tudv v/ith Vinyl Chloride" an ac Jitiou:al C: 00 aura: group 33 lowii: g par,- '.j " : 1J TIila experimental 9roup it. to consist of 100 rats of the same co:if to fco exposed to vinyl eh lor ids vapors at a concentration of 5.000 ppm v/v. rood, water, and _ bedding aro to bo present in the cages in which the animals are exposed during tho entire exposure period. Otherwise, experimental procedures, including exposure conditions, tJieir documentation and control, and the handling, observation and necropsies of animals shall confom to those described in the Protocol incorporated by reference in the subject agreement, and hereby so incorporated in this agreement extension. 1 The cost for this additional exposure group will be $15,000, payable in three equal installments, the first and second payable on the first day of the 7th and 16th months, respectively, of the study period covered by the basic agreement, and tho third upon receipt of the final report from UIO-TEST. css2J2SE|rM4 sub'5' *i 14th j-- 1!0 90-4837 court ^rvsn. ^ CMA 001328 ft;. 0. C. ;;ay v\ l''7:. Wage `i'v.'o Please indicate your acceptance by signing the enclosed copy of this Letter in the space provided and returning to us. Sincerely, <; fl >t gtA^1x4-' Accepted for: Industrial EI0-TE3T Laboratories, Inc. Signed V . Ts7. a r>s. Title President_____________________ * Date _____ May 22, 1973 CMA 001329 ALBEnT C. CLARK VICE PRESIDENT technic*!. DIRECTOR MANUFACTURING CHEMISTS ASSOCIATION 182b CONNECTICUT AVENUE. N W VVAClll r.r, TON. C rOOOO (202) 483-G12G August 31, 1973 Dr. J. C. Calandra, President Industrial BIO-TEST Laboratories, 1810 Frontage Road Northbrook, Illinois 60062 Inc. Dear Dr. Calandra: By this letter, the agreement dated Felrruary 1. 1073 between Industrial BIO-TEST Laboratories, Inc. (DIO-TEST) and the Manufacturing Chemists' Association (MCA), and the agreement extension thereto dated May Id, 1^-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 .his 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 , lv73, at which time all exposure tests will be restarted with new animals. All other elements of the test protocol will continue to be governed by the referenced prior agreements. There will be no change in cost to MCA by the implementation of the terms of this amendment. CMA 001330 Dr. J. C. Calandra August 31, 197?. Page rwo Please indicate your acceptance of thin amendment by signing the enclosed copy of this letter in the space provided, and returning to me. Sincerely, Accepted for: Industrial BIO-TEST Laboratories, Inc. Signed ^ A C-- Titlo Assistant to the President Date September 7, 1973 xo ?.09s- n 3n' c-v ,Si8U me. . 90'^93r COMT^ CMA 001331 TADLE I (Revised August 31, 1973) Chronic Vapor Inhalation To\icity Study Organisation of Groups Test Katerini None Group Control Kico Ha Ip** To'Ti le3 Number of Anirnls Pats Kn les F'e *:n 1 nn J-` A ni o " r Kales Ye ' a'~ > 100 ICO 100 100 100 Vinyl Chloride TE-I* (Ethylene derived) Low level 30 ppm TE-I I* Interned iate level 200 ppm TE-III* High level 2,300 ppm TE-IV** High level 2,500 ppm 100 100 100 100 100 ICO 100 LOO 100 100 100 LOO 100r; . 103 100 100 ICO ICO ICC 001332 Ho food, water, or fceddinj in cages during e:po3ure Q loo.:, water, and bedding to regain in cages during exposure All rats of same se:c, either eu permitted COEFTDSfl?TAL Subject to Protest Lvts Order Ross v. Conoco, Inc^_Ho. 90-48o7. ijo v . --_____ :-------------------- j. 14th Judicial Distinct Cour Calcasieu Parish, Louisiana JAN JO 1975 THE DOW CHEMICAL COMPANY January 27, 1975 BENNETT BUILDING 2030 DOW CENTER MIOLANO. MICHIGAN ASE-10 Mr, Milton Freifeld Manufacturing Chemists' Assoc 1025 Connecticute Ave, N.W. Washington, D,C. 20009 in Vo.90-^337 ,^ct Court Louisiana. Dear Mr. Freifeld: 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 lour, 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 l 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 lengcr 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 g.one 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 tilings. Sincerely yours, Theodore R. Torkelson Corporate Medical Department kjf end ce:. Distribution List Attached ^nunirf'* CMA 001333 cc: Vinyl Chloride Research Coordinators: Hr. Zcb G. Bell, Jr. I'PG Industries,-Inc. One Gateway Center Pittsburgh, PA 15222 Dr. Walter D, Harris UNIROYAL, Inc. Oxford Management 5 Research Center Middlebury, Conn. 06749 M. N. Johnson, M.D, The R.P. Goodrich Company Medical Center 500 South Main St. Akron, Ohio 44318 Mr. H. L, Kusnetz Shell Oil Company P.O. Box 2463 Houston, TX 77001 Dr. W. Mayo Smith Air Products Chemicals P.O, Box 538 Allentown, PA 18104 Dr. William Rinehart Ethyl Corporation Medical Department 451 Florida Avenue Baton Rouge, LA 70801 Mr. R. N. Wheeler Union Carbide Corp, Chemicals 6 Plastics Div. P.O. Box 8004 _C_O__H__F_T__D_E__T_STIM. -Subject to Protective Order In S. Charleston, W. VA 25303Ross v. Conoco, Inc, No. 90-4837i 14th Judicial District Court Po*r*i _ Louisiana. M. L. Keplinger Industrial BioTest Laboratories, Inr. 1010 Frontage Road Northbrook, ILL 60062 J. Goode Industrial BioTest Laboratories, 1810 Frontage Road Northbrook, ILL 60062 Inc. CMA 901334 t s:.;?,v:v::.:g a;;i;*ais at i:-r: ag o? jah. 20, 1975 Inhaled Concentration Of Vinyl CLlorid2 [ ' <_________________________________ j : |:s:o ppn Hamsters Male Female ' 16 0(3) j2Dh ppc 26 41 . - j mrTi ;. 2, 50 17 22 t*? iC2 Male Te^alG ^ Male ?.<v-n Female 0 0 0(7) 15- 0 0 0(2) ** 0(4) 54 69 75 0 1355 77 Female ,ith 0(7) " 1 bO '-;n" f 1 gnr* > ---- 1 V; 1^0 C()W?JV. HTJ.AL Subject to Protective Order in Boss v. Conoco, ino.. Ko. 90-4837 14th Judicial District Court Caloasiou Parish, Louisiana CMA 0 0 1 3 3 5 TNF'nrTiATION COPY 'MCNTAI. sciences > SCIENCES CICNCC3 Mn^huiM Bio - TEST J'aAowMvr, 1. DECATUR RESEARCH i80o cast rEesHiNG poad OECATUr. ILLINOIS 63526 ' August Z, 1973 *bca coot in tclcphonc 0 7?* 'i i>.'Dr. H. S la tin rMKManufacturing Chemists Association ;|j^Srl826 Connecticut Avenue, N. W. AvpjjtWashington, D.C. Z0009 f>wi:'tvA**ri' ijlJBDear Dr. Slatin: c Subjactlc Boss. y. 24th Calcasieu j ce^c^-t^v"1 . 1,0 ' ro"4SS7 Court Louisiana iJpDue to problems which have occurred in the early stages of the Ufevinyl chloride inhalation project, 113'!' 663-03222, we respect fully request that we be allowed to restart the study. tf?In our opinion, two major problems make this request necessary: f(a) The design on the animal feeding system is not working satis factorily, 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 lie redesigned. (b) Some of llie changes deemed necessary hy the MCA committee on their last visit to the laboratory, have been made hut others fare delayed due to shipping dates on equipment. y" (In our opinion, to continue such an important project with animals rwhich have been stressed 'and in which sampling and air handling ^equipment would he changed in the near future, would compromise Afcijithc data and leave Dio-Test open to eventual criticism. frWc feel that all equipment changes ran be made hy September 1, ij.E1973, at. which time the study would lie restarted with new groups Tof animals. CMA 001336 [>am sure that a favorable decision on this matter wilt allow Hio-.Tcst >.conduct a study which will be. belter received by the scientific community. Sincerely, f ifohn W. Goode, Ph, I). ^"^Manager Decatur Research Laboratories f.i `V In }h ?rv L'or. % c c v> $ . c5 r fr VZo* i'ao0' o^o **A fr CMA 001337  . t`4T C. CLAPK 1-'** wtsiotwr fUmu*. oimctob & 'Afr- ' .ft1-' ...uJ.v.a;'IOfl COPY manufacturing chemists association 18?i CONNECTICUT AVENUE. N W. WASHINGTON, C .'orn i.-c'i oc-'2s August 3, 1073 US4?hn w* Goode, Ph,D., Manager ISifiecatur Research Laboratories iustrial Bio-Test Laboratories, BOO East Pershing Road :atur, Illinois 62526 Inc. 'iro-ce--1 Eq>i9QS'i Co^. osS-V' T-TAvjl^1 137s *LouisiaJia gg.'1-e^' Dr. Goode; Thank you for the courtesies extended to Mr. Harry Slatin the representatives of our member companies. Dr. T. R. fkelcon. Dr. 2. G. Bell, Dr. W. D. Harris, and Mr. 11. L. letz in their visit to your laboratories August 2, 1973. ijj We were all sorry to hear, as you told. thr'm n->d vouv .fitter of August 2, 1973, .indicates, that the current sf.:rt on %-vinyl chloride inhalation project, IBT-663-03222, is such 'lat you recommend a restart of the study on September 1, 1973. ^understand from discussions at the time of the visit that 5e total cost of this study to MCA will remain as originally treed. 'p MCA and its member representatives concur with you that a start of the study is desirable and advise you to proceed. r* It .is appreciated that the changes you have made in your ,-sical setup, as well as those you contemplate will help the Jy appreciably.. /.If there are any other problems, please advise us. Sincerely, / ( t * CMA 001338 1 y` COIIFIVEITHAL Subject to Protective Order in Boss v.. Conoco,, Inc..,, Ho. 90-4837, i!4tK Judicial District' Court Calcasieu Parish,, Louisiana June 15, 1973 _ 1* -- ' Zeb Dell Walter Harris ( Russ Maycock Maurey Johnson, Dill Rinehart ' R. N. Wheeler . ' ' * cc: John Goode ^' / Ken Johnson Howard Kusnetz Moreno Keplinger VISIT TO INDUSTRIAL BIO-TEST LABORATORIES, DECATUR, ILLINOIS On June 7, 1973, Ken Johnson (MCA) , Howard Kuznetz (Shell) , and myself, visited the Decatur Research Laboratories of Industrial Dio-Test Laboratories, Inc. The purpose of the visit was to observe the equipment and facilities ana 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 exnosures would be underway in 10-14 days, but after viewing the incompleted facilities, wh 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 were made, including the following: '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 hv trays, there was possibility of channeling of air through the chamber. ' It was suggested that CMA 001339 r 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 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 to assure closure of the chambers and operation of the pumps so that the animals do not die of asphyxia. Because it was considered necessary to do very frequent 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 bo feedback into other chambers and that cross contamination should be carefully guarded against. 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. 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 chock out the operation of the chambers and that they would have more permanent attachments. Kxhaust 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 bo included in the setup to assure movement of air through the chambers. CMA 001340 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 Dio-Test for information. It was felt undesirable to allow 20 companies to bo asking for information. It was determined that no information would be given by Bio-Test to anyone except Ken Johnson unless Dio-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 Dio-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 arc 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. Sincerely yours, T. R. Torkelson Registration Section Ag-Orgnnics Department la CMA 001341 0p INDUSTRIES R. E. Widing INTER-OFFICE CORRESPONDENCE U"''' August G , i:1: F'anv Zcb i;. nJl, Jr. Lu^1"J''' i v idit Subjcc indur.t ririi biotvst Labor-itory Vi'.it, Decatur, Illinois As ri member of tho MCA-VCM Technical Cocrdi nn torr- Tush Crouj', t;h-_undersigned vit-itc-ci die Industrial Sict^st Laboratory facilic iu. Decatur, Illinois, where the VGA innsincion study on VCM is b(.ing performed. There were some problem; in the test clumber desiur reported by Dr. T. TorKelsori 'Dew) cr. his Just visit there. This visit revealed that these concitier., have b< <'n or .in being recciliody We (MCA) have been advised tluou.jh r:,e attached letter that u-re early problems have developed resulting in their recommendation that the study be re-started. This :onstitutes a lurcher delay in getting this program "off the ground", huwwer. it i' a very wise move since the experiment may neve e.au to be terminated at a later date because of th^se factors anyway. Industrial Biotest Laboratory has acted in good faith, in complying with our recommendations, but they rave had seme uniortunace uncon trollable circumstances develop that prompted them to suggest a re-stari t.-i I see that we have no other choice than to concur. .1 Zeb G. Bell, Jr. f --- ZGBtrmp Attachment cc: J. A. Clapperton L.`B. Grant, M.D. J. L. MacMillan ,H. -Slatin (MCA) JT. _ R.. Torkelson (Dow) .s^0r'l9r 90'4S^ -)ot C^1 CMA 001342 MANUFACTURING CHEMISTS ASSOCIATION \92b CONNECTICUT AVENUE, N. W WASHING TON, 0, C 20009 (202)480-6126 August 10, 1973 Memorandum TO: A. C. Clark FROM: H, L. Slatin SUBJECT: Visit August 2, 1973 Industrial BIO-TEST Laboratories, Inc. Decatur, Illinois At the meeting of the Technical Task Group on Vinyl Chloride Research, July 11, 1973, considerable concern was expressed over certain aspects of the ani mal studies being performed by Industrial BIO-TEST Laboratories (IBL). To assure that discrepancies in the facilities and program noted during the visit to IBL by Drs. 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: For MCA Dr. T. R. Torkelson Dr. Z. G. Bell, Jr. Dr. W. D. Harris Mr. H. L. Kusnetz Mr. H. L. Slatin IBL Dr. J. W. Goode Mr. Ken Sch^deberg 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 001343 2- - 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 oat 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. r 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 ^ <Ji CJ. CQ 1 0^3 H o^ > tS', t-' ,d 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, pVS v\<- % information on all of the animals as to their background and the number of multiparous litters from which they . o So\i%d came. o \ jj i r ctj o -a 3 In any case, if everything was not ready by "o wpeptember 1, 1973, but the animals were, the experiment q\ jirould 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 001344 n -3- of the VCM/air mixtures. It took about 35 minutes for the chambers to reach equilibrium, which remained steady thereafter. The chambers have a complete air change every ten minutes. The current animals will be used to check out the feeding part of the experiment. Industrial BIO-TEST agreed to make suitable arrange ments for a possible leak and/or rupture of one or more containers of vinyl chloride. Changes will also be made to the air exhaust system so that the air intake will be at a point up and away from the air exhaust. ` Subsequent to the meeting, committee members M. N. Johnson, M. D., Dr. W. E. Rinehart, and Mr. R. N. Wheeler were contacted by phone and all concurred with the decision to restart the testing procedure September 1. r HLS:mb H. L. Slatin CMA 001345 TABLE I Mouse Mortality Data DATE Controls FM February 10, 1974 28 GROUP TI TII FM FM 6 26 24 Till FM 78 April 12, 1974 5 11 9 31 13 7 13 18 > *' CMA 001346 MjjAOug.1 BIO -TEST 3nc. imo r r o mia f. r road nonlimROO'' "M-IOIS ^0()A7 Summary of Tumors in V i<u 1 'blonde Kvposcd Mice UST Number 0b 3-U 3222 -MCA TABLE II Group, Animal No. , Sex T-I 102 3 Male 1110 Female 1119 Female 1200 Female Histopathologic Findings - Date of Heath Lung Live r Skin AA (s)* HS (s)** AA (s), Metastatic Skin Tumor HS (s) Metastatic Skin Tumor EC (para-aural) 3-20- 3-24-74 EC & MC+ (Femoral region) 3-30-74 T-II 1347 Female 1309 Female 1889 Male 1382 Female 1350 Female 1299 Female T-Ul 1538 Female 1532 Female 1562 Female 1598 Female 1405 Male 1494 Male 1574 Female 153 1 F emale 1588 Female 1593 Female 1505 Female 1565 Female 1409 Male 1543 Female 1544 Female 1546 Female 1535 Female 1432 Male 1477 Female Metastatic Skin Tumor HS (s) AA (s) HS HS (s) AA (s) HS (s) AA (s) AA (s) AA (s) AA (s) AA (s) AA (s) AA (s) AA (s) HS (s) HS (s) HS (s) HS (s) * HS (s) IIS (s) HS (s) AA (s) AA (s) AA (s) AA (s) AA (s) AA (S) AA (s) HS (s) HS (s) HS (s) IIS (s) IIS (s) HS (s) HS HS (s) A A (s) HS (s) AA (s) A A (s) HS (s) Metastatic Skin Tumor? EC(Abdomen) 3-5-74 3-18-74 3-25-74 4-2-74 4-5-74 EC & MC (Inguinal Region) 4-9-74 LS 3-6-74 3-7-74 3-8-74 2-25-74 3-22-74 3-22-74 EC h MC (Femoral region) 3-23-74 3-25-74 3-30-74 4-3-74 4-3-74 4-5-74 4-5-74 4-5-74 MC (Axillary region) 4-5-74 4-7-74 4-8-74 EC (Para-Aural) MC ( Abdomen) EC( Pelvic region) 4-9-` CMA 001347 Group T-I T-II T-1II TABLE III 9n&uAi/uxil BIO -TEST JldyyujJtinlgA,, 9nc. 1810 FRONTAGE HOAD NORTHBROOK, ILLINOIS 60062 Summary of Mortality 8t Tumor Data Among Vinyl Chloride Mice IBT Number 663-03222 (MCA) No. Mortalities with Neoplasms - Location of Tumors Lung Liver Skin Metastasis-* 4 (1 Male, 3 Females ) 2(50%) 2 (5 0%) 2450%) 2 6 (1 Male, 5 Females) 19 (4 Males, 15 Females) 3(50%) 4(66. 7%) 2(33%) 1 17(89. 5%; 17(89.5 %) 3(15. 8%) Key to Symbols Alveologenic Adenoma of Lung (AA) Hemangiosarcomn of Liver ( HS) Epidermoid Carcinoma of Skin (EC) + Mammary Carcinoma of Skin (MC) Lymphosarcoma of Thymus (s) Multiple tumors of indicated type - c;-r YO v'&a-v Co / CMA 001348