Document 9MQbXdan9p3aJqVGE3xYYxN5

V SUMMARY REPORT I. INTRODUCTION II, EXPERIMENTAL PROCEDURE A. Exposure Procedures for Toxicology and Carcinogenesis 1. Doses 2. Exposure and Sampling Technique 3. Observation 4. pathology a. Cross and Light Microscopy b. Electron .Microscopy B, Reproduction Study and Carcinogenicity III. . RESULTS ` A. Toxicology (single and multiple exposures) 1. Observations During Exposure - 2. Observations After Exposure B. Cross Pathology C. Light Microscopic Pathology 1. Mice (single exposures) 2. Mice (10 exposures) 3. Mice (100 exposures) 4. Rats (single exposure) 5. Rats (multiple exposures) 6. Rats (49 exposures from the reproduction study) 7.* Summary of Light Microscopic Studies D. Electron Microscopy Study E. Multlgeneratlon Study in Rats 3 ucc 066166 * t I. Toxicology, Carcinogenicity jn'i Reproductive Effects of Single and Multiple Exposures to Vinyl Chloride in Rats and Mice INTRODUCTION. The background information on vinyl chloride- ronorner (VCM) with technical details is reviewed in "Scientific and Technical Assess ment Report on Yinyl Chloride and Polyvinyl Chloride", 05 Environmental 1' Protection Agency, EPA-600/6-76-004, June 1975. VCM studies in rats and mice reported herein were conducted at the Chemical Systems Laboratory (CSL) under interagency agreement with Consumer Products Safety Commission (CPSC). II, EXPERIMENTAL PROCEDURES, A. Exposure Procedures for Toxicology and Carcinogwicity. 1. Doses. Male and female rats (Fischer 344) and mice (A/4 or ICR) were totally exposed In one of the following ways: a. One single one-hour exposure at 0, 50, 500, 5,000 or 5Q.OOO ppm. (Fischer 344 rats, ICR Vice) (Appendix, Table I) b. Ten one-hour exposures at 500 ppm (one-hour per day, five days per week for two weeks). (Fischer 344, A/J Mice) (Appendix, Table II) c. One-hundred one-hour exposures at 50 ppm (one-hour per day, five days per week for 20 weeks). (Fischer 344 rats, A/J Mice) 2. Exposure and Sampling Techniques. The exposures were conducted In 1000 1 iter,- stafnless steel dynamic flow chambers of the Rochester type. Construction Insured laminar flow and uniform exposure of the test animals. During one-hour expdwe periods four 0.5 cc gas samples were collected at selected times for concentration analysis, A Hewlett-Packard series 5830A Reporting Gas Chromatograph equipped with a dual-flame 1ont2at1on detector was used ftor VCM analysis. UCC 066167 an 18-month sacrifice. The latter is minimum suggested by the National Cancer Institute for cancer bioassays In small rodents. Tor the multiple dose studies (500 ppm x 10 exposures; 50 ppm x 100 exposures) in mice the final sacrifice was at 20 months rather than 24 months. The chaxige was made in consideration of the risk of animal loss through death and possible cannabolism. b. Electron Microscopical Studies. For the electron microscopical studies the following animals were selected at random: Three groups consisting of five males and five female Fischer 344 rats from each of the single one-hour (50, 500, 5000 and 50,000 ppm) exposures with equal numbers of their corresponding control group. The three groups were sacrificed at'8, 16 and 24 months, respectively, after the exposure. Three groups consisting of five males and five female Fischer 344 rats from each of the multiple one-hour exposures (10 x 500 pp,, 100 x 50 ppm) with equal numbersof their control group. The three groups were sacrificed at the end of 16 and 24 months, respectively, after the final exposure. One group of five male and five female Sprague/Dawley/VMstar rats from the parenteral generation of the reproduction group (49 x 50 ppm, 49 x 500 ppm) with equal numbers of their control group. This group was sacrificed 24 months after the final exposure. The rats were anesthetized with pentabarbital and their livers were perfused via the vena cava with chilled electron microscopical fixative consisting of 41 formaldehyde, IS glutaraldehyde In 0.1 M phosphate buffer2 (E.M. McOowell & B.F. Trump, Histological Fixatives Suitable for Diagnostic Light and Electron Microscopy, Arch. Path. Lab. Med. 100:405-415, 1976). After mincing the tissues were post-fixed in 12 phosphate buffered 7 ucc 066168 ataxia were noted. At 59 minutes tremors were seen. Females showed some hyperactivity at 40 minutes and 255 showed respiratory difficulty and ataxia after 55 minutes. No other effects were noted. There were no remarkable signs of toxicity during the ten repeated exposures of mice and rats at 500 ppm of VCM, nor In rats during the 49 exposures at 500 ppm, nor in either species during the 100 exposures at SO ppm. 2. Observations After Exposure There were no consistent or dose-related differences between control and exposed (single or multiple) mice or rats in: death rate, (Appendix, Fig I IX, Inclusive) toxic signs, gain in body weight. (Appendix, Figs X-XVIII inclusiv. B. Gross Pathology There was a suggestion of a higher frequency of masses in the lungs and livers of mice and rats exposed once or repeatedly at the higher dose levels. (500, 5,000, 50,000 ppm) C. Light Microscopic Pathology 1. Mice (single exposure) Histological examination at 8 and 18 months in ICR mice exposed once to concentrations of 50, 500, 5000 or 50000 ppm showed the following changes attributable to VCM. (Appendix, Table IV-VI, Inclusive) The development of adenomas Increased with exposure to hiqher dose levels of vinyl chloride: control - 12/120 or 102 50,000 ppm - 45/137 or 3j.fc ' 5,000 ppm - 24/143 or 16.81 500 ppm - 18/139 or 12.92 50 ppm - 14/139 or 10.12 Progression to carcinoma was minimal: <7 UCC 066169 4. Rats (single exposures) Except for aggravation of latent pulmonary changes, particularly bronchopneumonia, changes attributable to VCM were not apparent in any of the tissues evaluated microscopically at 8, 16 or 24 months from Fischer 344 rats exposed to concentrations of 50, 500, 5000 or 50,000 ppm. (Appendix , Tables XI-XIV, inclusive) 5. Rats (multiple exposures) No changes attributable to VCM were apparent in any of the tissues evaluated microscopically at 8, 16 or 24 months from Fischer 344 rats exposed ten times at 500 ppm or 100 times at 50 ppm. (Appendix, Tables XV-XVII, Inclusive) 6-. fets (49 exposures from the reproductive study) The following histological observations were made 24 months post exposure In Sprague-Dawley/Wistar rats which had been exposed 49 times at 50 ppm or 503 ppm of VCM. (Appendix, Table XVII) Neoplastic and non-neoplastie lesions were observed in approxi mately equal frequency In control and test animals. The only lesions that occurred in higher frequency in the VCM exposed animal than in control rats were eosinophilic cell alterations presented as foci and/or areas. The appearance of these foci was related to dosage. The nature of these lesions Is controversial. Some pathologists * feel that basophilic lesions have greater significance with respect to neoplasm development than do other cellular alterations. Others feel that all of these cellular alteration: may be part of a spectrum capable of progressing to the formation of neoplastic nodules. * 7. Sutjntnary of Light Microscopy Studies The carcinogenic, or possible related changes (eosinophilic foci) attributable to exposure of VCM in rats and .mice are sunmarized in Table 1. u T ucc 066170 0. Electro^ Microscopical Results. 1. General. In general, these studies indicate mat expesur;* to v'nyi chloride increased organelle turnover (Fig. XIX) as well as loss of volume control (bleb formation) and Increased lysosomal activity in the liver of rats (Figure XIX). These alterations progressively decrease! as recovery time after exposure Increased. Hepatocellular earcinoma was seen In one male Fischer rat which had received ten exposures of 500 ppm. Lymphosarcoma was noted in one female Fischer rat which had received a single exposure at 500 ppm. 5ince these were individual cases, and since no cancers were seen at 50,000 ppm, the lymphosarcoma and the hepatocellular carcinoma are not likely related to the vinyl chloride exposure. Thus, it appears- that exposure to vinyl chloride did not produce cancer in rats In any of these single or multiple exposures. General conclusions concerning these various segments of the electron microscopical results follow. /. 2. General Conclusion of 8-Month Recovery to Single Exposure ,, $6, SOQ, 56o0, 50,000 ppm-hr) of Vinyl Chloride in Fischer Rats. a. Alterations from control (Fiq. XVIII) occurred In all treated animals at each concentration. b. Changes were less severe in female animals. c. Hepatocytlc alteration Included lipid accumulation (Fig. XIX), increased dense bodies (Fig. XX), llpofuschin granules (Fig. XX) and residual bodies. These are an indication of cytoplasmic sublethal injury. tion. d. Alteration was Incremental with Increasing exposure concentra ?e. Host severe changes Involved cellular necrosis with subsequent phagocytosis by Kupffer cells* {figure XXl)(seen In single and multiple exposures) -T /J ucc 066171 6. General Conclusion to 24-Month Recovery from Single Dose T50,''S0b,~5000. 50,000 ppm) Vinyl Chloride in Fischer Rats. a. Age-related changes Including formation of cleft-like spaces (possibly related to hemoglobin/hemosiderin), inflammatory infiltrate (pericholan gitis) and some collagen accumulation were seen in controls (Fig. XXIV) and treated animals In this group. b. In this group hepatocytlc Injury - not encountered in controls was observed. At 5000 ppm one female showed evidence of lymphosarcoma. 7. General Conclusion to 24-Month Recovery After Multiple Doses 50 ppm X 10) of Vinyl tfrloride in Fischer Rats. a. Controls and treated animals showed changes similar to those seen after 24 months recovery to single exposure. b. These changes were regarded as age-related and non-specific I Fig.* 8. General Conclusion to 49 Exposures for 1 Hr at Daily Intervals followed by 24 Month of Recovery (50 and SOD ppm) (Sprague/ bawley/Wistar featsT" a. Age-ralated non-specific change was encountered In all groups. b. Most advanced changes were related to 500 ppm group of male rats In which cell swelling and platelet aggregation were seen. E. Multigeneration Study in Rats (Spraque/Dawley/Wistar). No consistent changes attributable to VCM were found in FQ parents which were exposed to 50 ppm or 500 ppm of the vinyl chloride monomer one hour per day. five days per week for ten weeks before mating and evaluated for numbers 'of matings, percentages of pregnancies, fertility and lactation indices. The Fj, Fg, and Fj offspring were evaluated for litter size, percent of stillborn pups, post-natal growth, vialjiHty, survivability and reproduction anomalies. (Appendix, Tble XIX - XXV# Inclusive) Electron microscopical examination of the parent rats which were held for 24 months after the 49th exposure revealed age related changes, cell swelling, and platelet aggregation but no tumors, wei^aecn (Fig-. XXV).' ucc 066172 The possibility is recognized that "no effect" doses may exert carcinogenic effects which are too weak to be detected with the numbers of animals used in routine testing. The concept of lifetime accumulative, non-tumorigenic and tumorigenic doses of radiation has been adopted. The Federal Radiation Council 18 stated that for occupationally exposed personnel the accumulated dose of radiation to the whole body, head, trunk, active blood forming organs, gonads or lens of the eye shall not exceed: 1. In any calendar quarter, 1.25 roentgen equivalent manrnal (rem) 2. Total lifetime dose of 5 (N-18) rem where N equals the present age In years. B. .. Vinyl Chloride and Carcinogenicity. Maltonl described a dose-response relationship for the carcinogenic effect of vinyl chloride In animals. The neoplastic response was affected by 19 20 the length of exposure. * 21 Lee et a!., noted that the incidence and severity of tumors Increased with the concentration of VC and the length of exposure. The above statments indicate thafthe total dose (concentration *\ X exposure time} may be of Importance in the carcinogenicity of vinyl 22 chloride. Total Inhaled dose can be approximated by the Haber concept. In its simplest form this concept states that the total inhaled dose, Ct (mg min/cu m) Is the product of C (concentration in mg/cu } X t (time In minutes). The concentration can be expressed also in part per million (ppm) and the time can be expressed in hours producing Ct In ppm-hr. Factors for breathing rate and detoxication can be added when these data are available. However, the simplified Ct approximation of total Inhaled * dosage Is sometimes useful. *7 Uqq 066173 28,800,000 ppm-hrs. A. Caputo, P.L. Viola and A. Bigotti24 exposed rats to vinyl Chloride four hours per day, five days per week for 12 months. The concent rations were 20,000; 10,000; 5,000; 2,000; 500; or 50 ppm. The total dose (Ct) for the 50 ppm was 48,000 ppm-hrs. No tumors were produced at this level. The total dose for 500 ppm was 480,000 ppm-hrs. Tumors-did occur at the latter dose appearing as early as eight months. The total Ct in the 500 ppm study in eight months was 320,000 ppm-hrs. Tumors appeared In the rabbits after nine months at 10,000 ppm. Thus the lowest total dose was 7,200,000 ppm-hrs. M.L. Kepllnger et al.,^ exposed rets, hamsters and mice to vinyl chloride. Only the data on mice was sufficiently complete for examination of total dose effects. The animals were exposed seven hours per day, five days per week for eight months. The lowest Ct was 55,000 ppm-hrs. This Ct and all higher ones did produce tumors in mice. Consumer Products Safety Commission Studies (Tables 1 and 2) * Tabel 2 Species Results (carcinogenesis) ICR Mice 50 and 500 ppm-hrs - negative 5000 ppm-hrs - borderline positive 50,000 ppm-hrs - positive A/J Mice 5000 ppm-hrs - positive Fischer Rats 50, 50, 5,000 and 50,000 ppm-hrs - negative 24,500 ppm-hrs eosinophilic loci, no cancers These calculations indicate strongly positive carcinogenic effects may not appear in rats until the total dose (Ct) of VCM reaches or exceeds /f * *- ucc 066174 As an additional consideration in the total dose concept, Ct's of 5000 ppm-hr produced increased incidences of adenomas in mice when the exposures were at 5000 ppm for one day, 500 ppm for 10 days or 50 ppm for 100 days. The increased incidence of adenomas produced by the single exposure of mice at 5000 ppm is of borderline significance. However, there is the indication that even single exposure of sufficient magnitude may be carcinogenic in sensitive species. The dose-response relationship and the "no effect" dose concept have been described for other carcinogens. It is difficult to relate these animal studies to man. Data on vinyl-chloride exposure in plants have beer, limited. However, acute dizzyness, headache, nausea and chronic liver damage have been seen in vinyl chloride workers. It is assumed that peak exposure levels of several thousand parts per million were experienced at times. Air monitoring of one group of plants during 1950-59 indicate that time-weighted (S-hr) average exposure were 120-385 ppm. (This would give dally Cts of 960-3080 ppm-hrs). Peak exposures probably exceeded 1000 ppm. This may not have been typical of all polyvinly chloride plants.^ Data on vinyl chloride in ambient air are limited also. Atmospheric measurements in the vicinity of production plants indicate that concentrations are below 1 ppm. One peak grab sample of 33 ppm has been reported at 0.5 kilometer from the center of one plant.^ The time-weighted threshold limit value of the American Conference of fiovemment Industrial Hyglenest for 1977 is 200 ppm. There is a notice of Intended change 97 . The Environmental Protection Agency has established the following emission limits for vinyl chloride: (1) formation and purification processes is 10 ppm, (2) emissions from equipment preceding and including the 'M UCC 066175 IV. CONCLUSIONS. A. Except at the highest concentration, 50,000 ppm, where possibly anesthetic-type effects were seen vinyl chloride produced no pharmaco-toxic (excluding pathology) signs in mice or rats during or after exposure. B. No reproductive or teratogenic changes attributable to vinyl chloride were found. C. Vinyl chloride seemed to produce pneumonitis in mice and to aggravate bronchopneumonia In rats. I /f r D. Vinyl chloride produced eosinophilic changes in rats but no frank (light microscopy) carcinogenesis. E. Electon microscopical studies revealed some hepatocellular changes but no carcinogenesis related to the vinyl chloride exposures at Ct's of 50,000 ppm-hrs or less. F. The findings from these Consumer Products Safety COmnlssion tests are in agreement with results of previous studiesJ^S69,10,11,13,15,16,17 1. The carcinogenic effectiveness of VCM depends upon concentration 4 5 fi and exposure time, Ct- * * 2. There were VCM doses which were not carcinogenic and there appeared to be a total accumulated dose above which tumors were produced.1^*19,1,17 Similar effects have been noted with other chemicals. 3. Tumors were not seen in mice at Ct's of 500 ppm-hrs nor in rats at 50,000 ppm-hrs or less.4'5,6,9,10,11 . 4. Carcinogenic effects of VCM were seen in mice at total doses (Cts) of 5,000 ppm-hrs and above".--'11 ucc D 066176 04. Eschenbrenner, A.B., and Eliza Miller. Studies on Hepatomas. I. Size and Spacing of Multiple Doses in the Induction of Carbon Tetra chloride Hepatomas. J. Natl. Cancer Inst., 4:385-388, 1944. 15. Blum, H.F., On the Mechanism of Cancer Induction by Ultraviolet Radiation. J. Natl. Cancer Inst., 11:463-495, 1950. 15. Finkel, Miriam P. Mice, Men and Fallout. (The potential danger of strontium 90 is appraised on the basis of data from animal experi ments). Science 128:637-641, 1958. "17. Mole, R.H. . The Dose-Response Relationship in Radiation Carcinogenesis. Brit. Med. Bull. 14:184-189. 1958. `J8. The Federal Radiation Council (Report No. 1, Background Material for the Development of Radiation Protection Standards, 1960, Government Printing Office, Washington, DC). 19. C. Maltoni. The Value of Predictive Experimental Bioassay in Occupational and Environmental Carcinogenesis. An Example: Vinyl Chloride. Ambio. 4:18-23,-1975. 20. C. Maltoni and 6. Lefemine. Carcinogenicity Assay of Vinyl Chloride. Ann. NY Acad. Scl. 246:195-218, 1975. ' 21. C;C. Lee, J.C. Bhandari, J.M. Winston, W.B. House, R.L.-Qixon and J.S. Woods. Carcinogenicity of Vinyl Chloride and Vinylidene Chloride, 0. Tox. Environ. Health 4:15-30, 1978. 22. F. Haber, "Funf Vortrage aus den Yahren 1920-23": No. 3. Die chemie 1m Kriege: No. 5. Zur geschichte des gaskampes, Juluis Springer, Berlin, 1924 - reference through Prentiss: Chemicals in War, HcGraw-Hill Book Company, Inc., New York, 1937. ~ 23.. P.L. Viola, A. Bigotti and A. Caputo. Oncogenic Response of Rat Skin, Lungs and Bones to Vinyl Chloride, Cancer Research 31:516-522, 1971. 24. A. Caputo, P.L. Viola and A. Bigotti. at Low Concentrations in Rats and Rabbits. 1974. * , Oncogenicity of Vinyl Chloride J. Int. Res. Commun. 21:1582, 25. M.L. Keplinger, J.W. Goode, D.E. Gordon, and J.C. Colandra, Interim Results of Exposure of Rats, Hamsters and Mice to Vinyl Chloride. Ann. NY Acad. Sci. 246:219-224, 1975. 26. Threshold.Limit Values fw_Chemical Substances and Physical Agents in The Workroom Environment with Intended Changes for 1977, American Conference of Governmental Industrial Hygienist. 27; Title 40-Protection of the Environment. Environmental Protection Agency, Part 61-National Environmental Standards for Hazardous Air Pollutants, Stand ard for Vinyl Chloride, Federal Register, Vol 41, No. 205, Thursday, Oct 21, 1976. p ucc 066177 * APPENDIX Table fl. Exposure Schedule for Animals Exposed Repeatedly to VCM Species Fischer Rat A/J House Fischer Rat A/J Moua Sex .u F H t fr u F M F Dose ppm SO 500 50 500 50 500 50 500 Neg. control Neg. control Neg. control Neg. control Exposure periods days 100 10 100 10 100 10 100 10 100<c) 10(c) 100(c) 10(c) 100(c) 10(c) 100(c) 10(c) Exposure dates From To S/27/75 7/7/75 8/27/75 7/7/75 7/7/75 8/27/75 7/7/75 8/27/75 -- - -- 1/26/76 7/18/75 1/26/76 7/18/75 7/18/75. 1/26/76 7/18/75 1/26/76 - -- - NOTE: (c) control for corresponding dose above. Exposure Group slze(s) Start End 90 86 90 90 90 87 90 90 90 87 90 90 90 88 90 90 50 50 50 50 50 47 50 50 40 39 50 50 50 50 50 50 Age Start 21 14 21 14 15 8 15 8 21 14 21 14 15 8 15 8 End wks 41 16 41 16 35 10 35 10 41 16 41 16 35 10 35 10 % 1Q0 Figure I SPONTANEOUS MORTALITY 00 00 70 00 50 40 1 30 20 10- 0- AGE Oi Htirt t-i w >1 D^t 60 PPM CONTROL 50.000 F-rr.i 5.000 PPM 500 PPM ucc 066179 Figure III SPONTANEOUS MORTALITY MALE FISCHER RATS SINGLE DOSE STUDY VINYL CHLORIDE MONOA\ER 50.000 s.ooo rr COWTRC SO PPM 500 PPM 1 ii r IS 17 18 19 20 21 22 ACE OF RATS (MONTHS) 31 ucc 066180 % MORTALITY (CUMULATIVE) Figure V SPONTANEOUS 'MORTALITY ' j ucc 066181 Figure VII figure XI **TM CURVES OF FEMALE ICR MICE EXPOSED ONCE to vcm - MEAN ANIMAL WEIGHTS IN GRAMS Figure XIII GROWTH CURVES OF FEMALE FISCHER RATS EXPOSED ONCE TO VCM WEEKS POST EXPOSURE * figure XV GROWTH CURVES OF A/0 MICE EXPOSED TO VjCM IN 100 DAT STUDY ! .F ! i/i <0=5> <Oz 2o 0o0> & .* 0 A * - 1 $ Figure XVII GROI/TH CURVES OF FISCHER RATS EXPOSED TO YCM IN 100 DAY STUDY ' f weights IN grans 1 I I i I gg2 coo 00 --J 4. -. * *:*'**. *' * it Ion ir i Spontaneous Deaths 0-6 Months 7-12 Months M F Total M F Total 8 Months 8 Months H _ F_ Total M ... F Total >0 0 0 0 5 11 16 33 32 65 4 1 5* * 0 022 2 6 22 27 *9 2 l 3 > 0 5 5 6 8 III 19. III 33 1 t --r 01 0 0 0 4 15 19 9 18 27 0 0 0 18 Months M F Total 7 17 24 5 13 18 5 24 29 2 14 16 r Totals Hale___1.. Finals------- 49 j 61 33 f ! 45 i 31 j 51 t \ 15 j 47 1 20201 i; 1 14 41 55 0 s 0 7 7 19 36 55 83 91 174 7 00 2 12 14 18 ; j 54 29 19 68 87 1 066188 Table VII . Over-all Summary Incidence of Hon-neoplastic Changes and Hlstologlcally-Proven Neoplasms Within .Hie Liver and Lungs of AJ Mice Exposed to Vinyl Chloride (Multiple Inhalation Exposure) Exposure ....................... ;....................Dose Level (PPM) ': Hours Exposure : Sex of Animal : Tissue/Response Animals Per Group* : '' . . .In1' t* ' ' : Number Evaluated lepatlc cell necrosis lymphoid cell Inflltfate lepatlc cell lipidosis.. ieutrophll Infiltrate tile duct hyperplasia iranulomatous foci ilnusoidal reticulosis tepatocyst amyloidosis tnglectasls . : RT 46 45 T 4 1 z 2 1 epatlc cell adenoaia holanglocarclnoma 1 : Number Evaluated dema neumonltls ronchlo-alveolar hyperplasia ronchlo-alveolar adenoma ronchlo-alveolar carcinoma : 43 2 15 Control 0 Incidence of Response Vinyl chloride --Trap--------- --TIT x"T"---- r ir 48 78 T 92 48 78 89 66 13 1 2 1 l 1 1 47 76 2 1 16' 56 3 12 90 1 2 68 10 tal includes animals from scheduled sacrificed (8 16, Zti month periods) And SpOrttadei)u> death! ucc 066189 0 Table VII . Over-all Summary Incidence of Non-neoplastlc Ghanges and Histologically-Proven Neoplasms tfithln .The Liver and Lungs of AJ Mice Exposed to Vinyl Chloride (Multiple Inhalation Exposure) - t V L'*1' v " \ ........... .................. Tissue/Response Exposure Dose Level (PPM) Hours Exposure Sex of Animal Animals Per Group* # : ee> ' ' "7 . .s t? * * `` lepatlc cell necrosis lymphoid cell Infllt/ate lepatlc cell lipidosis. leutrophll Infiltrate >11e duct hyperplasia iranulomatous foci * ilnusoldal reticulosis lepatocyst miyloldosls <ng1ectas1s : Humber Evaluated : epatlc cell adenoma hoianglocarclnoma H 46 I 4 1 2 2 1 1 Control 0 10 x 1 'Incidence of Response .... - - Vinyl chloride TBIT 10 x 1 . " F h ~T~~ 48 78 9? 48 78/ 89 6 6 13 1 2 1 1 1 1 1 1 1 Number Evaluated dema neumonltls ronchlo-alveolar hyperplasia ronchlo-alveolar adenoma ronchlo-alveolar carcinoma 43 2 15 47 2 1 16' 3 2i 56 12 90 1 2 68 10 tal includes animals from scheduled sacrificed (8\ 16, 20 month periods) and spontaneous deaths ucc 066190 bypoW Vlnyjrfitjfw/f ffaiQi^r in !'((< *li li la ip* i Ct* \ |. \ *?< .'-it-Vi v ;> i c >J j 50p|*HA loo C* OH+ro) SOO pjpt-i * o Cottfro I M T.r>i m f , r.ri h r :T.rTT * r- ~rrvf*7 OHtft o jo a i'l l * T n r a US cn L - r>-- C on I I 3. .? D MonWiS 8" fl o o Mcni 13 TT tfTM. lfi$ XO | 43 J u 3 5* O1 I A to 6 {i. a : 3 -x i t 3t (X7 63 6 ; 6 /X 14 21 /O i A- io S'? 47 O / 9 J__7_ !o I. 14 J |4 3 s 19 44 63 16 ! II 17 19 I 4/ 70 17 II ZB 4? 8T 33 3X Is 63 7f'137 ai zo 41 87 &* 172 lO IS" 4S' iro /5*9 . 9-1 + JT l* 066191 oc o I 1:u>.Table XI. Over-all-Summary Incidence of Non-neoplastlc Changes Within The lungs of Fischer Rats Exposed To Vinyl Chloride. Single Inhalation Exposure sue/Response Exposure Dose Level (PPM) Sex of Animal Animals Per Group* : Control :0 :H T : 89 74 L :Hymber Evaluated ironchopneumonla vn t Incidence : 85 26 67 10 : 30.6 14.9 ' Incidence of Response Vinyl chloride 50,000 F 5.000 H 505 --------- 50" H------ T n--T 86 87 83 93 87 100 90 91 * 80 77 80 87 85 95 80 74 45 13 13 , 10 15 3 28 3 56.2 16.9 16.3 11.5 17.6 31. 6 35.0 4.1 . Total Includes animals from scheduled sacrifice (8, 16, and 24 month periods) and spontaneous deaths. 066192 oo V * A-' ' '+ * rrff 1 c< Organ riod Tissue eduled Luna months Liver Kidney Stomach Other* Total nonths Lunq Liver Kidney Stomach Other* Total Months Luna Liver * K1dney S tomach Other* Total 50,000 ppm HF 00 00 00 00 20 20 20 0 0 0( 0 0 0 22 42 02 |3 00 01 20 28 21 3* Total 0 0 0 0 2 2 2 0 0 0 * 6 2 It 0 1 48 55 5,000 ppm H F Total M 0 00 0 0 00 0 0 00 0 0 00 0 0 00 0 0 00 0 0 00 1 0 0o 3 0 00 0 0 00 0 5 1 6 12 5 1 6 13 0 0 0} 2 _5 8 0 0 01 01 10 34 49 83 70 37 52 89 82 500 ppm F 0 0 0 0 0 0 0 0 0 0 0 0 __ 3 4 0 0 30 37 Total 0 0 0 0 0 0 1 0 0 0 12 13 12 1 0 100 119 H 0 0 0 0 0 0 1 0 0 0 4 7 1 *i 0 0 54 44 50 ppm 0 ppm (control) F Total H F Total 00 0 0 0 00 0 0 0 00 0 0 0 00 0 0 0 00 0 0 0 00 0 0 0 0 10 00 0 00 0 00 0 0 0 0 0 0 0 0 0 0 4 II 3 0 7 II _ 3 2332 3 12 ? 1 00 1 0 14 14 _s_ 10 1 000 1 1 22 74 47 23 70 27 91 40 27 87 t o ucc 066193 n VP ^UtiWBUIIPIp y|x^ctl -)o Yi>i^) C'Jcy'*1* &hivtd*+r (' *^l1- j.4f 1 n rV.ow.'-c j ^17 I-hr I li loti on Cypn^ti to Vi "l 1 CUot >d ;/CVi *~hs McuH1: 50 pp*" X lOO M P Ti-Tvl , O O C.o rO ! jroopps-x IO M tr 1 i r Iv~ I! O o o . __ t1i (> . --- I o fo r" Co n't' n 1 p < t * i'l '` O o *> o 1 3, i. , Mfc-if; M 6 oc *> V11... * t, * ** ' ' "* a Hi 5/ V S3, -- 1 --' SI 5^ 24 i f -2 ; .1. i~Y Totals VC M Kf 1 P7 1 Coitfrc i___ fi,.! , 1; o r> I1 o .............. - "1------ -------- oo m ZA- 17. 11 ? /3 *0 s*r 1 'iCC iHj o oo dO o O1 1 i i i." C C* 1 c- on\li * ro \$r A 1 \0 \ n 0 c> IS n 4- 43! oiiUi 43 U " 2f/ t/ 42 7/ //3 *9 r/ oc. S5~ 1/4- /o/ S iu! tt 0 tu S</ "+ /ot 12X \oS >1 16 (, 0.?0 Zl z '7.0/ . 1 * I- 066194 coo n*'ifl'T opwwwn1 !"> will ..... . Tf T 13 V ucc 066195 ^|rr|f|f* Period 8 Honths . Tissue Luno Liver Kidney Stomach Other* Total 16 Honths / 26 Honths , Luna Liver _ Kidney Stomach Other* Total Lung Liver Kidney Stomach Other* Total I * 1 I'* >1 ii< . Scheduled Sacrifice 50 PP*" x 100 Control H F Total H F Total 500 Ppm* tttt^ H F Total 0 0_ 0 0 0 0 0 o 0 0 0 0 00 n0 00 00 00 00 0 O 0 0 0* 0 0 0 0 0 0 0 00 0. n 00 00 0l 01 0 0_ 0 0 1 1 0 0 0 9 0. 0 0 0 n 0 0 n 0 ____ 0__ . _0_. _ 0-. . 0 _o 0 0 o. 0 0 0 1 2 2 0 0 00 0 0 0 0 0 8 10 18 6 15 819 8 10 18 6 1 5 10 1 II 1 0 11 12 626 7 2 9 2 3 5 to 1 11 0 0 00 00 2 0 2 0 0 00 0 0 0 0 0 35 61 76 29 25 56 26 68 96 63 63 86 32 29 61 62 71 113 Control Hf 00 00 00 00 00 00 0... 0 0 0 0 0 3 5 0 1 60 69 0 0 0 0 0 0 0 6 0 0 23 27 Total 0 0 0 0 0 0 0 n_ 0 0 0 0 3 9 0 1 fl3 96 A. W Table XXII. Percentage of Stillborn Upus In the VCM Three-Generation Study Control ' f1 {ration Total* Pups Born 195 Total Stillborn 1 t Stillborn o.sr Total Pups Born 202 h ration 1239 0 0.00 234 f3 TatIon 225 2' 0.89 204 J 50 DDffl Total *t Stillborn Stillborn 5 2.48 .________ 500 DDffl_______ ) t Total Pups Born Total Stillborn 184 3 X Stillborn 1.63 i | j 2 0.85 255 2 0.78 | t 5 2.45 265 3 1.13 066196 <o_ o Table XXIV. W Numbers* Sex, and Heights of F^ Generation e Total Number of Pups t Average Height (Grams) PS ys Conitrot 50 ppm 500 ppm Control 50 ppm Male Female Jfrle____ Female____ -Male____Female.-- Hale___ Temale..- , Male Female . 1 120 119 114 118 123 130 6.38 6.13 6.55 6.16 500 ppm Male Female 6.52 6.18 4 118 119 114 117 122 130 9.70 9.13 9.82 9.21 10.00 9.27 7 118 119 113 116 122 130 14.38 13.85 14.57 13.45 14.72 13.97 _i 1 14 118 119 113 116 122 130 27.77 27.26 28.10 26.15 28.80 27.44 i l a `118 119 113 116 122 130 40.89 40.57 41.54 38.67 42.93 41.20 i ^ 3 066197 oo I Table XXVI. Viability, Survival, and Lactation Indexes In a Three- Generation Study of Reproductive Performance After Exposure of the Fq Parents to VCM Gas. Low Dose High Dose Generation' Control 50 ppm SOO ppm Viability Index F1 F2' 100 99.2 100 * 99.7 99.4 99.6 ' F3 100 ` .100 100 Survival Index Diy 21 Lactation Index F1 F2 F3 F1 F2 F3 98.5 99.2 99.6 * 98.5 100 99.6 99.5 98.7 99.5 99.5 99.1 99.5 Viability Index * Day 21 Survival Index Lactation Index Ho. of pups alive at Day 4 x 100 No. of pups born alive No. of pups alive at Day 21 100 No. of pups born alive * ,uu No. of pups alive at Day 21 No. of pups alive at Day T * ,uu Banerjee, B.N., Course Director, Teratology-Principles and Procedures Related to Fetal Development. The Center for Professional Advancement, Somerville, New Jersey. September 1974. Course Notes. 99.4 99.6 97.3 99.4 100 97.3 t?5 ucc 066198 'Figure XVIII Control - 8 months FIGURE IECESD Cbntrol hepa.tocj'te morphology with normal appearing endothelium adjacent. X5,000. Negative #198,063 t ucc 066199 Figure XXII Controls - Multiple Exposure - 16 months post-exposure FIGURE LEGEND Hepatocyte contains nunerous dense bodies and Upoftirf^n granules, deft-like white spaces in dense bodies may represent crystalline material extracted during processing. X5,000. Negative #197,157 ucc 066203 Figure XXIJI Multiple Exposure - 16 months post exposure FIGURE LEGEND - _____ Indented nucleus at center of field consistent with aAnr>raTg-tnrfTri Cell at upper left is necrotic and shows mitochondria with high amplitude selling and flocculent densities. 25,000. * Negative #197,434 T Figure XXIV Controls - 24 months FIGURE IIGEVD Normal appearance of hepatocyte la this control STO'S** X5.000. Negative #200,298 ucc 066205 .. * Figure XXV VF77 67-71 ALES * ' 10 WEEKLY DCPOSinCS TO PPM V^iYL GILCR1DE POST EXPOSURE 106 WISCS * * * , General Sunnary of Findings! Qianges within bepatocytes included increased lipofuchsin granules and endoplasmic reticulun dilatation with a material of low electron density filling endoplasmic reticulun cistemae. in addition/ bile canaliculi frequently slicked distended lvj.xsns with Mrs cimplication of * the plasna membrane at this site. Non-hepatocytie changes included enlarged Kupffer cells with abundant lysosoraes and dense bodies and a mononuclear infiltrate into hepatic porcnchyuia. *t ucc 068206 Summary of Comments by Robert H. Harris at the April 4 Meeting We have analysed the CPSC vinyl chloride study by using methods that employ time-to-tumor data to calculate the car cinogenic potency (TD50) of the compound. The TD-q is the daily dose (mg/kg) required to reduce the probability or being tumorfree by 50% when given over a standard life time (24 months in mice and rats). The statistical methods employed used loglikelihood techniques. To date, we have analyzed only those sites with a suggestion of a treatment-related effect based on summary data. For the experiments employing single 1-hour administration over the dose range 50 - 50,000 ppm, vinyl chloride-caused lung alveolar/bronchiolar adenomas or carcinomas in both male and female ICR Swiss mice and liver adenomas or carcinomas in female ICR Swiss mice; in Fisher rats, vinyl chloride caused an increase in adrenal pheochromocytomas in both sexes, which can be considered only a suggestion of a carcinogenic effect since this site is known to have shown a variable response in historical controls. In the multiple exposure experiments, exposure to 50 ppm (1 hour x 100) caused lung alveolar/bronchiolar carcinomas in female. A/J mice, but not in male A/J mice or in Fisher rats of either sex. At 500 ppm (1 hour x 10), vinyl chloride produced lung alveolar/bronchiolar adenomas in both male and female A/J mice, .lung alveolar/bronchiolar carcinomas in male A/J mice, but it failed to produce tumors in Fisher rats. It was evident from our quantitative analysis, that for the same lifetime cumulative dose, vinyl chloride produced a con siderably larger carcinogenic effect when administered at higher doses over short periods of time (500 ppm, 1 hour x 10) compared to lower concentrations administered over longer periods of time (50 ppm, 1 hour x 100). Furthermore, based on the experi ments with ICR Swiss, mice and A/J mice, vinyl chloride was more potent as a carcinogen than was indicated from previous'bioassay tests published in the literature. ucc 0662