Document ykvKo72ONKmbNzj4D598r2MNn

VINYL CHLORIDE CARCINOGENICITY : AVAILABLE SCIENTIFIC EVIDENCE AND CONTROL MEASURES Pr. Cesare MALTONI Direttore Istituto di Oneologia 4 Viale Ercolani I - 40138 BOLOGNA SPI-00347 JUNE 1986 ADVANCE COPY of a publication prepared fc r the Association of Plastics Manufacturers in Europe (APME) J anuary 14, 1936 VINYL CHLORIDE CARCINOGEN [CITY: AVAILABLE SCIENTIFIC EVIDENCE AND CONTROL MEASURES Cesare Maltoni (Institute of Oncology, B ologna, Italy) I) INTRODUCTION The history of viny.. chloride (VC) carcinogenicity re- presented a highlight n the field of carcinogenesis for the lessons it gave, a:nd it was a unique, exciting experience for all people nvolved: scientists engaged in experimental and epideifr iological research, who produced the scientific evidenc , and representatives of Governments, International Agencies Industries and Unions, who prompted regulatory measures an{l preventive actions, The aim of this rep ort is to review that history, to sum marize the present sta e of our scientific knowledge on VC carcinogenicity, give ome references about the preventive measures which have be< n taken, and finally to underline and comment the major essons we have learned. II) GENERAL INFORMATION Exhaustive reviews are available on the chemical and phy sical characteristics, production, uses and occurrence of VC, the exposed popula ions, the pathological effects of the monomer on humans and on experimental systems, and the regulatory preventive treasures (Milby, 1978; Warren et al. , 1973; IARC. 1979; Malt <t>ni e t al. , 1984). Some basic, general information is give n in Tables 1-5. SPI-00348 2- - Ill) RESULTS OF VINYL CH -ORIDE CARCINOGENESIS STUDIES VC has been produced commercially since the end of the twenties, and it is one of the most important compounds of the plastic industry, and one of the petrochemical products synthetized in the argest quantity. However, for more than forty years, neither experimental research, nor epidemiolo gical and clinical nvestigations were undertaken to study and assess its poss ble carcinogenic potential. 1) Viola's pioneering findings and other early observations. A considerabl number of studies were published at the end of the fifti s and in the sixties, reporting the appear ance of a unique syndrome, acro-osteolysis, on workers en- gaged in cleaning polivynil chloride (PVC) polimerization reaction vessels, This syndrome consists of bone changes (osteolytic and s clerotic lesions of the bones of the hands, mainly of distal phalanges, of larger bones and sacroiliac joints), skin chs nges (scleroderma-like lesions),and stri- king vascular ch nges associated with Raynaud-like phenome non. In 1967, P.L. Viola, a doctor at the Italian Solvay factory of Rosigr ano (Italy), attempted to produce acro-osteo lysis on experime ntal animals. A group of 26 3-month-old ma le Ar/IRE Wistar rats was exposed to an atmospheric concen- tration of 30,00C ppm commercial grade VC (99% pure), for 4 hours/day, 5 d sy s/week, for 12 months; the experiment was terminated at 54 weeks. SPI-00349 The outcome of this research was a surprise. Skin tumours developed in the submaxillary parotid region in all of the 17 surviving rats (14 epidermoid carcinomas, 2 mucoepider- moid carcinomas, 1 papilloma); in addition, lung tumours developed in 7 ra ts and osteochondroma in 5. No tumours we- re observed in 25 ontrols killed at un unstated time. T In his first rep ort on the results of 12 months of exposu re, Viola (1970 a) described metaplastic changes in bones, which he conside red to be similar to human acro-osteolysis. The data on care inogenic effects of VC were disclosed for the first time ty Viola (Viola, 1970 b) at the 10th International Cancer Congress (Houston, 1970), and then extensively published in 1971 (Viola et al, 1971). At the same t ime, at the Bologna Institute of Oncology, the cytological examinations of sputa from workers of VCPVC industry, sh owed a high incidence of atypias of the cells of the res piratory epithelium (Maltoni et al., 1974 ) Immediately a fter the Houston report, we communicated with Professor V iola, who kindly put at our disposal the manuscript of hi s extensive report, then in press, plus se veral slides of the tumours. On the basis of his results and material, we reached the conclusion that the tumours described as cut aneous were carcinomas originating from Zymbal glands, a nd that the pulmonary tumours were most li_ kely metastases from Zymbal gland carcinomas. The neoplaStic lung lesion s were in fact morphologically similar to Zymbal gland car cinomas, and all were observed in animals bearing Zymbal gl and tumours. 2) The Bentivoglio (BT) Project SPI-00350 On the basis of Viola's results and of the cytological observation on s puta, a systematic and integrated plan of experiments was started at the Bentivoglio (BT) Research Laboratories of the Bologna Institute of Oncology, The project w as sponsored by the Administration of the Bologna Institut e of Oncology, and by a Consortium of Euro pean Industries: Montedison (Italy), Rhone-Poulenc (France), So 1vay (Bel gium) and ICI (Great Britain). It began in 1971 and lasted for twelve years. The project tudied the carcinogenic effects of VC admi_ nistered by dif" erent routes, at different dose-levels, and for differen t periods, to animals of both sexes, and of various species strain, and age. The finaliti( s of the BT project may be summarized as follows: 1) to detect th< possible carcinogenic effects of VC; 2) to evaluate 1 he full carcinogenic potentialities of VC on different organs and tissues; 3) to detect the most specific target organs prone to the carcinogenic effects of VC; 4) to provide ds ta on the relationship between the dose of VC and the ne oplastic response, with reference to different concer trations or daily dose, length of treatment, and number of treatments; 5) to quantify t he carcinogenic potential of VC, with particular refer ence to low doses; 6) to study the effects of different routes of administration of the c ompound, namely: inhalation and ingestion which are the two main potential routes of human exposure, as we 11 as intraperitoneal, subcutaneous injection, and transplac ental (prenatal) exposure; 7) to investigate the effects of species, strain, sex and age, of the animal 5 on VC carcinogenicity; 8) to provide in formation on the natural history of the most important turn turs, with particular reference to liver an giosarcoma; 9) to produce an r information, important towards the under standing of t lie pathogene tical mechanisms of VC carci- nogenesis. SPI-00351 4- -......- * -r - -- 1 ' . ...- ... The plan of the BT Project, which included more than 7,000 animals, is shown in Tables 6-13. Information on the test compound is given in Table 14. All the anirr als were periodically weighed and submitted to control for the detection of gross lesions. They were kept under obse rvation until spontaneous death. Full necrops / was made on each animal, and systematic histopathology nas performed on major organs and tissues, and, whatever t ae site, on all the pathological lesions (Table 15). VC, on the basis of the BT Project, appeared to be a multipotential :arcinogen (affecting different organs and producing a var.ety of tumours in all the tested species) in animals of both sexes and of different ages, at diffe rent doses, with different schedules of treatment, and by different routes of administration (inhalation, ingestion and via p acenta, and possibly intraperitoneal and subcutaneous in ec tion). In the three treated species, the spectrum of VC corre lated tumours v ried from species to species, and included an ample range c f neoplasias, namely: - in rats (Sprag ue-Dawley and Wistar): malignant mammary tumours (parti cularly adenocarcinomas), Zymbal gland car cinomas, nephr-oblastomas, angiosarcomas, angiomas and fi broangiomas of liver and of other sites, hepatomas, ence phalic neurcbl.astomas, forestomach papillomas and acan- thomas, lung aidenomas, and possibly cutaneous epithelial tumours; SPI-00352 - in mice: mammary carcinomas (adenocarcinomas), pulmonary adenomas (at high percentages with cellular atypias), an giosarcoraas, a igiomas and fibroangiomas of liver and of other sites, and possibly hepatomas, cutaneous epithe1 i n1 - in hamsters: ang:. osarcomas of liver, forestomach papillomas and acanthoma s, acustic duct epithelial tumours, and possibly extrahep atic angiomas and fibroangiomas, cutaneous epithelial tumours, melanomas, and lymphomas and leukaemias. The range of the observed tumours, the relative incidence of the different ty pes of tumours, the incidence of single type, and total neoplasias varied by changing different exp rimental factors such as: concentration or daily dose of VC, schedule of treatment with particular reference to the length of exposure, age, s train, and species of the animals used, and routes of admin istration of VC. The data are summarized in Table 16. There was a good correlation between dose and neoplastic response, particularly when total malignant tumours/100 ani mals were considerei (Table 17). The results of tie experiments testing VC by ingestion are shown in Tables 18-23. When VC was given by ingestion, the range of the tumours produced by the compound was narrower than following inhala- tory exposure. The carcinogenic effect was mainly expressed by the high incidence of liver angiosarcomas (Tables 18, 21). As shown following inhalatory exposure (Table 17), the neoplastic response was clearly correlated to daily doses (in the range 50-3. mg/kg body weight) (Exp. BT 11), also when the compound wis administered by ingestion (Table 20). The results of the experiments on Sprague-Dawley rats treated with different concentrations by inhalation for 52 weeks, and with different daily doses by ingestion for 52-59 weeks, have been submitted to statistical analysis, using the Fisher exact probability test (Maltoni et al., 1930) and the correspondence analy sis (Tassignon, 1980). SPI-00353 Following statistp. cal analysis using the Fisher exact probability test (p 0.05): a) the total number f cancer bearing animals per group were in excess at the doses indicated in Table 24; b) of the nine tumour s considered to be correlated to VC treatment, in the statistically analyzed experiments (mammary adenocarc inomas, Zymbal gland carcinomas, nephroblastomas, li\ er angiosarcomas, extrahepatic angio sarcomas, hepatoma s, neuroblastomas, forestomach papillomas and acanthorr as, and possibly cutaneous epithelial tumours), six appe ar significantly in excess, at least at one dose level and in one sex (Table 24). The Fisher exact probability test at 95% confidence is probably not "sensitive" enough, under the tested experimen tal conditions. In ou:' opinion, there are tumours at lower doses which must be considered biologically correlated to VC treatment (Table 2!>). In the experiment FT 27, no specifically VC related tu mours were observed ir animals that were administered 0.03 mg/kg bw by inges tion (which, on body weight basis, would correspond to 2. 100 mg in a man of 70 kg). Other studies SPI-00354 - Subsequent experime its , on a limited scale, conf i rmed the results of the BT uro ject. Groups of 100 male and 100 female CDI Swiss/ChR mice (ag unspecified) were expo ;ed to 2,500, 200, 50 ppm VC (purity unspecified) in air fo ' 7 hours/day, 5 days/week for 9 months and were observed for an additional 9 months. Fol lowing 8 month's exposure, 49 untreated animals died with tumours, meanwhile no tumours were observed in 200 controls (100 females, and 100 rjaies). VC was found to produce lung adenomas, liver angiostrcomas, and mammary carcinomas. A dose-related carcinogeric effect was evident (Keplinper et 8- - Two groups, each of 12 male and 12 female, 3 month-old. NMRI outbred Albino mice, were exposed to 500 or 50 ppm VC in air for 6 hours, day. 5 days/week. The 500 ppm group was exposed for on! y 25 weeks (due to the poor condition of mice) and the 50 ppm group was exposed for 52 weeks, at which time the experiment was terminated. Groups of control ani- mals were included in the experiments. Under these experi- mental conditions, VC caused, at high and low concentrations, pulmonary adenomas, extrahepatic angiosarcomas, and, at higher concentrations, an increase in mammary carcinomas, and one liver angiosarcoma (Holmberg et al., 1976). Groups of 36 mal e and 36 female,2-month-old,Albino CD mi- ce were exposed to 1,000, 200 and 50 ppm VC (99.8% pure) in air for 6 hours/day , 5 days/week for 52 weeks; at that t_i me, 70, 52, 46 and 38 animals respectively were still alive, Control animals wer e available. VC was found to cause lung adenomas, angiosarc cmas of liver, extrahepatic angiosarcomas, and mammary carcino nas. A dose-related carcinogenic effect was evident for lung adenomas and liver angiosarcomas (Lee et al., 1977 , 1978) . Groups of 36 mal ; and 36 female, 2-month-old, CD rats were exposed to 1,000, 2 30, 50 and 0 ppm VC in air (99.8% pure) for 6 hours/day, > days/week for 12 months, at which time the surviving anima s (72, 70, 58 and 51 respectively) were killed. Liver and lung angiosarcomas occurred in rats treated with 1,000 and 250 ppm. A dose-related carcinogenic effect w as evident (Lee et al. , 1977 ) . SPI-00355 Groups of 62 male and 62 female Wistar rats were exposed to 5,000 and 0 ppm ) C in air, 7 hours/day, 5 days/week for 52 weeks. Tumours ws re observed in liver (hepatocellular car cinoma and angiosarc oma), brain, ceruminous glands, and na- sal cavities (Feron :t al, , 1979 b; Feron and Kroes, 1979) . 9 Small groups of male, 5-week-old, CD1 Swiss/ChR mice were exposed to 6,000, 2 ,500 and 0 ppm VC in air for 5 hours/day 5' days / week for 5 and 6 months. Under these experimental conditions the anirr als were sacrificed between 2 to 37 days following the end of the treatment. VC was found to cause lung adenomas in 26 of the 27 treated animals. None of these tumours were found in the 16 controls. Light and electron mi_ croscpic studies suggested that neoplastic cell originate from type II alveolar epithelium via its hyperplastic form (Suzuki, 1978, 1981 Hehir et al. (19 31, and Unpublished Report with limited circulation) studie i the effects of the exposure to several concentration (50,050, 5,000, 500 and 50 ppm) of VC vapour, administered 1 hour once, on Fischer 344 rats, and in ICR mice. The same total dose, 5,000 ppm, was delivered in 10 (x 500 ppm) or 100 x 50 ppm) times, for 1 hour/day, 5 days per week, on Fische 344 rats, and in A/J mice. Animals of both sexes were use (i. The age of the animals at the start varied from 8 to 21 weeks. The animals were kept under obser vation up to 24 mon ;hs (rats), and up to 20 months (mice), Interim sacrifices \< ere performed at different periods of the experimental biophas e. This study was sponsored by the Consumer Products Safety Comm ission (CPSC) (USA), The most importar t results of this study are : - the enhancement oi total tumours in Fischer rats, following 10 and 100 1- hour exposure to 500 and 50 ppm respectively; - the clear-cut ends'ncement of pulmonary tumours and of total tumours in ICR mic e, following the exposure to 50,000 ppm for 1 hour; SPI-00356 - the enhancement of total tumours and of pulmonary tumours (also of adenocarc inomas) in A/J mice, following 10 1-hour exposures to 500 om.and of total tumours, following 100 T 1-hour exposures t<b 50 ppm. Groups of male arid female Sprague-Dawley rats* of different ages (6, 18, 32 and 52 weeks) were exposed to 940 ppm VC by inhalation, 7 hours/jday, 5 days/week for 24 weeks. In each age group there were 110 to 128 males, and the same number of females. Control groups, which were not exposed to VC, consisted of the same number df males and females, in each age group (Groth et al. , 1981) . All animals died spontaneously, were sacrificed moribund, or were killed at schedule times (3, 6 and 9 months after initial exposure). The Authors summarized their results as follows: "The older the rats were when they were first expo sed, the greater the incidence of angiosarcomas. The incidence of angiosarcomas in the four age groups (from youngest to oldest) in the exposed males 0/37 (0%); 0/44 (0%) in the non-schedules sacrifice groups were: 3/45 (6.7%); and 13/55 (24%). Similarly, for the females, these incidences were: 2/38 (5.3%); 7/47 (15%); 23/49 (47%); and 11/34 (20%). Most of the angiosarcomas were highly anaplastic, primary tumours in the livers that metastasi zed to the lungs. Onljy one agiosarcoma was seen in all the con trol rats; that occurred in subcutaneous tissues. This study demonstrated that older adult animals (in the studied range of ages) and females are more susceptible to the angiosarcoma-in ducing effects of vinyl chloride than young adult animals and males, respectively."! SPI-00357 Four treatment grojjps (80 male Sprague-Dawley rats per group) were treated as follows: inhalation of 600 ppm VC, 4 hours/day 5 da>s / week for 52 weeks; VC, with the same regimen, and 5% ethanol in drinking-w&ter (V/V) (the ingestion of ethanol was begun four weeks prior to inhalation of VC, and continued for life or termination off the study); ethanol, with the same regimen, and filtered air; and filtered air. The study lasted two and one-half years from the first VC exposure. Inhalation of VC induced liver angiosarcomas in 23% of the exposed animals; - i1 - ethanol in addition to VC inhalation increased the incidence to 50%; concomitant administration of VC and ethanol also produced an excess of hepatocellular carcinomas and lymphosar comas. Ethanol, with or without VC, had a strong tumorigenic effect on the endoc ine system. In this model system, ethanol appears to potentia ;e the carcinogenic response to VC (Radike et al, 1981) . IV) EPIDEMIOLOGICAL EVIDELC 1) Liver angiosarcoma Following the eg ly 1973 results of the experiment of the BT project (Maltoni 1974 a; Maltoni and Lefemine, 1974 a, b). in 1974, more than forty years after the introduction of VC in industry, Creech and Johnson (1974) reported for the first time an association of exposure to VC with cancer in man. Three cases of liver angiosarcoma were reported in men who were employed in VC PVC industry, in a single VC polymeriza- tion plant in the U 5A. Further retrospective investigations showed that in prev ous years (precisely since 1955), workers exposed to VC had d ed for liver angiosarcoma, but, in absence of experimental ind cations, these cases were misdiagnosed and not correlated ith VC exposure. In the same and the following years, by reviewing medical records and patholo ical material, on the basis of clinical observations,and by systematic medical screening and epidemio logical investigati ns, other liver angiosarcomas in workers exposed to VC were reported in the USA, as well as in other Countries (Forman e al., 1935) . At present 1191 i\er;angiosarcomas have been reported in dif ferent countries (T able 26). SPl-00358 The high majority of liver angiosarcomas were observed in VC-PVC polymerizati o c plants, and particularly among cleaners nf run - o i <'mo t~; - 2) Other tumours An excess of tumours involving different organs and diffe rent histotypes (othe:N than liver angiosarcoma) has been correlated to VC occupational exposure, starting from 1974 (Maltoni et al., 1984 . These tumours include: angiosarcomas of the duodenum, heart, kidney, and other sites, tumours of the brain and cen tral nervous system (glioblastoma multiforme), large-cell undifferentiated care: nomas of the lung, lymphomas and leuke mias; carcinomas of the biliary tract, carcinomas of the.pancreas, marmary car cinomas in the women, carcinomas of the urinary tract, hepatocarcinomas, and malignant n elanomas. The degree of evidence varies from tumours to tumour s. The most evident correlation is found between VC expos ure and tumours of the brain and central nervous system. V) THE MILESTONES The most important ste ps towards the knowledge of VC carcino genicity, including sped fic oncological research and toxicological pertinent contribut ions, are listed in Table 27. VI) THE MEASURES OF CONTROL 1) Work environment SPI-00359 Until 1973 the Thre shold Limit Value (T.LV) (ceiling) for 3 VC in work-place was 5 DO ppm or 1.300 mg/m . It has been claimed that TLV was i i fact reduced to 250-200 ppm in Ameri can and European facto ries some years before. It must be poin ted out, however, that during that period the concentration in work-place was not submitted to systemic controls, meanwhile, many engineers, workers and medical doctors reported that frequently the co icentration level of VC in PVC polyme- rization unit reached ;he olpnactory level (the not unplea- sant odor of VC can be detected by someone at concentrations as low as 30C ppm, but other people cannot detect it until the gas reaches much h ,gher concentrations). The Occupational Safety and Health Administration (C3HA) issued for the USA an emergency standard limiting VC air le vel to 50 ppm, following the first experimental and epidemio logical investigation: that VC causes liver angiosarcoma and the Maltoni1s report at OSHA (1974 b) that liver angiosarcomas were observed in anima 1 exposed to VC at the concentration of 250 ppm. This standard was then lowered to Time-Weighed-Avera ge (TWA) of 1 ppm, fol lowing the report that VC causes angio sarcoma in animals down to a concentration of 50 ppm (Maitoni and Lefemine, 1975) . At present in the USA, OSHA's health standards for exposure to air contaminan ; s require that an employee's exposure to VC not exceeds an e:. ght-hour time-weighed average of 2.6 3 mg/m (1 ppm) in the wo rk-place air in any eight-hour work shift of a forty-hour vfork week. During any work shift an employee's exposure maj not exceed a ceiling concentration ,3 , limit of 13 mg/m (5 pp m), averaged over any period of 15 minutes or less (US Occ upational Safety and Health Administration, 1974) . In August 1977, the lvalue proposed by the Commission of the European Communities for the member Countries was 3 ppm over one year, for existing and future plants, with an "alarm-value" of 15 ppm, Technological improvement in VC-PVC factories made it possible to fulfill the reqjmired standards. Food. SPI-00360 The Commission of the European Communities adopted a level of 1 mg/kg (1 ppm) : s the amount of VC which can be present in packaging, and C .01 mg/kg (ppm) in foodstuffs packed in PVC (Commission of th e European Communities, 1977, 1978) . The levels of the res idues of VC in PVC used for food packaging and beverage con tainers, and therefore the possibil.1 ty of migration of the m cnomer from PVC containers to food and beverages, have been progressively and sharply decreasin g in the las- ten '/<= p In 1974 and 1S7 ;r,:ent of VC in . a _ _ s c: w; wine and edible ci 1 containers and in the contained liquids was determined by Wol f (Clichy, France) and other (Dorlyl, BAP, BAP-Solvic, Rhone- Poulenc) laboratories. The sensitivity limit of the analytical methods was 5 ppm for VC in the walls of the containers, and 0. 35 ppm in the liquids. The results of the analyses showed a Level of VC in the walls ranging from not de tectable level to L3 ppm. The content of VC in the liquids were below the level of the sensitivity of the methods. In 1975 the. con :ent of VC in the walls of mineral water, wine and edible oil con :ainers was again determined by Wolff Labora tories, with a method whose sensivity limit was in the order of 0.2 ppm. The results of these analyses showed that the VC con tents were ranging front not detectable level up to 0.7 ppm. In 1976 Wolff Laboratories analyzed the content of VC in se veral liquids (edible oils, vinegar, wine and mineral water) stocked in PVC (19"5) containers, after 6 months of stockage. The sensitivity limit for VC in oil was 15 ppb and for VC in aqueous liquids 2-0 ppb. The content of VC varied from 15 to 30 ppb in oils, wa: 9 ppb in vinegar and wine, and varied from 2 to 3 ppb in mineral waters. In 1985, with the same analytical method in the same Wolff Laboratories, no VC was detected in natural mineral water (of different origins a:nd types), spring water (of different sources), soft drinks c f different types, red wines and edible oils of different types. VII) CONCLUSIVE REMARKS The experimenlal I project, and the entire body of research (experimental, epiden iological, pathological, clinical, environ- mental) which follow? or. VC carcinogenicity, have brought for important specific in formation, progress, decisions and facts in the field of VC ca rcinogenesis and of occupational and envi- ronmental carcinogene sis in general. SPI-00361 * As specified by the E 1C Commission DIRECTIVE 81/432/CEE, April 29th, 1981 15 1) The studies on VC carcinogenicity have led to the control of VC exposure, and hopefully the avoidance of additional cases of VC related dis eases. 2) They demonstrated that experimental findings can be extrapo lated to human pathology. 3) They have constitu ted a model for research protocols in the field of studies in environmental and occupational carcino genesis, including a large part of the ones enclosed in the Good Laboratory actice Acts, for long-term carcinogenicity bioassays. 4) They have promoted carcinogenicity studies of numerous chemically correlate*:. compounds, to assess their potential risk. 5) They have stimulated national and international regulations and acts for the control of environmental toxic agents, encom passing the ones requiring pre-production testings. 5) They have contribc ted to the basic knowledge of factors and mechanisms in cane erogenesis. Finally, VC carcinogenicity has brought forth an important lesson: the studie s in the field of environmental and occupational carcinoge i?sis, particularly in industrialized countries, must no longer be considered a retroguard ancillary research, but rather they must represent an important component of the d cision making processes which regulate the developmental :rends of society. SPI-00362 REFERENCES COMMISSION OF THE EUROPEAN COMMUNITIES. Proposal for a Council Directive on the approximation of the laws of Member States relating to materials and articles containing vinyl chloride monomer and intended t;o come into contact with foodstuffs, Off. J. Eur. Communitliies. No. C16: 8-12, 1977. COMMISSION OF THE EUROPEA 'J COMMUNITIES. Annexe I et Annexe II, J. Off. Communautes Eu r. No. L44: 17, 1978. CREECH, J.L. Jr. and M.N. JOHNSON. Angiosarcoma of liver in the manufacture of polyvin rl chloride. J. Occup. Med. 1_6: 150-151, 1974. FERON, V.J. and R. KROES. One-year time-sequence inhalation toxi_ city study of vinyl ch oride in rats. II. Morphological changes in the respiratory trao t, ceruminous gland, brain, kidney, heart and spleen. Toxi ol. 13: 131-141, 1979. FERON, V.J., B.J. SPIT, H R. IMMEL and R. KROES. One-year timesequence inhalation to? icity study of vinyl chloride in rats, III. Morphological char ges in the liver. Toxicol. 13_: 143-154, 1979. FORMAN, D., B. BENNET, J. STAFFORD, and R. DOLL. Exposure to vinyl chloride and angiosarc dma of the liver: a report of the register of cases. Brit. J. Ind Med. 42: 750-753, 1985. GROTH, D.H., W.B. COATE, B M. ULLAND and R.W. HORNUNG. Effects of aging on the indueti Dn of angiosarcoma. Environ. Health Perspect. 41: 53-57, 19 1 . HEHIR, R.M., B.P. McNAMARA J. McLAUGHLIN Jr., D.A. WILLIGAN, G. BIERBOV/ER and J.F. HARD [STY. Cancer induction following single and multiple exposure t a constant amount of vinyl chloride monomer. Environ. Health Perspect. 4_1: 63-72, 1981. HOLMBERG,B., T. KROVENI an M. V/1 NELL. The pathology of vinyl chloride exposed mice. eta Vet. Scand. 1/7: 328-342, 1976. IARC Monograph on the eval ation of carcinogenic risk of cnemicals, 19, "Some monomer, plas ics and synthetic elastomers,and acrolein" Lyon, pp. 377-438, 1979 SPI-00363 KEP LINGER, M.L., J . V; . GOODE , D.E. GORDON and J.C. CALANDRA. Interim results o! exoosure o. hats, hamsters, and mice to vinyl chloride. 17 LEE, C.C., J.C. BHANDARI J.M. WINSTON, W.B. HOUSE, R.L. DIXON and J.S. WOODS. Carcinogen icity of vinyl chloride and vinylidene chloride. J. Toxicol Environ. Health 4: 15-30, 1978. LEE, C.C., J.C. BHANDARI J.M. WINSTON, W.B. HOUSE, P.J. PETERS, R.L. DIXON and J.S. W<CfODS. Inhalation toxicity of vinyl chloride and vinylidene chi ride. Environ. Health Perspect. 21: 2532, 1977. MALTONI, C. Occupational carcinogenesis. Report to the Second Inter national Symposium on Cancer Detection and Prevention (Bologna, April 9-12, 1973). Advances in Tumour Prevention, Detection and Characterization 2: 19 26, 1974.a. MALTONI, C. Testimony at the Informal fact-finding bearing on possible hazards of vinyl chloride manufacture and use. Occupational Safety and Health Administration (OSHA), pp. 43-63, February 15, 1974 b. MALTONI, C. e G. LEFEMINE Le potenzialita dei saggi sperimentali nella predizione dei rlischi oncogeni ambientali. Un esempio: il cloruro di vinile. Acc ademia Nazionale dei Lincei. Rendiconti della Classe di Scienz Fisiche, Matematiche e Naturali 56 (VIII, 3): 412-424, 1974 a. MALTONI, C. and G. LEFEMlflE. Carcinogenicity bioassays of vinyl chloride. I. Research lan and early results. Environ. Res. 7 387-405, 1974 b. MALTONI, C. and G. LEFEMIfll E. Carcinogenicity bioassays of vinyl chlo ride: current results, In: I.J. Selikoff and E.C. Hammond "Tox_i city of vinyl chloride polyvinyl chloride". Ann. NY Acad. Sci. 246: 195-218, 1975. MALTONI, C., G. LEFEMINE, P. CHIECO e D. CARRETTI. La cancerogene- si ambientale e profes ionale: nuove prospective alia luce della cancerogenesi da cloru di vinile. Gli Ospedali della Vita 1 (5/6): 7-66, 1974. SPI-00364 MALTONI, C., G. LEFEMINE, A. CILI3ERTI, G. COTTI and D. CARRETTI. Vinyl chloride carcino gjenicity bioassays (BT project) as an experimental model for risk identification and assessment in environmental and occu ational carcinogenesis. Report to the XX Meeting of "Le Club de Cancerogenese Chimique" -on "Epidemio logie animale et epide iologie humaine: le cas du chlorure de vinyle monomere (Insti ut du Radium - Fondation Curie, Paris, 10 novembre 1979). Pub lications Essentielles, pp. 15-112, 1980. MALTONI C., G. LEFEMINE, A CILIBERTI, G. COTTI and D. CARRETTI. Experimental research oh vinyl chloride carcinogenesis. In: C Maltoni, and M.A. Mehl an, Archives of Research on Industrial MILBY, T.H. Cancer control monograph; vinyl chloride: an informa tion resource. Stanford Research Institute International, Menlo Park, California, 197$ . RADIKE, M.J., K.L. STEMMIR and E. BINGHAM. Effect of ethanol on vinyl chloride carcinc genesis. Environ. Health Perspect. 41 : 59-62, 1981. SUZUKI, Y. Pulmonary tunors induced in mice by vinyl chloride mo nomer. Environ. Res. 16: 285-301, 1978. SUZUKI, Y. Neoplastic ard non neoplastic effects of vinyl chloride in mouse lung. Enviror . Health Perspect. 4_1: 31-52, 1981. TASSIGNON, J.P. Methodologie du traitement des donnees de 1'Etude du Professeur Maltoni. Report to the XX Meeting of "Le Club de Cancerogenese Chimique ' on "pidemiologie animale et epidemiologie humaine: le cas d u clorure de vinyl monomere (Institut du Radium - Fondation Cur ie, Paris, 1979) Publications Essentielles, pp. 113-125, 1980. US OCCUPATIONAL SAFETY AN D HEALTH ADMINISTRATION. Standard for exposure to vinyl chloride . Fed. Regist. 39: 35890-35898, 1974. VIOLA, P.L. Pathology of |vinyl chloride. Med. lavoro 6_1: 174-180, 1970 a. VIOLA, P.L. Carcinogenic ffects of vinyl chloride (Abstract), Proceedings of X Inter: lational Cancer Congress, Houston, Texas, vol. 291, 1970 b. VIOLA, P.L., A. BIGOTTI a: id A. CAPUTO. Oncogenic response of rat skin, lungs, and bon s to vinyl chloride. Cancer Res. 31: 516-522, 1971. WARREN, H.S., J.E. HUFF a nd H.B. GERSTNER. Vinyl chloride. A review, An annotated literatur collection 1835-1975. A literature compilation 1976-1977. ORNL TIRC-7S/3, Oak Ridge, Tennessee, Oak Ridge National Laboratory, 1 78 . Sp/-00365 o ii o ro OJ lable 1 VC : structural and molecular-formulae and mol ecular weight H Cl \/ /\ HH C H Cl Mol. wt.: 62.5 SPI-00366 - 20 - Table 2 VC P roduc tion Methods of produc tioi: VC is produced commercially by : - halogenation of ethylene - addition of hydrogen chlo ride to acetylene World production (1376): 10 million tons per year Major geographical areas of production: Western Europe, USA, Japan, Eastern Europe SPI-00367 - 21 - Table 3 VC : uses Major uses: production of the homopolymer, polyvinyl chloride ( PtVC) and copolymer resins (mainly vinyl chlo r|ide-vinyl acetate and vinyl chloride-vinylidene chloride copolymers) Other uses: production Df methyl chloroform Miscellaneous uses ( in :he past): as a refrigerant, as an extracti on solvent for heat-sensitive materials, in the production of chloroacetaldehyde, as an aerosol propellant, as an in gredient of drug and cosmetic products, and, in medicine as an anesthetic SPl-00368 - 22 - T ab 1 e 4 VC : occurrence (1) Natural sources: it is no : known to occur as a natural produe t Workplaces : where PV(t, VC copolymer resins and VC, and other products containing VC are produced, used and stocked Air : general atmosphere around the plants of VC-PVC - around incinerators _W__a__t_e_r - effluent discharged by chemical plants - raw wate - finished drinking-water Food and drink (stocked i n PVC containers) : - butter ar d margarine - edible oi Is - alcoholic beverages Other : - new auton obile interiors - cigarett s and little cigars - marijuana cigarettes (1) IARC, 1979; Maltoni e t al., 1984 SPI-00369 22 data on b io lo g ic a l e ffe c ts re le v a n t to c a rc in o g e n e s is (1) 1984 0P 1 to co 5 cO c p co H Cn H 03 Cn 0 P r aCn 03 Cn cO > rH u rH CO CO - 3c 3 0 0 0 CO P Cn bfl U C. H C H E0 O rH in E P cC <1) P o CO 0 P (J C CO 1 rH X> rH rH 3 (0 CO Cn u a) O co "O a 3 Cn 0 xz P P O CO rH CO x: a X c0 o H TO P H co P o *. 0, E 3 rH H (0 rH O0 3 XI (J rH cO a 'O c cO - rH a) a a; > CO rH E Pc o Cn cd xz P 0 C sz CO - CO c CO V> x: P o o <D au - Cn >> X) rH fH 3 c rH CO CO X) CO CO H p in X (8 03 Cm CO rH a; a) rH o bO <D rH a a >> E D C rH 0 E 03 0 P Cn CO cO u 0 >0 0O > rH a3 T3 Op c4-> Cn cO O 0 a 0 a rH 4J CO rH rH 0 cO TJ C cti a? p in Pc cO o rH HUM W10 r*-Pi -c*H DO 4-> c 0 0Cn3 u bO 0 DO <D V C cd X) i > a) rH a o H cu rH DO P - rH -P o 0 0 X! p p CO 3 E rH rH "O H o c CO tn 3 rH H Q. CO CO c H co co E 0X x: 0 CO CO a c o H H CO p O in -p 0) c -P Cp 0 p 4P o oc in o 0 3 CO Co oo >E o oO CO CO E > C X) u C CO 0 cO cH CO 0 o P P bO P CO rH SH CO Eo p *H >> c DO o rH 0 a o CO rH CO o 0 a cd P in CO 0 c CO o x: c o p CO 0) rH P CO Cm rH a 0 o p c P p 10 o 'O rH > in P CO 3 a> cd to 0 u rH rv 0 CO O CO a CO tN a a c P o 1 01 cd c> Cn CO Cn E cO o pO CO p 0 XE H bO >> H rH x: c oa CO P co o rH o cO CO 0 3 cCn rH rH 0 P P O 3 -p C rH CO CO to P 0 CO O C 0 > cO >> E 3 c o CO CO o a; crH (0 0 o co 030 C 3 o c 2COT3 *j H T3 0 Oa x: CO o rH o CO 4P 0 3 in (0 p 0 P CO o H Cn cd CO a CO p 0 T3 in E cd aj a jj P rH > 3 C 33 0 aP 0) CO DO Cn E a a C3CO o a 3 O in P a 30 0 rH in (0 CO Cn o C 0 cd o t-, H -C o >> CO >> P in cn a >> U o C o p 0) > (0 > arN a X r--s f--V H DJ CO X in Co CO > E 3 X--v CO u r-1 C a > 0rH --s Cn UO >P ^x o 0 o H P 0 c Cn rH 0 P cd P ai E o cd p -u c CQ O CO o H< .r--V Cfl 0 o < CQ cn oa < hH 15PI-00370 Route o f a d m in is tra tio n : in h a la tio n T e st a n im a ls : S prague-D aw ley ra ts SPI-00371 cO D U 1-' n! a3 OL. L-. L, x> dc Cxl De 1) a 3 O - DO C. <D CL 'a->< ccd -H C. _] f/1 loO O' C . j to lx S in CO ! o nj D <d -h CL -J -/) o '3 C 'w* <d -I a. -2 <n Lx. S o o 1 o o ro Vc Id a .j /) Li. s; o oj o in <J 0) <*-> u s: <v >|r ^X 0) o DC| J3 o <tOD o a L. a3* c < <DOil X(DDAL 3 C <4 cd t- CO w D o d a LO ro i a> 3 is DO QJ cd uJ oao 03 a U Cc3d t--T* in Q cc o; in c r\i ro OJ 3 is DO OJ 03 ^4 L3 CL 03 00 Q A0J3 cc c oi-4 4_> Cd L. 3 Q AJ c 0) EU tj > (0 L0) t- ri to D U Q ADJ 0 cc 1 LU 1) 3 a a; y Li --4 2s3 H D cd D o 3 10 X. cn D to is D u cd 3 SZ T3 OJ or m in ^-4 > O O cr4 Oin > (0 --i = OJ - Ea Q. OL AJ 10 o a. i. O c ^ c) o o ID O0 in a "O 4-> C o u C 1 ) ) dJ _ o oo. o on OJ c oin uD 03 D AuJ c 3) *3 ADJ <TJ D E~ < A >> A> ( > 11 c o --4 i~> 03 id c. c is is H X V ft! *C <v 3 to ^3 D (0 is D t- nj 3 r -o CO in in c - E a CL o o *-1 io,n-i - O OoJ c 0 XJ 03 03 C OJ C-. ECQ 03 o d o ro O ro r- t D 3> 13 cd .^4 c. 3 Q. ctf to AcrJ3 dc > i-iHs H D <0 D "D 3 to ^3 to D w u >, CO D ? sz X) OJ *3 n n E CL CL O o o oro C O rH A-> Oj --4 CtJ r c lO 6rn O o o- O o OJ O O oj i J Cl) 3 is DO D (3 L3 a 03 to O Ar3J a: - is >--isi .-I D Cj D T3 3 in to 33 D tco >> D CtJ 3 r T) OJ *cr n n o E a Q. On c 0H u 05 --t cd r i--ci CO H cn O O tO o o ro O O n ro i d 3 is CC a> <d -H L* 3 Q. 03 ma -au3 cc - >> ^>--4 --< i--* J* a> cd D T5 3 to Js3 0) D CO is D U cd 3 JZ X5 OJ nn o " B a Cu --i " in * o *"1 iOnJ* c or4 W --cd4 cd .c c 1--1 i--ni CD T BT P r o je c t o n VC c a r c in o g e n ic it y . E x p . BT 3 , 10 : p la n SPI-00372 I to l, P 03 cd u t- o >, > .--0)1 2 c O 03 ai 4> L, CD 3 3 to DO o cd a ux a 4) in Cm O P as -pC E DO P c c 0) as r-t p 4) to r <y p E- Cm O C 0P (0 p Pu cd CD Cm rt Cm r 0) c OJ p c 0 Cm p O >> P cd c p l P o p oM to p c P 03 D c 3 DO -M --i 0 s "O 03 > -cp nl <D u <M O CD to 4) o pa 3 c. O3 CD CL c O 4> '-*[ --* .C i-i u u *-> dj c fd CL D t- X F= O3 0 1) a 3O DLO. L<D. CL <d op 2O 6- fn'> 0c1 1 a _ I -n C uif if) rp m e c < 0) Jto* 4) 0) 3 ---' CM 03 U p Cfi to P0) u 0) a to <x CD CM --i 1 V 3 >> a <1) cd p Li 3 Q cd V) Q p 03 tr . >> >, H p c p (D o cd 0) p p 03 T3 ? to . x CO 0) l CO >> 4J 3 L, cd 3 O r a C"v rr tn p Oo oID P c a> e i-> cd E o CM a > CL Cm o oD O on <D L> E-* 10 lO VD CO n o oM Qo o D oD n c o 0) p PftJ 3 coa iHaS jC. c L. P CD C a a> XE w <r> C-i fn V3 a'0 Orr' 'T' cd p p i a 3> 00 03 pa> C- 3 CL cd in Q p cd cc . - >, >> p ->> >> * p>> fp p cd V X 4) 4> 3 -p -p os - *3 CO P 4> 4) 3c >, 4) * * P 4> CO cd 3 *d CO X 0 X CD CO 4) CO L >, a; 03 0) CO u >> <D cd 3 L. >1 03 4) ? JZ *o x: 13 r *3 in m rr in in T !--"1 CM rr CM O G Cl a O O O to o O O o c o u cd as -C c o 6- m j T a b le SPI-00373 i (0 0) 4J DO ccd O l_ -1-4 >, O 03 --4 <d 3o <d o cj i> 0) 3 DO oj 03 4-J C- 03 CL C c C/3 03 <d a CO --4 CL 73 cd C E 03 rr H -4 c >v <T5 XJ - **-4 lO 4-3 u cn r4 e 03 CD e- c 03 DO O OJ C X fd LJ 4-> o c L. 03 03 >, a V 4-3 cd -4 ,--i O V CL > f-4 y? CCc 03 <d o DO t* O 4J c r-4 73 43 DO cd oC *4 (d o-t cd o ac o (0 o --4 4-3 > 4-3 CJ 03 03 c --H 0- o <d L-* r 03 4-3 c C3 h 03 03 r --3 o c >. o <M (d CL O C/3 4-3 C/) 03 c cd CD 1- o o 4-3 *--J --4 CO 4-3 C c-4 o3 cn --4 r-t E cd cn o > 03 r3 03 c O 0tfl> 03 0 ^30 t3a- CC CL c o D -I u- nlj v cl. cd CL <1 t3. O <x0 E Q 2. 3 3 30 13 {- 3 .3 ? EJ 73 C73 - a _J M LO n O <o o <0 aej cn c a) jx: < DO 03 < 03 5 C 03 L, 4-> C/3 {0 a; r4 o 03 a to to L- 7033 C3 0/ 13 C. CD i 03 0330 >03> 03 <--i ^3 a a) '/> a 4J a3 cr Ll, -T n i c\j r~> tD CD cn ^T Cl 1 (f) 03 DO o Td 03 Lr t- a u o 4J c c CM <X4 cd UJ -4 O c c o r4 4-> cd u 3 O u u c 0-1 03 o E 4-3 cd to o> 03 W o o L> 4--' VC Cl 03 xe (D EC l h(t3 t-0.0-. a4-o> D0L3O o ^ CL o . V) 4-J 0_t w >> o t- ns x: o C tl W >- c cm a) cd rr N t) c e CL a o o o to o o o o cd 4-3 c 03 o cd ^4 a CO u f-1 lO rHa 'w73 crt - Q. -j in Lu Ilj U7 ' ~7 cn n OJ cc CO OJ in *7 Cl t CO 4-> CW 03 f'J c, cd CL 03 D >> DO 03 a t- 2 a a3 to Q >, cd 'C -- (3 --1 03 *T cn L. w VC av T a b le SPI-00374 c m a id o o 1 f--* o o eCO a x LiJ cn D 4J 4 -*H -O O oj -4 HC 0) DO O c H a o3 O V > c 0 u (J 0) *"3 o L. Cl. 6-* CO (.0 i-J 03 L. >s U 5x "4 4) O . i --i 2c 03 0) Q act Io Dc 5o u 03 u Li Of aO CO O C/3 ,--i c 03 o 6 -4 0) c 00 03 03 L> o CO C 0> 03 E-* <D l, --4 D 03 V) A* 0 ca <D X (J ID o3 <--i <M aO c r. cO AJ L- on .U c D *o .--i c o3 <m O c o CO M AJ U o o3 D --( <M 03 <m aD c -4 D x: 4_> c o Cm 0 A> 03 c L. o AJ M (0 AJ i-4 03 c Z3 M <--H E 03 *a > 03 D <M oD CO Do ua D L. o3 or. a a r o L. L- a; fL o u03 O P-* OQI o nt o -iipnT cn a3 C < .--. cn D oo D <; D 2 -C4 03 L. a> CO W 4) i--i O D cao c o -1--1 aj 03 t. 3 Q in Li D o D OJ a) L, CD 1 D Z3 N QO D 03 --* t- 2 a 03 CO Q o00j >> 03 M 0 T3 >> t- _C X) AJ c OJ D Li a 'M W0 >> cu 05 c .u c0r3 _ H r--( 03 TJ D D 2 cn in x. L, cn D r. > D 03 2 T3 i cD m r- . >> M r--4 03 o D D 2 cn in X cn D r >> D 03 2 o ! CD m n- >, rH >> H 03 X o V D 2 cn in X Li cn o> r >> D 03 2 T3 i in rr in i-4 L^.1 u dc an xE I-I -- -.0 0*0 0 Hm01 rct ci *D lC aj ct3 Q, r--< in o3 c (3 C <- D HO C o u 0J --i m C T a b le 10 SPI-00375 CO p 03 L c OJ L --4 03 aP CO p --i (0 -j 03 E E- -p CQ C 03 Q. P X CO U3 13 H > pc .--i o (J p p p C 05 03 L cp o CO pc u p 0) E "D T3 o 03 L a. W O eCQ a; p D O re ! o c H u L 03 O U > C o c p 03 L p CO a; r p o c o p pp 03 p Do op p 03 c > 03 0) bC 03 CO o CL L HJ a co 0> ^ I -r^ u i~> 0) c Tl Q. u LPX E z OV Q a. c lin Li <r CL nj i_) o c -o Q. '0 Q n i Ooj p1 co i-i ca e c < :L 3 OJ a-) : - CO j> i) U < ) OJ CL 0l >> --^ i: p a; 0 -- 1: 4j W >D L 03 ^ c > n -a rr in omj o o CO P C 0) c. - OJ e o > a l CL P E p a3 c o o o o c o o <D L e- u a u c c o U0*1- -i0aJ) o 01 03 ou o -L o OP oc IP 3) c o P ap o3 o re 03 r c Lp 0aJ Cai x F= frl m 'V ri a >n o lo n L 03 p CO 03 re >* P p03 00)) *0 3 co X CO u CLO >cf,l <3u r O *0 1/1 lrOvi CO ^-1 o L 4-3 c o o T1J3 p03 E 01 Qa. pL> c p r> c o i-> 03 --i 03 sz c *p 6- (O T a b le 11 SPI-00376 c O-urti iD-> pLD0|,0u) p3 pO x0) E Q cn p 03 P CO X c 0) V o a c C ai Ctf I ai p >1 CO O CO c <H a> o CD E CO a CO x UJ 5 CO > V p c 0> DO 0 c p a p as o a c o CO 03 P o <v a o P c GaO; O c o 0P3 CJ o > c o P o a> <~> O p CL eCD 0) P 3 O cr CL 3 O PO DO in P O' CL rtJ O 4-5 o >n a u. iP to o <sj s: -X> e c < in <v <do a(D; 3 C as P ! w4-} 5 tn w o 03 cn <_> 3 <L> O a to -> '-H c o P 1, *a0i 3Ucu tO P ai <o a> p >i a? 3 , 05 5 Q | ^ o LD CO CO P Cu a; > t--i Eo ap Q, p H P Vj c <0 0) o oo in (J p CO _ X3 03 to o 03 mP o a cm rtJ 03 P OP Oc in <D p 3 O rr: pu 03 C O. 0) XE M I O co cO caj ca) T3 P -4 >> o to o to e (S3 X * >> >> p^ aops 0o3) w * to xa> tLo >(U, 1J) r ts ^ in on o o m to - -p cm E o ap - ap Oc oO o om o to o - in o CM o o-O oO -p lO V <v p a5 03 p p c rr as c cn H co 1 BT P r o je c t o n VC c a r c in o g e n ic it y . E x p . BT 1 2 , 13 : p la n SPI-00377 in p p >, U p 3p lU P Qo f -p 4> c 3 (U DO Ufl 03 o Pc a H CO o d (U in o --4 03 o E> -p Cc 03 o Pc in o 0) iH S-* p <13 u cp o in p p pc u t--t 43 E ,r*5 d 03 in O 3 O 4) 0) p c3 03 O PP 3 O a> 43 r 3p in (M o O c 03 in p o 03 <1) 4) j_> (U in p c 0) p in Eo o a 03 p p a3 o 03 C3- ^0 Q p| l, u a) *c Q, D X1) E VC '*-* -- Q. _J rn a 3 O UL. OX) C. O 4) '.> CL 0 2 (13 p O f- Cj_. in ciS E W C < <D X SO (D < 0) 3 C H <0 L P tn w a> o > DO 0) t-i ^3 3. 03 i0 Q a cc P c a> wE o3 a; l, g- p| PP a; C CX. 0F=) 10 in cr o P p p c (0 in Li o L, C O a) 3 e o ^ t) Q p3CC tj P U -P 03 c c CJ c > u o o Pp o c i--i ,--t 100? 0) p in p O p o Eo o Q 13 ir > p > rj p c p , 1 o ,--i U 0a O 03 a? c oc u PO p 3 PP o 4) U Of. a. a> o^ V c cLi 3 04 CO pv Crtf _p3 aIfi in r> iOn O OD O r- > 00 0) (0 p iSan- a3o3 P 05 ct t u 13 C T) O c P P o oV o o Jo c rp rp P in *P GO o ip o E0 0) u 4? lO > p > OJ p c p p o rp oa o 10 3 oc a> o c^ (13 p py 3 0) o> .0 C 3 - rn CO 5rn- ) \ T a b le 13 SPI-00378 ^ L. XJ *C-fi *- 1Q3. DC l, x e IS O 13 Q c cl a >n cl a n >, XJ x'0j CO V uc 03 oo 0) o c 3 (0 a asD tI 0) c OCc as <--i CO t- u > 00Q. Q. c o co CM *--4 cO E C CO ECD XJ CO 03 a E-* x U2 0) X> XJ 3 XJ o M -C c o (0 0) 00 E o o 4-> c co c o CO L. XJ CO c iH E ~o cO V-t o 03 XJ o t- 0) XJ o in CO o o > c o XJ 03 o 03 c o r XJ o M XJ Cm u CL CO L. O c ECO xj CO M c o M XJ CO E 3 *M *0 C0 CO > Cm 03 O 03 0) XJ (0 o Da reO o, 3 CL b_ tco c c < CO .X 03 03 3 c 0: >> CO L, 0) 03 a --4 XJ t- 3 CO c. a) c/- o CO 03 <H C3 03 Q- a cr CD O 0 c? Q C O 03 G3O >0)> CO ^ cQ-. 3CO CO Q XJ rceo c o co y 0 03 xj as l, 3 a E 13 X 5 03 Lf 03 S c\j in CO CO - 03 03 >> 0) ID EM XJ <M X 03 0) 3 a c 03 CM 03 LD 5 IT) r rc --4 <c--1 --i r XJ M o n o XJ M o XJ c 03 O > Cm O G h) E GMO 03 if 5 03 >M i--4 o Gr-O1 03 oo 5 03 > M r--4 E l oE o XJ CO 03 t- 03 (0 03 CO >> t V 0 X) -M CO O --4 n >> a 0 i--4 M CO o a 0 i--4 6-* O Q 0 ) GO 03 E \X. >-I oL. XJ c * GO 03 GO E \x > M oL, XJ c tC/ GO --4 o E o CJ GO o E oo c c 03 uX Dy rOe 0 Gt c C o M XJ CO 0) GO c Li XJ 03 C a 03 xE C-i-1 H ra r*c^j tm ai r x> xj a X) co X D 03 * 3O xj (0 as o xj T3 0) c c CO Q. CO CO 3 XJ c 03 E xj (0 03 L. XJ 03 XJ co a 3 O Li GO O Li xj c o o *C C (0 o 03 CO o ao cX XJ 0) n 0) co E XJ *r-4 < o Cm O U <0 03 03 CO 3 CO 'm a O J0O3 (0 >H *0 03 03 Ea m a co as xj to O -I 03 X> L. OO Lu XJ - 32 - Table 14 BT Project on VC carcinogenicity: test compound Test compound A) Supplier : Montedison, Italy B) Purity : Vinyl chloride acetic aldehyde ace tilene allene butane 1,3-butadiene chlorophene diacetylene vinyl acetylene propine methyl chloride 9 9.9 7% 100 ppm 5 ppm 2 ppm 5 ppm 8 ppm 10 ppm 10 ppm 4 ppm 10 ppm 3 ppm 100 ppm SPI-00379 - 33 - able 15 BT Project on VC care nogenicity: histopathology Histopathological exanination was performed on brain and cerebellun, Zymbal glands, intersca pular brown fat, sa .ivary glands, tongue, th^ mus, lungs, liver, kidneys, adrenals, spleen, pancreas, (esophagu 5) (1), stomach, various segments of intesti :ie, bladder, uterus, gonads (tissues at th ; site of injection)(2), and any other organ with pathological lesions (1) Only in the experiments in which VC was administer ed by injection. (2) Only in the experime its in which VC was administered by injection (sup cutaneous and intraperitoneal) SPI-00380 a. --* m A a. 0.-0 o 0. eTM j*-z> u s -- -o 4> J=> OI O U_ > O i/> O' "O ----wee _l O' 6 rtJ O' JO lA on </t a. Table 16 SPI-00381 -as kable 17 BT Project Exp. BT 1 : incidence of total malignant tumours in Sprague-Dawley rats, in relation to concentration of VC administered by inhalation, for 52 weeks Experiment Concentrat: on (ppm) BT 1 BT 1 Control BT 1 10,000 6,000 2,500 500 250 50 0 Tumours/100 Animals Malignant tumours M F Total 80.0 46.7 53.3 23.3 23.3 83.3 73.3 73.3 80.0 36.7 81.7 60.0 63.3 51.7 30.0 6.7 23.3 15.0 - 26.7 13.3 SPI-00382 r> <s> o o i O a"! (VI o -r oo D is trib u tio n of the d iffe re n t types of tuoours SPI-00383 SPI-00384 o ooo o oo I o --o -- n O CM o - 38 - Table 19 BT Project. Exp. BT11 : exposure by inge tion (stomach tube) to VC in olive oil at 50.00, lb.bb and 3.33 me /kg body weight, once daily, 4-5 days weekly, for 52 weeks. Insults after I 3 weeks (end of the experiment). Distribution of the different types of miscellaneous ("others") tumours Group Sex No. No. Aninals bearing other tumours Benign Distribution of histotypes Malignant No. Distribution of histotypes 2 adrenal gland cortical adenon 1 pheochromocytoma 2 cholangiomas 2 pheochromocytomas 1 carcinoma of the parotid gland 1 pulmonary adenocarcinoma Total II 1 skin acanthoma 1 cholangioma 2 adrenal gland cortical adenom 1 pheochromoblastoma III M 1 F9 1 bladder papilloma 1 subcutaneous lipoma 3 adrenal gland cortical adenom 4 pheochromocytomas 1 polypus of the uterus 1 dermal fibrosarcoma 1 osteosarcoma 1 11 IV M 4 4 pheochromocytomas F6 1 subcutaneous lipoma 1 auditory tract papilloma 2 adrenal gland cortical adenoma 2 pheochromocytomas 1 adrenal gland cortical adeno carcinoma 1 bladder carcinoma SPI-00385 in , once da th e e x p e i tu m o u rs o o o >1 in rH os: 4-> as cd as 3 rH H CD o> 3 (U o > H LO rH 1 o or Gp rH o H > p c as E H . o -p s. <V 5 -P 4-S x: GO o rl Ch O as as TO E3 C O O 4-) >. CM CO a wo as ---CD as JO tH c os: as JO o GO CO *H X H P> \ as 3 CO GO lO <D E ClO co rH c CO H co u CO <V >, CO X 4-5 JO <D Cm TO <U as as c p CB co 3 C\J p CD LO in iH O CO a X CO as rM 3 u CO o <D cr p c 3 C GO H iH as E rH cd 4-i O 4J <H O o a C > -p CD OS (0 CO 3 33 E cO i--i H Q o CI < <D ID 3X GO OS CO 0) P5 a CO CJ -p P CO -p co 4-> CO o 2 X 0) CO 4) CD O a a 3 oo P2 O 50 . 16 . O m C- ID W CO nvn lD lD O <M tv O c\j co co OOO in in o lO O G' n in n p i-H co o in t .--t c\j w id co in m h OOO TT T CO OOO O' CO OOO OT V CD OOO 'TV o CM CO Cb 2 U- + Cb lb + 2 Cb lb *f 2 Cb 2 Cb + 2 GO GO 60 js; GO E JsC GO E JsC N. CO E r-H ' ' H iH o0 p o o LO CO CO CO as -p >c H O CO rH O O -b > M SPI-00386 3 P O H (a ) The percentages are re fe rre d to the number a t s ta r t. t* rf oo ooo D is trib u tio n of the d iffe re n t type's o f tunours SPI-00387 ooo (N OO 01 P ro je c t. t p . 01??: **pOi*>re by in g e s tio n (stoeach tu b e ) to VC in o liv e o i l a t 1 .0 . 0 .3 , /0 .0 3 09 1*9 body w e ig h t, once d a ily , 4-S days w e e k ly , fo r 59 weeks. R e s u lts a fte r 130 weeks (end o f the e x p e rim e n t). SPI-00388 Table 22 BT Project. Exp. 5T 27: exposure by i ngestion (stomach tube) to VC in olive oil, at 1.0, 0.3, 0.03 mg/kg body weight, once daily, 4-5 days weekly, for 59 weeks. Results after 136 weeks (end of the experiment) Distribution of the different `ypes of miscellaneous ("others") tumours Group No. Sex ------_____ No. I M3 An i r al s bearing other tumours Benign Malignant Distribution of histotypes No . Distribution of histotypes 3 dermatofibromas 0 f 9 1 dermatofibroma 1 Zymbal gland adenoma 2 cholangiomas 1 duodenal fibroma 1 caecum lipoma 1 pheochromocytoma 1 thecoma 1 odontoma 3 1 kidney fibrosarcoma 1 peritoneal fibrosarcoma 1 adenocarcinoma of the uterus II M 10 1 dermatofibroma 1 subcutaneous lipoma 1 adrenal gland cortical adenom; 7 pheochromocytomas f0 3 1 pelvis carcinoma 1 adenocarcinoma of the uterus 1 leiomyosarcoma of the uterus III M 10 4 dermatofibromas 1 Zymbal gland adenoma 1 subcutaneous fibroma 1 subcutaneous lipoma 3 pheochromocytomas F 5 1 skin acanthoma 1 adrenal gland cortical adenoma 1 pheochromocytoma 1 fibromatous polypus of the ute us 1 fibroma of the uterus IV M 3 1 adenoma of exocrine pancreas 2 pheochromocytomas F 5 1 glandular stomach polypus 1 cholangioma 1 aorenal gland cortical adenoma 2 pneocnromocytomas 0 1 fibrosarcoma of the uterus 1 leiomyosarcoma of the uterus 1 arrhenoblastoma SPI-00389 o 3 1 kidney adenocarcinoma 1 adenocarcinoma of the uterus 1 fibrosarcoma of the uterus Total 3 12 10 3 10 8 3 8 to y ro <d O) O5 p O') O tT; pH L o 4-5 Oh CO <-H rH pH oa 0) <D OJ >5 rH r-H CO o > p-n (0 4-> c *0 C rH 0) in E CJ i rH > <D o -a 4-5 X pH 0) r--- rH d) CO <D > 'O -C 3 4-5 P 0) o Vh jC c 0 ao CO -a E rc co C\J O 4-> CD 4-5 JZ -- CO bO <1) rH ___ rH CO (1) X c 3 0) CO e- 0 > 5 4-5 o CO o LO <D p CO bO pH C GO <H X L -- 0) >0 GO X-5 X* E a co 0) oo L 3 o co 4-5 CO o pH o3 a T3 CO X C 0) <D CO a m u D O E D 4-> P C c0 C GO H pH cO E rH cO 4-5 o 4-5 a O CL) a C <D T3 rH a C (--H C\J eG a x w O (D n o Li a co L 3 O E 3 4-5 4-5 c CO c b0 CO E CO -p O o2 H CQ -P -P tr cO (0 r -P CO >5 CO <D -p f--i cO CO 3 E cO TJ rH P r-1 cio < 0) d to GO X CO V Sr u cO -p to 4-> CO o 2 X <v CO a; CO 0 p co o c^* nt-h oro ^oo o ^ co o--j -- n--i ohn CO tO cm C--h"- ooo CD OVJ --CHD DC^O H OJ n Oi H o rH C\J Ifl O CO CM c\j lO ffl v H CM l ) lO o c* m Lf) lO O uO if) uO O ifi lo if) O O LO pH O O (JO a a+ a a+ a + GO til GO JjC .* 2C pH rH pH GO o o tsi E GO E E L C O cn o . rH c rH u ooo SPI-00390 co p o E- (a ) The percentages are re fe rre d to the number a t s ta r t. 44 Table 2<* BT Project on VC careinoggnlci tv', tumours sianificantly in excess (Fisher exact probability test P S 0.05) Total cancer bearing animals Mammary gland carcinoma Zymbal gland carcinoma Nephroblastoma Liver angiosarcoma Neuroblastoma Forestomach papilloma and acanthoma 30,000: 10,000; 6,000; 2,500; 500; 250; 200; 50 ppm. 50 mg/kg b.w. 30,000; 10,000; 6,000: 2,500; 500; 200; 150; 50 ppm. 50 mg/kg b.w. 150; 50; 25, 10; 5 ppm. 30,000; 10,000 ppm. 30,000; 10,000 ppm. 2,500; 200; 150; 100 ppm. 500; 250 ppm. 30,000; 2,500; 200 ppm. 50 mg/kg b.w. 30,000; 6,000; 2,500; 500; 200; 150; 50 ppm. 50; 16.65 mg/kg b.w. 10.000 ppm. 30.000 ppm. 30,000 ppm. SPI-00391 - 45 - '?able 25 BT Project on VC card nogenicity: tumours considered as VC correlated , at the lowest doses at 25 ppm at 10 ppm at 1 mg/kg at 0.3 mg/kg over 12 animals 5 liver angiosarcomas, 4 ZymbafL gland carcinomas and 1 nephroblastom a over 12(p animals 1 liver angiosarcoma, 2 extraftepatic angiosarcomas and 2 Zymbal gland carcinomas. over 1.50 animals 3 liver angiosarcomas, 1 extra! epatic angiosarcoma, 1 hepatoma and 5 Zymbal gland carcinomas. over 1501 animals 1 liver angiosarcoma and 1 hepatoma. SPI-00392 - 46 - Table 26 Distribution by countr y of 119 cases of angiosarcoma of liver among workers exposed to VC Country United States W Germany France Canada United Kingdom Sweden Italy Yugoslavia Czechoslovakia Japan Belgium Norway All countries reporting cases No.of cases 35 26 18 10 9 5 5 4 2 2 2 1 119 SPI-00393 - 47 - Table 27 The histor of VC c arcino oen i c i t y 1) 1970 Zymbal gland carcinomas were rejorted in rats exposed to 30,000 ppm of VC, by inhalation (Viola et al. , 1971) 2) 1970 An increase in atypias in resp atory cells was observed among workers heavily exposed to VC (Maltoni et al., 1974 a) 3) 1971 (July) A vast project of long-term cart inogenicity bioassays on VC was started in Bentivoalio, near Bologna, Italy (ST Project 4) 1972 (August) Zymbal gland carcinomas, nephroblastomas and liver angiosarcomas were observed in rats exposed to VC by inhalation (Maltoni, BT Project) 5) 1973 (April) The first data of the BT Project were released to the Scientific community: the oncogenic effect was observed up to 250 p p n (Maltoni, 1974 a, b) 6) 1973 Splenomegalic liver disease was ound among polyvinyl chloride production workers (Marsteller et al., 1973) 7) 1973 (December) For the first time a case of live r angiosarcoma in a worker of polyvinyl chloride production was correlated to VC exposure (Creech and Johnson, 1974) 8) 1974 , (February) On the basis of the BT Project d ata indicating a carcinogenic effect at 250 ppm, OSHA proposed a TIV of 50 ppm (Maltoni 1974 b) 9) 1974 (February) The BT Project data showed that V is a multipotential carcinogen, producing a variety of tumours, in different animal pecies (Maltoni, 1974 b, c) 10) 1974 The BT Project data indicated a c ..rcinogenic effect at 50 ppm. OSHA proposed new stricter rules (Maltoni, 1974 c; Maltoni a d Lefemine, 1975) 11) 1974 Early epidemiological observation (paralleling the experimental information) indicated an increase in tumours other than liven angiosarcomas (of brain, lung, hepatocytes, haemo 1 ymphoreticu1ar tissues) amo ng workers of VC-PVC industries (Wagoner, 1974) 12) 1974-75 BT Project data showed that VC had carcinogenic effects in rats also when given by ingestion (Maltoni et al., 1975 a, b) 13) 1976 In rats of the BT Project exposed to VC by inhalation, angiosarcomas were observed down to the level of 25 ppm, and Zymbal gland carcinomas down to the level of 10 ppm (Maltoni, 1977 a) SPl-00394 T