Document Qkmr1NKqkYVeX8xQXpYez5Gp8

VINYL CHLORIDE SUMMARY REPORT msooucnoN oteruohtal procedure C;upcsurs Procedures for Toxicology and Carcinogenesis 1* DOses 2* Exposure and Stapling Technicjue 3. Observation 4. Pathology a. Gross ud Light tlicroseopy b. Electron Microscopy Reproduction Study end Carcinogenicity RESOLIS 4 Toxicology- (single end multiple exposures) 1* Observations During Exposure 2. Observations After Exposure Gross Pathology Light Microscopic Pathology 1. Mice (single exposures) 2. Mice (10 exposures) 3. Mica (100 exposures) 4. Rees (single exposure) 5. Rees (multiple exposures) 6. Rats (49 exposures from the reproduction study) 7. Summery of Light Microscopic Studies Electron Microscopy Study Muleigcneraeion Study in Rees ucc 057778 rv DISCUSSION A* Factors In Carcinogenicity 8. Vinyl Chloride Carcinogenicity Y, CONCLUSIONS VI. Appendix a ucc 057779 Toxicology, Car::nogsr >i*y . and Multiple Exoocuros to I. nrrHODUCTlOfi. The background infornatisn oh vinyl chloride rnonoraer (ycM) with technical details is reviewed in "Scientific and Technical Assess ment Report on Vinyl Chloride and Polyvinyl Chloride**, US Environmental Protection Agency, EPA-500/6-76-0Q4, June 1975. YCM studies in rats and sice reported herein were conducted at the Chemical Systems Laboratory (C3L) under interagency agreement with Consumer Products Safety Commission (CPSC). II, EXPERIMENTAL Pf.QCECL'?SS, A, Exposure Procedures for Toxicology and Carcinogenicity. 1, Poses. Male and female rats (Fischer 344) and mica (A/J or ICR) were totally exposed In one of the following ways: a. One single one-hour exposure at 0, SO, 500, 5,000 or jj|*00 ppm, (Flavor 344 rats, ICR "fee) (Appendix, Table I) . b. Ten one-hour exposures at 500 ppm Cone-hour per day, five days per week fdr 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,'stainless steel dynamic flow chambers of the Rochester type. Construction insured laminar flow and uniform exposure of the test animals. % During one-hour exposure periods four 0.5 ce gas samples were collected at selected times for concentration analysis, A Hewlett-Packard series 583CA Reporting Gas Chromatograph equipped with a dual-flame ionization detector was used for VCM analysis. UCC 057780 The system is sensitive to 50 parts per billion of vinyl chloride. Following exposure the animals were air-washed in the chamber until less than 1 ppm of VC1 was detectable. They were then placed in the animal holding area for the remainder of the observation period (up to 24 months). 3. Observation Animals were observed twice daily far indications of the general heelth. The following signs were noted: mortality, health external sores, subcutaneous masses, alertness, * 'and- activity. All test groups were weighed weekly for the first eight weeks post exposure and monthly thereafter. No blood chemistry or hematology studies were performed. 4. Pathology a. Sross and Light Microscopy _ _ A dftplete gross pathological examination-was performed on most control and exposed animals which died or were sacrificed. Autolysis precluded such examination in a few cases. Light microscopic examination was made of the following tissues: lung, trachea, heart, liver, stomach, small intestine, large Intestine, spleen, kidneys, bladder, bone narrow (sternum), adrenals, pancreas, duodenu, brain (2 sections), pituitary, spinal cord (cervical), skin, thyriod, utarus-ovaries, eye, ear, nose, muscle and bone (femur). Particular emphasis was placed on examination of brain, lung, liver and the Zymbal 9land in the rodent ear. All rodents were'*5 be serially sacrificed at 6, 16, 24 months post exposure. However, the life span of the mica forced some changes in the later times of sacrifice and termination of mouse experiments. For the sinole exposure the planned 16 and 24 month sacrifices wens root2=2-1 by an 18-month sacrifice. The latter is minimum suggested by the National Cancer Institute for cancer bioassays in small rodents. For 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 change was made In consideration of the risk of animal loss through deeth and possible cannabollsm. b. Electron Microscopical Studies. For the electron microscopical studies the follow ng animals were selected at random: Three groups consisting of five males and five female Fischer 344 4 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 from each of'tht 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/Qawley/Wlstar 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 2 consisting of 4S formaldehyde, IS glutaraldehyde in 0.1 H phosphate buffer (E.M. McDowell & 3.F. Trump, Histological Fixatives Suitable for Diagnostic Light and Electron Microscopy, Arch. Path. Lab. Med. 100:405-415, 1975). .After'mincing the tissues were pcst-fixad in IS phosphate buffered 3 ucc 4 057782 osmium tetroxide* dehydrated in graded alcohol solutions, cleared in propylene oxide and embedded In Epon^ (J.h. Luft, Improvements in Epoxy Resin Embedding Methods, J. Biophys. 81ochem. Cytol, 9:409-414, 1961). B. Reproduction Study and Carcinogenicity. Female and female parents Sprague/Oawley/Wistar Rats were exp^ed ta SO ppm or 500 ppm of VCM one-hour per day, five days per week for 10 weeks (49 exposures) before they were mated. (Appendix, Table III) This assureexposure of all forms of male germ cells. The females were exposed durirg all phases of the oogenic cycle. The parents were evaluated for numbers of matings, percentages of pregnancies, fertility and lactation indices. The Fj, F2 and F^ off-spring were evaluated for litter-size, percent of stillborn pups, post-natal growth, viability, survivability and reproduction anomalies. The parenteral generation of Sprague/Oawley/Wistar Rats were .maintained for 24 months post exposure for carcinogenic evaluation. '%_***' III. RESULTS. A. Toxicology (single and multiple exposures). 1. Observation during Exposure, Exposures of rats and mice for one-hour to concentrations of 50, 500, 5,000, and 50,000 ppm produced no remarkable sings of toxicity except for mica exposed to the highest level. Fifty percent of the males * were hyperventilating aftar 45 minutas of exposure; twitching and possible UCC 057783 ataxia were noted. At 59 minutes tremors were seen. Females showed some hyperactivity at 40 minutes and 25' 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 nice and rats at 500 ppm of VCi, nor In rats during the 49 exposures at 500 ppm, nor in either species during the 100 exposures at 50 ppm. 2. Observations After Exposure There were no consistent or dose-related differences between control k i and exposed (single or multiple) nice or rats in: death rate, (Appendix, Fig I IX, Inclusive) toxic signs, gain In body weight. (Appendix, Figs X-XVIII Indus 8. Sross Pathology There wes a suggestion of a higher frequency of masses In the | lungs and livers of nice 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 IC3 nice exposed once to concentrations of 50, 500, 5000 or 50000 ppm shewed the following chanc * attributable to VCM. (Appendix, Table IV-VI, Inclusive) The development of adenomas Increased with exoosure to higher dose levels of vinyl chloride: control - 12/120 or IQS 50,000 ppm . 45/137 or 32.85 ' 5,000 ppm - 24/143 or 16.3S S00 ppm - 18/139 or 12.95 50 ppm - 14/139 or 10.15 Progression to carcinoma was minimal: ucc 057784 control - 0/120 or 05 50.000 ppm - 3/137 or 2.25 5.000 ppm - 1/143 or 0.75 500 ppa - 1/139 or 0.75 50 ppm - 0/139 or OS Pneumonitis was evident In all animal groups which were exposed to VCM in doses of 500 ppm or more. 2. Mice flO exposures) Changes attributable to YCi In A/3 mice exposed ten times at SOQ ppm . examined at 8,16 and 20 months are as follows (Appendix, Tables VII-X, 4 Incluslvt The Induction'of pulmonary adenomas: controls - 31/90 or 34.45 500 ppm - 124/166 or 74.75 Progression to malignancy (carcinoma) in the test group was greater than In the controls: controls - 3/90 or 3.35 500 ppm - 22/166 or 13.35 3. Mice (100 exposures) Marginal Increases in the occurrence of adenomas of the lungs were attributable to VCM in A/J mica exposed 100 times at 50 ppm and evaluated at 8, 16 and 20 months. (Appendix, Tables YII-X, Inclusive) controls - 29/34 or 34.55 50 ppm - 65/158 or 41.15 Progress to malignancy (carcinoma) was apparent: controls- 2/84 or 2.45 50 ppm - 7 n58 or 4.45 UCC 057785 Single Exposure (ICR Nice) Control 50,000 PPM 5,000 PPM 500 PPM 50 PPM Summary of Pulmonary findings Vinyl Chloride Inhalation Pulmonary Adenomas (06 10 Ho. Sacrifice) 12/120 45/137 24/143 10/139 14/139 10.Ot 32.04 16.04 12.94 10.24 - Progression to Cardnomnn (lit Ho. iSacrifice) 0/120 3/137 1/143 1/139 0/139 0.04 2.24 0.74 0.74 0.04 Multiple Exposure (A.d. Mice) Controls 500 PPM x 10 Controls 50 PPM x 100 Pulmonary Adanomaa (0,16 C 20 Ho. Sacrifice) 31/90 124/166 34.44 74.74 29/04 65/150 34.54 Progression to Carcinomas (IS * 20 Ho. Sacrifice) 3/90 22/166 3.34 11.34 2/04 7/130 2.44 4.44 ucc GO 4. Rats (fingle 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, SCO, 5000 or 50,000 ppm. (Appendix , Tables Xl-XIV, Inclusive) 5. Rats ^multiple exposures) No changes attributable to VCM were apparent in any of the tissues evaluated mi;roscop1cally at 3, 16 or 24 months from Fischer 344 rats exposed ten tires at 500 ppm or 100 times at 50 ppm. (Appendix, Tables XY-XVII, inclusive) '" 6* Rats (49 exposures from the reproductive study) t The following histological observations were made 24 months past exposure in Sprague-Oawley/Wistar rats which had been exposed 49 times at 50 ppm or 00 ppm of VCM. (Appendix, Table XVII) ^ Iteoptestfc and non*neopTast1c 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 alterations may be part of a spectrum capable of progressing to the formation of neoplastic nodules. 7. Summary of Light Microscopy Studies. The carcinogenic, or possible related changes (eosinophilic foci) attributable to exposure of VCM in rats and mice are sunraarlzed in Table 1. S=e~=t UCC ___________ ___ 057787 Table 1 VINYL CHLqfl|P STUDIES eriital U|> 1 A* C* A* 0* 0* C* A* A* PPM ' ---------50,000 (1 hr/day) - 1 (ppm-hrs) 50,000 SPEClES/NUHDER EXPOSE ICR Mice Fischer Rats 100 176 500 49 24,500 Sprague-Dawley/ HI star Rats 49 5,000 500 controls 1 /_ '10 5,000 ___ 5,000 ICRMice Fischer Rats AJ Nice Fischer Rats 100 100 100 100 50 100 controls 5,000 AJ Hlce FI seller Rats 179 100 50 49 2,450 Sprague-Hawley/ Ulster 47 500 1 500 ICR Hlce 100 Fischer Rats 190 50 1 50 ICR Mice 100 Fischer Rats 100 00 0 ICR Mice 170 AJ Hlce 190 SD-U Rats 45 * Fischer Rats 371 TOTALS . 3039 * Controls - A, 0, C ti RESULTS 33% adenomas negative Eosinophilic changes 16.OS adenomas negative 74% adenomas negative 41% adenomas negative Eosinophilic changes like controls negative like controls negative 0. Electron Microscopical Sesults. 1. General. In general, these studies indicate that exposure to vinyl 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 aarcinoma was seen In oie male Fischer rat which had received tan exposures of 500 ppm. Lymphosarcoma was noted in one female Fischer rat which had received a single exposure at 00 ppm. Since these were individual eases, 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. Z. " Swara! 8"Hnth Recovery to Single Exposure . 50j_ 500, 5000, 50,(Mo ooa-hr) of Vinyl Chloride in Flscnsr Rats. a. Alterations from control (Fie. XVIII) occurred in all treated animals at each concantration. b. Changes were less severe In female animals. c. Hepatoeytic alteration Included lipid accumulation (Fig. XIX), Increased dense bodies (Fig. XX), llpofuschln granules (Fig. XX) and residual bodies. These are an Indication of cytoplasmic sublathal Injury. tion. d. Alteration was incremental with increasing exposure concentra jo. Most severe changes Involved cellular necrosis with subsequent phagocytosis by Kupffer calls# figure XXI, (seen in single and multiple exposures) 9 UCC 057789 f. Extruded areas of hepatocyte cytoplasm (in bleb formation)(ri;. z; may indicate a means of removal of altered portions of cells. 3- a. Changes were seen in male and female treated animals. (Fig. XXI) b. Less alteration was encountered in female rats. c. Cellular changes was greater than that seen In single josa animals. d." Alterations involving hepatocyte nuclei, not seen In slgle dose animals, were encounttred in males of this group. 4. general Conclusion of 16-Month Recovery After Single Exposure T5ty, 500, 5Q6o, 56.000 ooct x 1 nr) to vinyl Chlor^ce ir> Fiscner Rats. a. Normal morphology (Fig. XXII) was noted after IS months in the Tower exposure concentrations.' When compared to the alterations in the 3 months in the 8 months animals, the access recovery period appeared to be sufficient attainment of control morphology. b. When changes In controls were subtracted from those In treated animals, the most significant finding was hepatocyte necrosis in high dose males. a. Electron microscopic evidence supportive of a diagnosis of hepatocellular carcinoma was seen in one male given 10 doses of 500 ppm vinyl chloride. (Fig. XXIII) b. Other changes included cleft-like spaces In hepatocytes and Kupffer cells. These were Interpreted as age-related changes In hemoglobin/ hemosiderin metabolism. e. Changes were mors severe in males. 10 4 UCC 057790 (S0, SuG. 5000. 50.COO ocz:) Vinyl Chi onge In r'iscner ?S'%. i. Age-related changes Including formation of cleft-like spaces (possibly related to hemoglobin/hemosiderin), inflanraatory infiltrate (pericholar. 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. 6eneral Conclusion to 24-Month Recovery After Multiple Doses of Vinyl Chloride in rischer Sacs. " 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(Fig. 8. General Conclusion to *9 Exposures for 1 Hr at Daily Intervals fallowed by 2<( Month of Recovery (50 and oflQ acm> tSoraoue/ TSwley/Wistar kats). a. Age-related non-specific change was encountered in all groups. ,* b. Most advanced changes were related to 500 ppm group of male rats In which call swelling and platelet aggregation were seen. 2. Multi generation Study in Rats (Seracue/OawleyAH star).1 No consistent changes attributable to VC1 were found in FQ parents which were, exposed to 50 ppm or SCO 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, Fj, and Fg offspring were evaluated for litter site, percent of stillborn pups, post-natal growth, viability, survivability and reproduction anomalies. (Appendix, Table XIX - XXV , Inclusive) Electron microscopical examination of the parent rats which were he for 24 months after the 49th exposure revealed age related changes, cell swell in; and platelet aggregation but no tumors, (Fig-. XXV). n 4 ucc 057791 IY. 01 SCISSION. A. Factors In Carcinogenic!ty. Theoretically, a single molecule of a carcinogenic substance may produce a cancer-if it is not destroyed in the body before it reaches a suscept ible body cell, if it makes a carcinogenic biochemical combination (hit") with the cell, if this combination is not repaired, if the cancer cells are not de stroyed by the Immune system, and If other host factors are favorable to carcinogenicity. On the other hand it may be assumed that not every molecule will make a carcinogenic "hit", that some "hits" will be repaired, and some "hits" may not develop Into tumors because of unfavorable host factors, and In some situations the cancer cells may be destroyed by the bodies Immune system. i The higher the dose rate the-greater the number of hits and the greater the freguency of tumor production. The above considerations suggest the existence of "no effect" doses, threshold doses, and dose response curves which have the hockey stick shape d^cribed by Bryan and Shimkin.4 These considerations have been discussed for radiationS fi and chemical carcinogenesis7'*&8 by numerous authors. The Food Protection Committee, Food and Nutrition Board of National Q Academy of Sciences - National Research Counicl noted that dose-response re lationship applied to carcinogens. The higher the dose, the greater Is the incidence of response and the shorter the time required to elicit the response. This relationship has been reported for 1,2,5,6,-dibenzoanthracene (DBA)4, 20-methylcholenthrone (MC)1^, and CMBA plus croton oil p-dimethylaminoazo- benzene13-, and carbon tetrachloride. 14 Oose response curves have been given . for ultraviolet light16 and ionizing radiation.16,17. There are non-tumorigenic levels of'exposure to carcinogens for given experimental conditions. Carcinogens do not produce cancers in all . exposed animals. In bioassays, the lower dose levels sometimes do not produce tumors while higher dose do produce tumors.11,1^*16 12 ucc 057792 B{.WW-W The possibility is recognized tnzt "no effect1' 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 tuoori genic doses of radiation has been adopted. The federal Radiation Council13 stated that for occupationally exposed personnel the accumulated dose of radiation to the whole body, head, trunk, active blood forming organs, gon*ds or lens of the eye shall not exceed: 1.. In any calendar quarter, 1.25 roentgen equivalent manual (ran) 2. Total lifetime dose of 5 (ff-18) rem where M equals the present age In years. 4 8. .. Vlnvl Chloride and Cardnooenlcity. Mai toni described a dose-response relationship for the carcinogenic effect of vinyl chloride in animals. The neoplastic response was affected by the length of exposure.13*20 Lee et al.,21 noted that the Incidance and severity of tumors increased with the concentration of VC and the length of exposure. The above stataents indicate tha^the total dose (concentration \ X exposure time) may be of Importance in the carelncgeniclty of vinyl chloride. Total Inhaled dose can be approximated by the Haber concept.22 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 m) X t (time in minutes). The concentration can be expressed also In part per million (ppm) and the tine 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. 13 ucc A rough calculation of total dosagos has been made for some of the data of Mai torn' 19 ' 20 ; lee at al 21 Viola et al., 23 Caputo at al.. 24 ., 25 and Keplinger et al. These Ct calculations are sussarited as follows; MALTONI STUCISS 19,20 Test an BTZ BT6 ' BT7 Species rats rats .rats rats 8T4 sice *K * tnousand lOGQ) Results (carcinogenesis) no effects at S23C* ppn-hrs negative at 17K, 85K and 170K ppm-hrs positive at 850K, 20G0K; 3000K ppm-hrs positive at 24.500X ppm-hrs ' negative at 52X, 260K. 52QK, 2SOOK, 62001 ppm-hrs positive at 10,400 ppm-hrs negative at 3QK ppm-hrs positive at 1SOX* 3Q0K, ISOOX, 3600K and BOOK ppm-hrs LEE st al.. Studies ^ Test Species Results (carcinogenesis) Table 1 Table 2 Table 3 nice nrica nice All tests essentially negative below 48K* ppm-hrs and positive at 48K ppm-hrs and above *K * thousand (000) In the studies of P.L. Viola* A. Bigotti and A. Caputo^ tumors were seen in rats which had been exposed to 30,000 ppa of vinyl chloride four hours per day, five days per weefe for 12 mcnths. The total dose (Ct) was 14 = UCC 057794 23,200.000 ppm-hrs. A. Caputo, P.L. Viola and A. Sigotti^ 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; 5C0; or 50 ppm. The total dose (Ct) for the 50 ppm was 43,000 ppn-hrs. Ho tumors were produced at this level. The total dose for 500 ppm wes 430,000 ppn-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 wes 7,200,000 ppm-hrs. M.L. ICeolinqer et al.exposed rats, hamsters and mice to vinyl chloride. Only the data on mice wes 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 56,COO ppm-hrs. This Ct and all higher ones did produce tumors In mice. W ______ _____ _ M, . _A ..J Mil iJ - - /* L * * Species ICR Mica * Tabel 2 Results (carcinogenesis) 50 and 500 ppm-hrs - negative 5000 ppm-hrs - borderline positive 50,000 ppm-hrs positive A/0 Mice 5000 ppm-hrs - positive Fischer Rets 50, 500, 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 15 :=^. UCC 057795 50,000 ppm-hrs. The maximum response in the rats was the appearance of eosinophilic calls which night suggest a pre-canesrcus change. The CPSC VOi tests in mice indicate that increased frequencies of adenoma may appear in this species at Ct's of 5.000 ppm-hr and above. This total dose for carcinogenicity Is In general agreement with Lee etal. ,21 (48,000 ppm-hrs) and Maltonl 19,20(between 30,000 ppm-hrs and 150,000 ppm-hrs) and the other Investigators.23'24*2S in general, in orders of magnitude carcinogenic tendencies are seen in some species at Ct's of 5,000 to 50,000 ppm-hrs. Definite carcinogenicity appears in both rats and mice at Ct's of 50,000 to 500,000 ppm-hrs, and high incidences of carcinogensls are noted fn mice and rats at Ct's of greater than 500,000 pps-hrs. The previous studies19'20'21*23,2*.25 and present CPSC study are In agreement as to the dose-time relationship for carclnoganesls related to vinyl chloride exposure. All of these studies considered collectively may TM*1cata that there may be a life-time total dose for vinyl chloride below which carcinogenicity Is not likely to occur. This "no cancer" Ct seats to be below 500 ppm-hr for mice. For histological confirmed carcinogenesis the "no cancer" Ct in rats appears to be 750,020 ppn/hrs. The results of the light or the electron microscopical study did not reveal carcinogenic responses in rats at Cts from 50-50,000 ppm-hrs. However, Ct's of 2450 ppm-hr produced eosinophilic loci but no tumors in rats Iri the CPSC tests. 16 ucc 057796 As an additional consideration in the total dose concept, Ct's of 5000 ppm-hr produced increased incidences of adenomas in .-nice 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 toneept have been described for other carcinogens. It Is difficult to relate these animal studies to man. Qata on vinyl*chloride exposure in plants have been limited. However, acute dltzyness. 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 minion were experienced at times. Air monitoring of one group of plants firing 1950*59 indicate that time-weighted (S-hr) average exposure were 120-38$ ppm. (This would give dally Cts of 960-3030 ppa-hrs). Peak exposures probably exceeded 1000 ppm. This may not have been typical of all polyvinly chloride plants/1) 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/1) The time-weighted threshold limit value of the American Conference of Government Industrial HygiwSt for 1977 is 200 ppm. There Is a notice of intended change . The Environmental Protection Agency has established the following emission limits for vinyl chloride: (1) formation and purification processes is 10 ppm, (2) emissions from eoulpment preceding and including the 17 * ucc 057797 stripper in the plant process flow is 10 ppts, (3) amissions from equipment following the stripper are to be controlled by stripping dispersion resins to 2000 ppm and other resins to 400 ppm. Assuming that man is as sensitive as the mouse or rat the car cinogenic effects of vinyl chloride might be expected after an accumulated Ct of 5000 ppm-hrs or 150,000 ppra-hr respectively. Based on the high pollution values given above (1000 ppm-hr per day) carcinogenic doses could have been accrued in one week (mouse) or 30 weeks (rat). At the TLV of 200 ppm (dally Ct of 1600 ppm-hr) the time to accumulate a carcinogenic dose would be 3 days (mourtej or about 19 weeks (rat). Comparable accumulation times at 10 ppm (80 ppm-hrs per day) would b* about 12 weeks (mouse) or 375 weeks (rats). ' ** The calculations are based upon a five day working week. 18 UCC 057798 IV. CONCLUSIONS. A. Except at the highest concentration, SO,COO ppm, where possibly anesthetic-type effects were seen vinyl chloride produced no pharaaco-toxic (excluding pathology) signs In mice or rats during or after exposure. 8. 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. 0. Vinyl chloride produced eosinophilic changes in rats but no frank (light microscopy) carcinogenesis. . 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 Comnlsslon tests a^e fn agreement with results, of previous studies.1 *5,6,9,10,11 ,13,15,15,17 T. The carcinogenic effectiveness of VCM depends upon concentration 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.^3,15,16,17 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.*'*,*1<1*11 4. Carclnoganlc effects of VCM were seen In mice at total doses (Cts) of 5,000 ppm-hrs and above?**11 ucc 051199 1. Scientific end Technical Assessment Report cn Vinyl Chloride and Polyvinyl Chloride. US Environmental Protection Agency, EPA-6QO/5-75-OC4, June 1975. 2. E.M. McDowell & B.F. Trump. Histological Fixatures Suitable for Qignostic Light and Electron Microscopy. Arch. Path. Lab. Med. 100:405-414, 1975. 3. J.H. Luft, Improvements In Epoxy Resin Embedding Methods, J. Blophys. Blochem. Cytol. 9:409-414, 1961. 4. Bryan, W.R., and M.B. Shlmkln. Quantitative Analysis of Dose-Response Data Obtained with Three Carcinogenic Hydrocarbons in Strain C3H- Male Mice. J. Natl. Cancer Inst., 3:503-531, 1943. 5. J.8. Storer. Radiation Carcinogenesis, Chapter 16, pp 453-433 in Cancer 1. Etiology: A Comprehensive Treatise. Editor: F.F. Becker. Plenum Press, N.Y., London. 1975 *" < . A.C. Upton, J.L. Randolph and J.W, Conklin. Late Effects of Fast Neutrons and Gamna-Rays In Mice as Influenced by the Cose (Ute of Irradiation: induction of Neoplasia, Radiation Res. 41:467, 1970. 7, U. Safflottl. Identifying and Defining Chemical Carcinogens, pp 13111362. Origins of Human Cancer, Book C. Human Risk Assessment. Editors: H.H. Hiatt. J.O. Norton, J.A. Winston. Cold Spring Charter Conferences In Cell Proliferation. Yah 4. 1977. Cold Spring Charter Laboratory. 4L T.H. Maugh II, Chemical Carcinogens: How Dangerous art Low Doses? lienee, 202:37-41. Oct 1978. j., . Problems In the Evaluation of Carcinogenic Hazard from the Use of .-cod Additives. Publication 749. The Food Protection Committee, Food and ."utrition Board of National Academy of Sciences - National Research Council. December 1959. 10. Horton, A.W., and Oorothy T. Denman. Carcinogenesis of the Skin. A Re-examination of Methods for Quantitative Measurement of the Potencies of Complex Materials. Cancer Research 15:701-709, 1965. 11. Poet, W.C. Effect of Carcinogenic Oosage and Ouratlon of Exposure on Skin-Tumor Induction In Mice. J. Nath Cancer Inst., 22: 19-44, 1959. 12. Graffl, A. Untersuchungen uber den Mechanisms dir Carcerogenese und die Wlrkungswelse cancerogeftlfl* Raize. Abhandl. deut. Akad, Hiss. Berlin, 53:1-27, 1953. * 13. Qruckery, H. 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The Value of Predictive Experimental Bioassay In Occupational and Environmental Carcinogenesis. An Example: Vinyl Chloride. Amblo. 4:18-23,-1975. 20. C. Maltoni and G. Lefealne. Carcinogenicity Assay of Vinyl Chloride. Ann. NY Acad. Scl. 248:195-218, 1975. 21. C.C.. Lee, j.c. Bhandarl, 4.M. Winston, W.8. House, R.L. Olxon and J.S. Woods. Carcinogenicity of Vinyl Chloride and Vinylidene Chloride, J. Tox. Environ. Health-4:15-30, 1978. *%2. F. Haber, "Funf Vortrage aus den Yahrtn 1920-23": No. 3. Ole chemle 1m Kriege: No. 5. Zur geschlchte des gaskampes, Juluis Springer, Berlin. 1924 - reference through Prentiss: Chemicals in War, McGraw-Hill Book Company, Inc., New York, 1937. 23. P.L. Viola, A. Blgottl and A. Caputo. Oncogenic Response of Rat Skin, Lungs and 3ones to Vinyl Chloride, Cancer Research 31:516-522, 1971. 24. A. Caputo, P.L. Viola and A. Blgottl. Oncogenicity of Vinyl Chloride at Low Concentrations in Rats and Rabbits. J. Int. Res. Coouun. 21:1582, 1974. 25. M.L. Kepllnger, J.W. Goode, Q.E. Gordon, and J.C. Colandra, Interim Results of Exposure of Rats, Hamsters and Mice to Vinyl Chloride. Ann. NY Acad. Sci. 248:219-224, 1975. 25. Threshold Limit Values foe-Chemieel 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 81-National Environmental Standards for Hazardous Air Pollutants, Stand ard for Yinyl Chloride, Federal Register, Vol 41, No. 205, Thursday, Oct 21, 4 21  fible I. Slfljjle (uosurA Schedule of AnUuls To VCH*^ Species Fischer Ret f Sex Oose lP Exposure date m_____ PH . H 50 3/4/75 . 500 3/11/75 5000 3/10/75 SOOOO 3/25/75 F SO 500 5000 SOOOO 3/4/75 3/11/75 3/10/75 3/25/75 H ICR House - F SO 500 SOSO 50000 3/4/75 3/11/75 3/10/75 3/25/75 SO 500 5000 SOOOO 3/4/75 3/11/75 3/10/75 3/25/75 Rat ` H Ney/Coot. F Mey/Cout/ House M Nuy/Coiit. F Hoy/Coat. Exposure eroup sliefsl * 90 90 05 90 90 100 95 80 90 90 90 90 90 90 90 90 92 79 02 00 Aflu at time of exposure weeks 15 16. 17 lii 15 16 17 10 15 16 17 18 15 16 17 10 15-10 15-10 15-16 15-10 o* APPCHPU Table II Exposure Schedule tcgf AnInals Exposed Repeatedly to VCU Species Sex Dose Fischer Rat U F A/J House u L. V Fischer Rut A/J House U F U F ppM 00 600 60 600 60 600 60 600 Nag. control Nog. control Nag. control Nog. 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) Exposu re dates Prow To 8/27/76 7/7/75 8/27/76 7/7/75 7/7/76 8/27/76 7/7/76 8/27/76 - 1/28/70 7/18/76 1/26/70 7/18/78 7/18/76 1/20/70 7/18/76 1/20/70 - - - NOTE: (c) control tor corroeponding dose above. Exposure Group size( b) Start End -90 86 90 00 00 87 00 00 00 87 00 00 00 88 00 00 60 60 60 60 60 47 60 60 * O J9 60 60 60 50 50 60 Age Start 21 14 21 14 15 8 16 8 21 14 21 14 16 8 16 8 End wka 41 10 . 41 10 :t5 10 26 10 41 10 41 10 :is 10 us 10 APPENDIX Table III. VCHHultl generation Study Fft Parents Group I Compound Air Dose Control (lumber of . Hales 25 II VCH low Dose 25 (SO ppm) - VCM Nigh Oose 25 (500 ppm) Number of Females 25 25 25 H lS is o o o ; 100 Figure I SPONTANEOUS MORTALITY SO PPM A cowrnou 50.000 PPM 5.000 PPM 500 PPM M o n r^ irv icumulativci* Ac? or r-. UCC 057805 100 figure n SPONTANEOUS mortality FEMALE ICR MICE SINGLE dose study VINYL-CHLORIDE MONOMER *<>MMIV |CUMULA?IVf| so. X S3 - v 20 - 10 - T 4 AGS OP Mica (MONTHS! vurm.'n .-y 50.000 s.ooo m; so mi CONTROL :co WM UCC 057806 MORTALITY (CUMULATIVE!* 50,000 PP 5.000 PPM CONTROL O SO PPM 500 PPU UCC 057807 ucc 057808 iJAiivimmai Ainviuori %