Document nNbO7yk52Nw5q8gJd4pD03ynG

} l /6?"/7 / f R&S 138820 ( P7081417 #*#*####*## ax#-##*##***###*#.# *##***********##*********w**#tf*****#*x* # * THIS IS AN OFF-LINE BIBLIOGRAPHIC CITATION LIST GENERATED BT * ** * HEP LAPS II * ** V N.L.M.'S NATIONAL INTERACTIVE RETRIEVAL SERVICE * #* c* * ( VINYL CHLORIDE NUM3ER OF CITATIONS PRINTED = 300 JANUARY 27, 1983 THIS SEARCH UAS PERFORMED CN THE CANCERLINE FILE. ( SORT WAS NOT REQUESTED PLEASE SEND THIS LISTING TO c STAN KLESNEY PCD 1704 566 BLDG MIDLAND, MICHIGAN, 40660 Vj SSP|g^iR5M - . > ' . - . ^ V , j- * -* 00005729 VINYL CHLORIDE PAGE I 1 AU AD TI SI SO LA AB 2 AU AD TI SI SO LA AS Lawther PJ M.R.C, Toxicology Unit, Clinical Section, ST. Bartholomew's Hasp., London, England TOXICOLOGICAL ASPECTS OF THE AIR WE BREATHE. CARC/79/07063 Proceedings of the 1st International Congress on Toxicology: Toxicology as a Predictive Science, held in Toronto, Canada, 30 Harch- 2 April 1977. Pica CL, Ouncan WA, ed. New York, Academic Press, Inc., 670 pp., 1973. ENG Toxicological evaluations of air pollutants, expecially in The United Kingdom, are reviewed. Since passage of The Clean Air Act (1966), a series of studies suggests That The concentration of benzotaIpyrene (BP) in the air is 1/10 of what it was 25 yr ago. There are also signs that the urban excess of lung cancer is declining. An association has been found between occupation in or residence near asbestos works and pleural mesothelioma. There is evidence That exposure need be only minute and that the resulting tumors may not be clinically manifest for up to 90 yr. Urban air Contains many metals in trace amounts, some of which have been associated with cancer among occupational groups> eg, nickels, chromium, and beryllium. Concern about pollution cf the communal air by industrial carcinogens has also been stimulated by the induction of angiosarcoma in workers using vinyl chloride monomer. Carbon monoxide exerts deleterious effects on the CNS and cardio^ascular system. The effects of high dose of lead in adults and children are well-known, but There is conflicting evidence about the subclinical effects of body burdens formerly thought to be insignificant. (99 Refs) Kline SA ! Solomon JJ J Van Ouuren BL Lab. Organic Chemistry and Careincgenesis , Inst. Environmental Medicine, Hew York Univ. Medical Center, New York, NY, 10016 SYNTHESIS AND REACTIONS OF CilLOROALKENE EPOXIDES, ICD3/79/29736 J Org Cheml 93(13 ):3596-3600 1973 E KG The chloroalkene epoxides, vinyl chloride oxide (1), trichloroethylene oxide (2)> tetrachloroethylene oxide (3), clsand trans-l-chlorooropene oxide (9 and 5), and els- and trans-1,3-dichloropropene oxide (6 aid 7), were synthesized from their respective chloroalkcnes via either autooxygenation (in The case of 2 and 3) or m-chloroperbenzoic acid oxidation (in the case of 1 and 9-7). 01 chlorobenzene was a byproduct in the svnthesis of both 6 and 7. In the case of 6, its formation was determined to be a result of bimolecular reaction involving an intermediate in the synthesis of 6. Kinetics of hydrolysis at pH 7,9 and 37 C were determined for compounds 2-7, Kinetics of thermal decomposIT1 on in dilute hydrocarbon soln were determined for compounds 2, 9. 5, and 7. The hydrolysis and Thermolysis rates are discussed with respect to strueture'and mechanism of product formation. (Author abstract) (21 Refs) 0 . .i ( c 00005730 VINYL CHLORIDE 30 ** (/> _i 03 00 03 ro to /V PAGE Z fA c ' c f/ 1 ( r *. -X , - ^.`-'- -* ' : - -'. > .*.,, ; ( ( ".XXV'r:,iX \ ->: :*-?+* - rr~-* .- 3 AU ~ Stevenson J > Teimburro CH AD - Cancer Center> Univ. Louisville Sch. Nedl'cinei Louisville. KY, 602C1 TI - EDUCATIONAL PROGRAMS IN INDUSTRIAL-CANCER DETECTION AND PREVENTION. SI - ICD3/79/29591 SO - Prevention end Detection of Cancer. Pert I. Prevention. Vol. 2. Etiology-Prevention Methods. Proceedings of the Third Internal i on-al Symposium on Detection and Prevention of Cancer held 26 April - I May 1976 Hsu York NY, Nieburgs HE. ed.Neu York. Marcel Dekker, Inc., 2602 pp., 1973. LA - ENG AB - A system of educational programs for industrial cancer detection and prevention is outlined, and the effects of These programs on vinyl chloride industrial worker's is reviewed. The program should include employe* education on chemicals safety programs * medical screening programs, effects of self-cestruetlve life styles and specific diseases, and corporate-management, industrial medical personnel and community education. In implementing the program I the level of educational needs and the ease uith uhich the information can be comprehended should be considered. Before the program was initiated in a vinyl chloride plant, the voluntary particl pation uas 67k in a radiological screening (done at a hospital) and 95k in a biochemical screening program (done at the plant). After the educational program, participation uas over 87k for both screening programs . Partic1 pation in the history and physical examination program, for uhich there uas no educational brochure available, rose from 53k to cnly 72k in the same period of Time. Redesign of educational programs for small group discussions located outside The plant at more accessible locations resulted in greater attendance. (7 Refs) A AU - Greenberg RA i Tamburro CH J Kupchella CE AD - Cancer Center, Univ. Louisville, Louisville, KY TI - A PROSPECTIVE MEDICAL SURVEILLANCE PROGRAM FCR THE DETECTION AND PREVENTION OF INDUSTRIALLY RELATED CANCER. SI - ICD0/79/29579 SO - Prevention and Detection of Cancer. Part I. Prevention. Vol. 2, E tioloqy-PrewenTion Methods. Proceedings of The Third Internationa1 Symposium on Detection and Prevention of Cancer held 26 April - 1 May 1976 New York NY. Nieburqs HE* ed.Neu York* Marcel Oekker, Inc,. 2602 pp., 1970. LA - ENG A3 - A medical surve i 1 lance system under development for a chemical plant in Louisville* KY, is described. The aim of the svsTcm is to detect early occupational disease in a work force of about 1>200 employees exposed in varying degrees To a Known carcinogen* vinyl chloride. The medical sur''e i 11 ance sysTem is composed of four ordered levels of screening* each of which Tends to improve Total precision, but at an e^er increasing cost and compleoty. Job classification codes* employee work histories, the ranking of chemical exposure* and development of exposure indices all C r ( ( (' \ ( c ( e L C_ - 00005731 VINYL CHLORIDE PAGE 3 contribute to this system. The health of employees is monitored through annual and semi-annual physical examinations and through semi-annual and quarterly screening tests. The screening tests will be evaluated in terms of their usefulness in detecting overt diseases and in terms of their ability to detect early abnormalities that may be indicative of future overt disease. Mortality and morbidity rates will be monitored and compared with the best estimates of expected rates. The data being collected are being coded and stored on magnetic discs. Computer programs for the rapid access and analysis of the data are being written. (1 Ref ) 5 AU Van Duuren BL AD - Lab. Organic Chemistryi New York Univ, Medical Center, New York, NY, 10016 TI - STRUCTURAL PROGNOSTICATION OF CARCINOGENICITY ANO TUMOR-ENHANCING ACTIVITY IN VARIOUS CHEMICALS. SI - CARC/79/06422 SO - Prevention and Detection of Cancer. Part I. Prevention. Vol. 2. Etiology-Prevention Methods. Proceedings of the Third International Symposium on Detection and Prevention of Cancer held 26 April - 1 May 1976 New York NY. Nteburgs HE, ed.New York, Marcel Dekker, Inc., 2602 pp., 1973. LA - ENG AB - Structure-activity relationships of direct-acting alkylating agents, tumor promoters, and cocarcinogens are reviewed. Among the 100 alkylating agents examined were epoxides (mono-, bi- and polyfunctional ) beta- and qamma-lactones, and a variety of chloro ethers. The beta-lactones are carcinogenic but the camma-lactones are not. The bifunctional epoxides exhibit carcinogenicity more frequently than the monofunctional analogs. In monofunctional agents, the presence of a reactive adjacent functional group results in carcinogenic activity. Trichiaroethylene (TCE ) and vinwl chloride (VC) may be metabolised via an epoxide intermediate. TCE is carcinogenic in mice but not in rats, and VC is a known human carcinogen. Because of the wide differences in chemical structure, reactivity, and physical properties of tumor promoters, cocarclnogens , and tumor inhibitors, they probably exert Their activities in several different ways. They may simply alter The rate of absorptten and disappearance of a carcinogen, cr they may alter its metabolic pathway. Tumor-promoting agents, particularly the phorbol esters, are likely to interact at the cell membrane. As a result of strueture-acTi"ity studies, it has become possible to assign bioloqical activity to certain classes of compounds that have not yet been tested. (41 Refs) 00Q0573Z VINYL CHLORIDE PAGE 4 AU - Hoffmann 0 > Schmaltz I ; Hecht SS I Brunnemann KO ; Uync'er EL AO - Naylor Dana Inst. Disease Prevention, American Health Founaation, Valhalla, NY, 10595 TI - VOLATILE CARCINOGENS: OCCURRENCE, FORMATION AND ANALYSIS. SI - CARC/79/06414 50 - Prevention and Detection of Cancer. Part I. Prevention. Vol. 2. Etiology-Fravention Methods. Proceedings of the Third International Symposium or. Detection and Prevention of Cancer held 26 April - 1 May 1976 New York. NY. Mieburgs HE, ed.Neui York, Marcel Dekker, Inc., Z4Q2 pp., 1973. LA - ENG AB - Carcinogenicity data (hum-sns and animals); levels in occupational environments, polluted air, and cigarette smoke! and analytical methods for several volatile chemical carcinogens, including vinyl chloride, chlorinated hydrocarbons, bis(chloromethy1 )ether, N-nitrosamines, and hydrazines, are reviewed. (33 Refs) AU - Kline SA ; Solomon JJ ; Van Ouuren BL AD - Lab. Organic Chemistry and Carcinogenesis, Inst. Environmental M'.dictne, New York Ltniv. Medical Center, New York, NY, 10C16 TI - SYNTHESIS AND REACTIONS CF CHLOROALKENE EP0XIDE5. 51 - IC0B/79/29226 50 - J Crg Cham-, 43( 13): 3596-3600 1973 LA - ENG A3 - The chlcroalkene epoxides, vinyl chloride oxide (1), trichloroathylene oxide (2), tetracnloroethylene oxide (3), cisand trans-l-chloropropene oxide (4 and 5), and els- and trans-1,3-dichloropropene oxide (6 and 7), were svnthesized from their respective chlcrcalkenes via either aut oox''genat i on (in the case of 2 and 3) or m-chloroperbenzolc acid oxidation (in the case of 1 and 4-7). 0lchlorobenzene was a bvproduot in The synthesis of both 6 and 7. In the case of 6, its formation was determined To be a result of btmolacuiar reaction involving an intermediate in the synthesis of 6. Kinetics of hydrolysis at pH 7,4 and 37 C were determined for compounds 2-7. Kinetics of thermal decomposition in dilute hvdrocarbon soln were determined for compounds 2, 4, 5, and 7. The hydrolysis and thermolysis rates are discussed with respect To structure and mechanism of product formation. (Author abstract) (21 Refs) AU - Environmental Protection Agency AO - Criteria and Standards Div., nvironmenTal Protection Aqer.cy, Washlnston, OC TI - AMBIENT HATER DUALITY CRITERIA: VINYL CHLORIDE. 51 - ICC3/79/25179 SO - Albion* Hater Duality Criteria: Vinyl Chloride. Available Through National Technical Information Service. Springfield, Va. , as FB-292 446/2GA:, 90 pp., 1973. LA - ENG A3 - Section 304(a) of The Clean Hater Act (33 US Corpress 1314(a)l> requires Envlronmenta 1 Protection Acency to publish and periodically update water quality criteria. These criteria are to 00005733 VINYL CHLORIDE PAGE 5 9 AU AO TI SI SO LA A3 10 AU AO TI SI SO LA AO reflect The lateot scientific knowledge on the i dent i f 1 able effects of pollutants cn public health end welfare, aquatic life, end recreation. This report presents water quality criteria for vinyl chloride. It presents concentration criteria for the protection of fresh water and saltwater aquatic life. It presents 'safe' ccncentrat i ons for hu.w'.ns> and in The case of suspect or proven carcinogens, gives various lawels of incremental cancer risk. A section 304(a) water Quality criterion is a qualitative or quantitative estimate of the conrentratlon of a water Constituent or pollutant in ambient waters which, when not exceeded, will ensure a water quail tv sufficient to protect a specified water use, Under the Act a criterion is a scientific entity, based solely on data and scientific judgement. It does not reflect considerations of economic or technological feasibility nor is it a water cualiiy standard and in itself has no regulatory effect. (Author abstract) Squirrell DC ; Thain W ; Davis N International Agency for Res. on Cancer, 150 Cours Albert Thomas, 69371 Lvcn Cede* 2, France MONITORING REQUIREMENTS IN THE FVC INDUSTRY. IC0S/79/24976 IARC Sc I Publ; (221:15-17,97-54 197-3 ENG The unification of regulations fer monitoring vitv'1 chloride in the Eurooean Community (EC) is discussed. A method for ccmcaring concentrat i on values measured o''er different time periods is explained. This technique allows the likely a" over a long time to be forecast from shor ter-t l n.e averages, (101 Refs) Squirrell DC ; Squirrell DC ; Thain W ; Davis W Internal Ional Aqancv Res. Cancer, 150 cours Albert Thomas, 69372 Lvcn Codex 2, France ENVIRONMENTAL CARCINOGENS: SELECTED METHODS OF ANALYSIS. STANDARDS FOR CALIGRATICM AND TESTING: PREPARATION OF STANDARD MIXTURES OF VINYL CHLORIDE IN NITROGEN CR AIR, PREPARATION OF STANDARD SOLUTIONS OF VINYL CHLORIDE IN ORGANIC SOLVENTS GY VOLUMETRIC AMO GRAVIMETRIC METHODS, AND PREPARATION OF STANDARD AQUEOUS SOLUTIONS OF VINYL CHLORIDE. ICQ3/79/24975 IARC Scl Publ; (221:123-140 1973 ENG Standards for calibration and testing for vinyl chloride cone ontra11ons are reviewed. Instructions are owen for the procuration of standard mixtures of "Mnyi chloride in nitrogen or air, standard soln of 'Mayl chloride in orqanic solvents by volume fr 1 c and qrav i .--e tr i c methods, and ste.odcrd aqueous soln of 'Mnyl chloride. Some procedures and parts of Tne necessary apparatus are illustrated, (no Pets) 3) 9P (0 ^88ev 00005739 VINYL CHLORIDE PAGE 6 II AU - Squirrell DC ; Squirrell DC I Thain W ; Oavis W AD - Intarnational Agency for Res. on Cancer> 153 coups Albert Thomas 69371 Lyon Codex 2, France TI - METHODS FOR THE MEASUREMENT OF VINYL CHLORIOE IN POLYtVINYL CHLORIDE), AIR, MATER AND FOODSTUFFS. METHOD 8-0ETERMINATION OF VINYL CHLORIOE IN FOODSTUFFS BY HEAD-SPACE SAMPLING GAS CHRCMATOGRAFHY. SI - ICCS/79/29979 SO - IARC Sci Pool; (221:113-120 1973 LA - ENG A3 - A method for dqterming vinyl chloride (VC) in food using head-space sample gas chromatography (GC) is specified. Analysis time, Under favorable conditions, is approx 10 min and detection limits are routinely 5 nanog (nq)/g. or 5 nq/ml, down to 1 ng/g, or 1 ng/ml. Five aliquots (5 mi for liquids and 5 g for solids) of food sample are sealed in separate vials. A standard Soin of VC (10 mg/liter) in water, tetrahydrofuran, dimethyl acetamide or other appropriate solvent is prepared. Using a microsyringe, 1, 2.5, 5 and 20 ul of the standard soin are added to four of the five vials to serve as calibration standards. The five vials are placed in the GC thermostated bath at 90 C and equilibrated at least 2 hr. VC peak heights on each chromatogram are corrected to a common recorder attenuation and plotted on the ordinate of a graph relating them to VC plotted on the abscissa. If the sample contains VC, the line will not pass through the zero VC value. The amount of VC contained in the sample is determined from the intercept with the abscissa: VC (ng/mi or ng/g) = intercept "aiue (ng) divided by vol (ml) or ut (g) of sample, (no Refs) 12 AU - Griciute L AD - Unit Environmental Carcinogens, International Agency Res. Cancer, Lvon, France TI - THE CARCINOGENICITY OF VINYL CHLORIDE. SI - CARC/79/05955 SO - IARC Sci PubI; (22):3-11 1973 LA - ENG AS - Data on the carcinogenicity of ,'inyl chloride (VC) are summarized. Chronic exposure of laboratory animals to VC produces hepatic lesions and bone changes similar to those described in humans. In the first animal study implicating VC as a carcinogen, rats were exposed to 30, COO ppm VC, 9 hr/day, 5 davs/wk, for 9-12 mo. The'/ developed auditory sebaceous gland tumors and osteochondromas . Inhalation exposure in rats, mice, hamsters, and rabbits produced angiosarcomas of the liver and other organs and malignant tumors of the lung, intesTlne. kidney, skin, mammary gland, and forestorach. VC is carcinogenic in rats at 25 and 50 Ppm in air and in mice and hamsters at 50 ppm in air. Ingestion of VC by qavaqe (50.0 and 16.6 mq/kq/day for 52 wk ) produced liver angiosarcomas and other tumors in rats, but 3.3 mg/kg/day produced angiosarcomas at sites other than the liver. Transplacental administration of VC to rats between days 12 and 18 of gestation produced angiosarcomas. The In vitro mutagenicity 00005735 VINYL CHLORIDE PAGE 7 of VC to bacteria is greatly enhanced by liver tissue homogenates from humans, mice, and rats. Chioroethylene oxide is considered to be the main active carcinogenic metabolite of VCI it is a strong alkylating agent that is responsible for mutagenesis in bacteria, yeast, and Chinese hamster calls. VC produces chromosome alterations in human lymphocytes. Primary liver angiosarco.ua is the tumor observed in workers in the polyvinyl chloride (PVC) industry. This Tumor is extremely rare in The general population, and those detected in PVC workers recresent a 400-fold increase over the expected incidence. IT i3 not known whether VC induces other tumors in nuuans. The av latent period between initial VC exposure and liver angiosarcoma diagnosis is 20 yr. (34 Refs) 13 AU - Natarajan AT ; Van Buul PP ; Raposa T AO - Oept. Radiation Genetics and Chemical Mutagenesis, Sylvius Labs. TI - AN EVALUATION OF THE USE OF PERIPHERAL BLOOD LYMPHOCYTE SYSTEMS FOR ASSESSING CYTOLOGICAL EFFECTS INDUCED IN VIVO BY CHEMICAL MUTAGENS. SI - CARC/79/05452 SO - Mutagen-lnduced Chromosome Damage in Man, Proceedings of a Symposium held in Edinburgh, Scotland, July 7-3, 1977. Medical Research Council Edinburgh, Scotland, 355 pp., 1973. LA - ENG AB - The use of peripheral blood lymphocyte svs Terns for monitoring populations exposed to chemical mutagens and for screenirg chemicals for Their in vivo mutagenic effects was invesTicated. Investigations included analyses of The frequency of chromosome aberrations in workers exposed to low levels of vinyl chloride! the frequencies of sister chromatid exchanges (SCEs ) in blood lymphocytes from patients receiving cytostatic Treatment, both during treatment and a few weeks after recovery! and chromosome aberrations and SCEs in iymphocvtes of rats after in vivo treatment with directly and indirectly acting alkylating agents. No strongly significant difference was noted between the control and the vinyl chloride groups of workers with regard To the occurrence and frequency of chromosome aberrations. Of the six patients Treated with cytostatic drugs, five received cyclcphosphamide and one Thiotopa. The control group had an av of 10.3 SCEs/cell, while in the treated group Two patients had slgniflcantiy higher frequencies of 5CEs. In a 76-yr-old patient with reticular cell sarcoma, the 5CE frequencies were 23.4. 15.6, 16.2, and 12.3 per cell on davs 13, 16, 13 and 20 of therapy, while the frequency decreased to 6.3 25 daws after therapy was terminated. In rats, despite a very high cose of diethyl nitrosamine (DEN), no effect on SCEs end chromosomal aberrations could be observed. Mlth both dimethyl nitrosamine and methyl nitrosourea, a dose-dependent increase In chromosome aberrations and SCEs was found. It is concluded that for low chronic exposures, this system is not sensitive in detecting mutaoenlo effects, while for assessing the in viv0 effects of chemical mutagens, particularly Those that need metabolic activation, this system may have value. (10 Refs) '' C 33 (/) 03 00 00 to oo 00005736 VINYL CHLORIDE PAGE 8 19 AU - Squirrel I DC ; Thain W AD - International Agency -for Res. on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 2, France TI - METHOD FOR THE MEASUREMENT OF VINYL CHLORIDE IN POLYtVINYL CHLORIDE), AIR, WATER AND FOODSTUFFS. REVIEW OF TECHNIQUES OF MEASUREMENT AND MONITORING OF VINYL CHLORIOE. SI IC0B/79/29569 SO IARC Sci Publ; (22)!19-54 1978 LA ENG AB The techniques of measuring and monitoring vinyl chloride (VC) as of raid-1978 were reviewed. The limits of VC detection with a flame-ionioation detector are about 1 ppm and about 0.2 ppm with a photo-ionicatlon detector. Because of long recovery time after exposure To The VC concentratlons during monitoring, a detector in which ionization occurs at high temperature in The presence of alkali metal salts is unsuitable for VC use. Electron capture detectors are affected by water vapor and are unsuitable for atmospheric measurements. The infra-red spectrum of gaseous VC shows absorption at approx 5.15, 9.8, 10.9, and 13,9 microns! the first is a region of strong absorption by water vapor and the second is comparatively weak; the stronger band of the Two remaining (10,9 microns) is used to measure concentration unless it is subject to interference from other substances. VC is transparent to radiation at A microns and this wave-lenqtn can be used as a reference if required. The limit of detection of VC by mass spectrometry is highly dependent on the sampling technique used. Oxidation systems work efficiently only if a certain water content is maintained. Reactions other than direct oxidation can be used, however, eg, brcmination with enrichment by liquid chromatography and gas chromatography (GC ). The sensitivity of color detectors depends on The detailed construction of the device and sample size. Thermal conductivity measurements in air are subject to interference from atmospheric impurities. Numerous semiconductor devices show changes in electrical properties when exposed to VC, which depend on adsorption of VC on The semiccnductor surface! while adsorption may be comparatively rapid, desorption is usually slow at low VC concentrations. Many of The VC measurement techniques are nonspecific and subject to Interference from other substances! The error increases as VC decreases, particularly at low concent rations . When interference is significant, a separation technique that chemically removes unwanted substances should be used, eg, GC. The specific informaticn required often determines the sampling techniques to be used. (101 Refs 1 c c c c c c c c e L L 00005737 VINYL CHLORIDE PAGE 0 15 AU - Squirrell DC Thain U AO - International Agency for Res. on Cancer. 150 cours Albert Thomas. 69372 Lyon Cedex 2. France TI - METHODS FOR THE MEASUREMENT OF VINYL CHLORIDE IN POLYtVINYL CHLCRI0E), AIR, WATER AND FQOOSTUFFS. METKOO 1-DETERMINATION OF VINYL CHLORIDE IN AIR BY GAS CHROMATOGRAPHY. SI - IC03/79/26363 SO - IARC Sci Publ; (22 ) 159-64 1973 LA - ENG AB - A method for determining cf vinyl chloride (VC) in air, which can also be used for ethyl chloride, 1,1-dichlorcethylene (vinylidene chloride) and 1,Z-dichloroethane, was presented. The limit of detection is 0.1 ppm tvol) with a precision of + -10X up to 10 ppm and +-5'A at higher levels. The total Time required is approx" 15 min. The atmosphere is sampled by a gas syringe, or other suitable method, and an aliquot is injected via a gas sampling valve onto the column of a gas chromafograph (GC). The vinyl chloride is detected bv a flame-ionipation detector. For GC calibration a standard mixture of VC in air (usually 600 ppm) is prepared and an aliquot is transferred To the GC column for analysis. VC concentration (ppm) = concentraticn of The standard (ppm) x VC chromatogram peak in sample x its attenuation divided by standard chromatogram peak x its attenuation, (no Refs) 16 AU - Squirrell DC ; Thain W AO - International Agency for Res. on Cancer, 150 cours Albert Thomas, 69372 Lyon Codex 2, France TI - NETHCDS FOR THE NEASUREMENT OF VINYL CHLORIDE IN POLY(VINYL CHLORIDE), AIR, WATER AND FOODSTUFFS. METHOD 2-DETERMINATION OF THE EIGHT HOUR TIME-WEICIITED AVERAGE CONCENTRATION OF VINYL CHLORIDE IN THE ATMOSPHERE USING A PERSONAL SAMPLER PUMP AND A CARBON TRAP. SI - ICDB/79/2A567 SO - IARC Sci Pub 1; ( 22 ):65-76 1973 LA - ENG AB - A method for determining of the time-weighted av concentration of vinyl chloride (VC) in air over an 3 hr sampling period, using a personal sampler pump and a carbon trap with gas chromatogranhy, was prszent-zd. The method is applicable in f he range 0.02-50 ppm for atmospheres of normal humidity, but may give low results for humid atmospheres. Manipulative time is approx 30 min. but the measurement cycle time is governed bv the duration of complete solvent elution from the chromatographic column and return to a stable recorder attenuation baseline. The cycle Time can be reduced b" the use of back-flush facilities. With a portable pump, the atmosphere is sampled at a constant flew rate Through an adsorption Tube containing carbon. VC is desorbed from the carbon with d i ch icron.e thane and determined by gas chroma toq-aohy (GC ). Other solvents or Thermal dssorptlon can also be used. For GC calibration a standard soln of VC in the desorption solvent is prepared. The scln is analysed by GC and a calibration curve prepared for calculating VC ccncentra 11on in the sample, (no Refs) 00005733 VINYL CHLORIDE PAGE 10 17 AU AO TI SI SO LA A3 13 AU AD TI SI SO LA AB Squirrel1 DC ; Thain W International Agency for Res. on Cancer, 150 cours Albert Thomas, 69273 Lyon Cedex 2, France METHODS FOR THE MEASUREMENT OF VINYL CHLORIDE IN POLYtVINYL CHLORIDE), AIR, WATER AND FOODSTUFFS. METHOD 3-DETERMINATION OF THE EIGHT HOUR TIME-WEIGHTED AVERAGE CONCENTRATION OF VINYL CHLCRIOE IN THE ATMOSPHERE USING A PERSONAL MONITOR FITTED WITH A DETECTOR TU3E. ICD3/79/2A566 IARC Sci Publ; (22):75-82 1973 ENG A method for determining of the time-weighted av concentration (TWA) of '/inyl chloride (VC) in air over an 8 hr sampling period, using a personal monitor fitted uith a detector tube, was presented. The indicator tube is calibrated over the ranges 0-5 ppm and 0-10 ppm on 9,6 and A.3 liter samples of air, respectively. The personal monitor consists of a low flow rate sa.upling pump and a Draeger detector tube. The tube consists of an alkali trap, to remove HC1 and chlorine, and by a potassium permanganate oxidation layer, to convert vinyl chloride to chlorine. A continuous analysis is obtained during the time atmospheric sample is drawn through the tube, producing a stain whose length is proportional to the time-weighted VC. Other unsaturated chlorinated hydrocarbons interfere, eo> trichloroethylene and vinylidene chloride, producing stains indistinguishable from those produced by VC. The Oraeger tube is calibrated before use using 0-50 ul VC. The TWA (ppm) of VC s VC readings from tube (ul) divided by air sample voi (liters), (no Refs ) Squirrell DC ; Thain W International Agency for Res. on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 2, France METHOOS FOR THE MEASUREMENT OF VINYL CHLORIDE IN POLYtVINYL CHLCRIOE), AIR, WATER AND FOODSTUFFS. METHOD A-DETERMINATION OF VINYL CHLORIDE IN AQUEOUS LIQUIDS BY HEAD-SPACE SAMPLING/GAS CHROMATOGRAPHY. ICDD/79/2A565 IARC Sci Publ! (22 ) :83-88 1973 ENG A method for determining of vinyl chloride (VC) in aqueous liquids using head-space sampling gas chromatcgraphy was presented. IT is suitable for VC concentratlons 0.001-1 uq/ml but is equally applicable to liquid effluents which contain higher levels of VC when solid matter is absent. Precision is + -25/ for concentrat i ons less Than 0.005 uq/ml , + -10X at 0.02 uq/ml level and +-S V. greater than 0.0A uq/ml. A vial is filled with 5.0 mi of sample, sealed, placed in the thermostated gas cnrcmatoqraah (GC ) bath at 30.0 C, and processed b" a set of calibration standards. The GC is calibrated by preparing a standard soln of VC in water (100 mg/1iter). Six vials are filled with 5.0 ml distilled water and sealed. Using a mtcrosyrlnge 0, 0.5, 1.5, 2.0 and 2.5 ul of 37 fio W 03 00 00 03 c ii ivr~-.hr! 00005739 VINYL CHLORIDE PAGE 11 c c ( V 13'*1 -i The standard VC soln are added to separate viols. The viols ore pieced in the GC both, allowed To equilibrate -for at least 1 hr, and are analysed by the automatic sequence. The height of the VC peak in The sample, corrected for recorder attenuation, is converted to concentration of VC (uq/mi) by comparison with the calibration graph obtained from the standard soln. (no Refs) 19 AU - Squirrell DC ; Thain W AO - Internallonal Agency Res. on Cancer, 150 cours Albert Thomas, 69372 Lyon Cede* 2, France TI - METMOOS FOR THE MEASUREMENT OF VINYL CHLORIDE IN rOLYfVINYL CHLORIDE), AIR, WATER AND FOODSTUFFS. METHOD 5-0ETERMINATION OF TRACES OF VINYL CHLORIDE IN AIR BY TRAPPING FOLLOWED BY GAS CHROMATOGRAPHY. SI - ICCB/79/29569 SO - I ARC Sci Pufal; (22)-- 89-95 1973 LA - ENG AO - A method for determining of traces of vinyl chloride (VC) in air using gas chromatography, applicable to 0.001 ppm (vol) ues presented. The gas chromatograph (GC) is calibrated daily. A standard VC in nitrogen mixture (usually 900 ppm) is precr.red. A 10 ml samole is withdrawn with a syringe, a 1 ml sample loop on the GC is filled and the remainder is injected on the GC column. VC is trapped from a 1-10 liter sample of air by passing it through silica gel at-76 C which adsorbs VC (sampling period should be less than 20 min to avoid blocking the trap with ice even when a drying tube is used). The trap is connected to a GC fitted with an Apiecone L Carbcpak B column and a flame-ionication detector. The trap is heated quickly to 100 C and purged with nitrogen to transfer The desorbed VC into the chromatograph. VC concentration (pom) = sample VC peak corrected for attenuation x vol of standard in sample val''e loop x concentration of standard divided by corrected peak of standard x sample vol. (no Refs) 20 AU AO TI SI SO LA A3 - Squirrell DC I Thain W - Internetlonal Agency for Res. on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 2, France - METHODS FOR THE MEASUREMENT OF VINYL CHLORIDE IN FOLYt VINYL CHLORIDE), AIR, MATER AND FOODSTUFFS. METHCD 6-DETERMINATION OF THE 29-HOUR TIME-WEIGHTED AVERAGE CONCENTRATION OF VINYL CHLORIDE IN AIR DY TRAPPING FOLLOWED BY GAS CHROMATOGRAPHY, - IC03/79/29563 - IARC Sc I Rubl; (22)197-103 1973 - ENG - A method for measuring the 29-hr tjme-ueIqhTed aw concentration of ln"l chloride (VC) in air using gas chromatoc-aphy was presented. The method is sensitive to VC concentrations down to O.C05 poo (vol). Precision under laboratory conditions is + -10H frcm 0.1-1 ppm! In The field at flew rates of 10 and 20 ml/min the coefficient of variation is 0.5k ow=r the range 0.05-0.5 ppm. The atmosphere Is sampled over a 29-hr period by pumping Through Two acT1vqTed-carbon adsorption Tubes In series. The adscraed c c c c I V k?-*- c c (. 30 fi (n c*> oo 00 00 ro 00005740 VINYL CHLORIDE PAGE 12 vinyl chloride is extracted from each tube with CS2 and The two soln examined separately. The gas chromatograph (GC ) is calibrated by preparing VC in CS2 standard soln (2-50 ul/ml), One ml aliquots are injected onto the GC column, peak height for each concerntrotion measured and a calibration curve drawn. One ul supernatant CS2 extract from each sample tube is analysed in the GC and the VC concentration determined from the calibration curve. The VC concentration (pp.n ) in the air sample = 2 x concentration in The extract divided by "ol of the air sample (1itens ). (no Refs ) 21 AU - Squirreil DC ; Thain W AD - Internalional Agency for Res. on Cancer, 150 cours Albert Thomas, 69372 Lvon Cedex 2, Franca TI - METHODS FOR THE MEASUREMENT OF VINYL CHLORIDE IN P0LY(VINYL CHLORIDE), AIR, WATER AND FOODSTUFFS. METHOD 7-DETERMINATICN OF VINYL CHLORIDE IN F0LY(VINYL CHLORIDE) BY HEAO-SPACE SAMPLING GAS CHRCMATOGRAFHY, SI - ICDB/79/24562 SO - I ARC Sci Publ; ( 22 1 ' 105-111 1973 LA - ENG AD - A method for determining of vinyl chloride (VC) in polyvinyl chloride ( PVC) using head-space sampling gas chrcmatograpny (GC ) was presented. Precision of the method is +rlOX at concentrations up to 10 ug/g and +-5V. at concentrat i ons greater than 10 ug/g. The method is applicable to PVC in the form of polvmer powder, pre-mixed powder, compound granules and fabricated articles. Concentrations less than 2 mg VC/g of PVC can be determined. The loner limit of detection depends on how much the impurities in the solvent interfere with determination of VC. If interference is sufficiently low, 0.1 ug VC/g of PVC can be detected. The analysis time is typically 30 min, but depends on The time Taken by the solvent or impurity peaks to elute and the recorder trace to return to baseline. To *rahydrofuran (5.0 ml) is rapidly added to 0.500 g sample in a 25 ml vial with a magnetic stirrer, the vial is sealed and stirring continued until complete dissolution occurs. The vial is then placed in the gas GC thermostat bath at 30 C and allowed to equilibrate for at ieast 1 hr. GC calibration standards are prepared similar To the sample preparation using 0,500 g monomer-free PVC for each of five vials and either 0, 1, 3, 7 or 10 ul of standard soln (40 mg VC/ml to trahvdrofuren ) to the five vials using a microsyringe (0-900 ug of VC is added). The GC automatic se.mollnq sequence is used and a graph of peak height (after correction for attenuation) is plotted aqainst added VC. The wt of VC is obtained from the calibration curve. The VC cancantration in the PVC sample (uq/g ) = VC wt/PVC wt. (no Refs ) c c c c c c. c L 33 03 CO CO CO CO CO V? v`:."' ' H ' ` lV *'-=*-7.v^;:; 00005791 VINYL CHLORIDE PAGE 13 c 22 AU - Squirrel1 DC ! Thain W C AD - International Agency for Res. on Cancer, ISO Cours Albert Thoma3, c C69372 Lyon Cedex 2, France TI - METHODS FOR THE MEASUREMENT OF VINYL CHLORIDE IN POLYtVINYL CHLORIDE). AIR, MATER AND FOODSTUFFS. SI - IC0B/79/29561 50 - IARC Sci Fubl. Vol. 22, 192 pp., 1973. LA - ENG A3 - A compilation of balanced and critical views of the methods c available for determining tne vinyl chloride (VC) monomer was presented. An introductory chapter on the careinoqenlciTy of VC was followed by a review of measuring and monitoring techniques. The detailed procedures have been brought up to date in light of c considerable experience since the first edition of this publication and correspond closely to those used in industrial and control laboratories. They include the following determinations: VC in air by gas chromatcqraphy; 3 hr c time-weighted av concentration of VC in the atmosphere using a personal sampler pump and a carbon trap, or a cersonal monitor f'tted with a detector tube) VC in aqueous liquids by head-space sam.pl ing/qas chromaTography, VC traces in air by trapping followed by gas chromatographyi 29 hr Time-weighted av concentration of VC in air by trapping followed bv gas chromatography; and VC in polytvinyl chloride) and food by head-space sampling gas chromatography. Also included is the preparation of standards for calibration and testing of VC mixtures in nitrogen or air, VC soln m organic solvents by volumetric and qravimetric methods, and aqueous soln of VC. (no Refs ) 23 AU - Bovland E AD - London Sch. Hyqiene and Tropical Medicine. London NCI. England TI - SIGNIFICANCE Or OCCUPATIONAL CANCER. 51 - CARC/79/09329 SO - Prog Biocnam Pharmacol I 19:76-31 1973 LA - ENG AD - The significance of studies of occupational cancer is surveyed, AT least 90/ of human cancers are due To chemical agents, and about GO/ are due to environmental factors. Many causes of human cancer have been found by investigation of occupational disease, and this approach is still the most promising. Because chemical Carcinogens are difficult To identify oy examination of human populations, it is essential To carry out animal tests on chemicals In The environment To obtain indications of carcinogenic activity, Chemical care 1 no-sens can be divided into two groups : the first group (eq, al)'."ia'lng agents) does not require metabolic Trans format i on for activity', the second group (eg. nitrosamlnes and polycyclic hydrocarbons) requires metabolic or chemical activation. The metabolic reactions involved in the activation of The second qroup are pa-t of the normal detoxification processes. The first step in the activation of polycyclic aromatic hydrocarbons is the formation of epoxides or t c c L L '"J&J :f c 00005742 VINYL CHLORIDE 33 C/5 CO 00 00 CO t* PAGE 14 c c c (. ( l ,y>VV' "v.l M.'ivi-f-Y; 24 AU AD TI SI SO LA A3 25 AU AD TI SI so LA AO arene oxides. Their action is due To The presence of an ethylene crouo or double bond That can be activated and to their similarity in shape to constituents of the Target 0NA molecule. Vinyl chloride and Trichloroethylene! two other carcinogens, combine ulth DMA in a manner similar To That of The arsne oxides of The carcinogenic hydrocarbons. Occupational cancers ha'e special significance because They can give indications of The specific causes of cancer, and recognition of causes of cancer in workers gl"es indications of the causes of cancer in the general population, (no Refs) Fishbein L Natl. Cancer for Toxicological Res., Jefferson, AR ENVIRONMENTAL SOURCES OF CHEMICAL MUTAGENS, II. SYNTHETIC MUTAGENS. CARC/77/OASIS Adv Mod Toxicol; 5=257-343 1573 ENG Comparative data are reviewed on the relative a'uounts, residues, and Transport in the environment of primariIv synthetic mutagenic end potentially mutagenic agents. The agents discussed include industrial mutagens (primarily The halogenated hydrocarbons I vinyl chloride, vinylidine chloride, trichloroethvlene, tetrachloroethylene, chloroprene, carbon Tetrachloride , fluorocarbons , polychlorinated biphenyls, chlorodioxins , haloethers, chloride, bromoalKanes , and fluorine, phthalate esters, pesticides (DDT, dichlorvos, formaldehyde, and ethylene oxide), and metals and metalloids (lead, mercury, and arsenic). Information is sparse concerning environmental reactions and intcractions , Transport, residence times, stability, and fates of these agents. Also, most environmental chemicals have not bean adequately studied to permit evaluation of Their relative mutagenicities fcr humans. (470 Refs) Malt cm C Inst. Oncology and Tumour Center, Bologna, Italy FREOICTIVE CARCINOGENICITY BI0A5GAYS IN INDUSTRIAL ONCOGENESIS. CA.R C/79/04 531 Prog Biochem Pharmacol", 14 = 47-56 1973 ENG The use of carcinogenicity bioassays to predict the oncogenic risks associated ulth Industrial chemicals is reviewed. The goal is to avoid human e>pcsure to carcinogenic chemicals. The fcur most important cases of enwironmental and occupational cancers discovered since 1970 were direct!" cr indirectIv predicted experimentalLy. The choice of agents to be tested should follow a list of priorities based on diffusion of the agent I number of people potential!" exposed, and direct and/or indirect data suggesting a possible risk. Long-Term care I nogen Icity bioassays Include first-level bloassavs in which the route of administrat1 on of the agent and affected tissues are not the same as those for humans", second-level bless says In which the route of administration of The agent is different but The affected Tissue 00005743 VINYL CHLORIDE PAGE 15 26 AU AD TI SI SO LA AB 27 AU AD rr SI so LA AB is the same ns that -for humans; and third leva! bioassays in which both the routa of administration and affected tissuas are the same as those humans. Preliminary results of bioassays of several inorganic compounds and vinyl chloride in Sprague-Dauley rats are given. (9 Refs) Downs TO Dept. Biometry. Univ. Texas Health Science Center at Houston, Sch. Public Health, P.0, eox 20136, Houston, TX, 77025 COMMUNITY RISK ASSESSMENT. ICD3/79/17S13 Tex Rep Biol Med; 37:113-122 1973 ENG A simplified account of a statistical method used to assess community risK from environmental carcinogens is presented. The method is called the linear model and is based on the assumption that the probability, or risk, of developing cancer from exposure to a relatively small amount of carcinogen is directly proportional to that amount. The linear model is illustrated with data on vinyl chloride inhalation in rats and subsequent development of liver angiosarcoma. Results from these experiments are extrapolated to humans. Rats were intermittently exposed to vinyl chloride at different ambient air concentrations. Exposures to vinyl chloride were maintained for 4 hr/dav, 5 days/wk, for a period of 1 yr. Following this, surviving rats were housed under normal conditions until death. Whenever a rat died an autopsy was performed to determine if the rat had developed liver angiosarcoma. The proportion of rats with liver angiosarcoma increased steadily as the dose concentrations of vinyl chloride increased. The proportion of rats with liver angiosarcoma seemed roughly proportional to the dose concentration. Use of the linear model was extrapolated to humans To quantify The risk of liver angiosarcoma for residents in the vicinity of a hypothetical vinyl chloride plant , (6 Refs) Tamburro CM Digestive Diseases and Nutrition Section, Sch. Medicine, Univ, Louisville, 511 South Floyd Street, Room 535, flDR Building, Louisville, KY, 40201 HEALTH EFFECTS OF VINYL CHLORIDE. CARC/79/0 3744 Tex Rep Biol Med; 37:126-144 1973 ENG The health effects of vinyl chloride (VC) are reviewed, and a medical surveillance system for detecting and following Its effects is described. An early finding in e'-'posed human and animals is actlwation of morohological changes in the sinusoidal lining cells of the liver without evidence of hepatoce1lu 1 ar toxicity. With progressive exposure To VC there is an increase in atypia of the sinusoidal lining cells, progressive worsening of The focal sinusoidal dilatation, and malignant traosformation of the sinusoidal lining cells, flos t data suggest that it is the endothelial lining cell that becomes malignant and forms the 00005766 VINYL CHLORIDE PAGE 16 ( angiosarcoma. Poliosis hepatis is often seen in nontumorous portions of the liver; whether this i3 a precarcinogenic or c preangiosarcomatous lesion in VC workers is under study. Preliminary epidemiological and histological data suggest That the frequency of lung cancer is increased among VC Workers. Two cases are reported in which the duration and degree of exposure to VC were almost identical, yet cne man developed primary hepatocellular carcinoma and the other angiosarcoma. The man in whom hepatocellular carcinoma developed had a history of extensile alcohol consumption, which may have played a role in the inability of the hepatocytes to detoxify VC metabolites. A \ prospective medical surveillance system has been designed based on classification of industrial environments into three categories according to the level of possible carcinogens. (10 Refs ) 28 All - Wyatt S AD - United States Environmental Protection Agency, Research Triangle Park, NC, 27711 TI - CONTROL STATUS OF VINYL CHLORIDE. SI - ICD9/79/17327 SO - Tex Rep Biol Med; 37:165 1978 LA - ENG AB - The Environmental Protection Agency (EPA) listed vinyl chloride as a hazardous air pollutant in December, 1975, and promulgated a national emission standard for it under the authority of section 112 of The Clean Air Act on October 21, 1976. Cn November 19, 1976, the Environmental Defense Fund (EOF) petitioned the United States Court of Appeals for review of the standard. Cn March 26, 1977, EOF and EPA moved To dismiss the court proceedings in view of a settlement agreement requiring EPA to propose certain amendments to the standard. These amendments to the standard were proposed on June 2, 1977. Since that Time EPA has received numerous comments from the industry on the proposal. The main issue involved is how carcinogens should be regulated under ( section 112 of the Clean Air Act. Section 112 of the Act requires that emission standards be set 'at the level which, in the judgment of The Adminlstrator, provides an ample margin of safety to protect the public health from such hazardous air pollutants.' It has not been possible to determine a threshold level of effects for vinyl chloride and it is not certain that such a threshold may be determined in The near future. Therefore, EPA has developed standards which require emission reduction to the \v lowest lewel achievable using tcchnoloqical means. (Author abstract) (no Pefs ) c 13 00005745 VINYL CHLORIDE 33 99 C/J 03 03 03 03 -I PAGE 17 c 29 AU - Heath CU AD - Chronic Diseases Div., Bureau Epidemiology, Center Disease c Controli Atlanta, GA, 30333 TI - ENVIRONMENTAL POLLUTANTS AND THE EPIDEMIOLOGY OF CANCER. SI - CARC/79/03005 SO - Environ Health Perspect; 27:7-10 1978 LA - ENG (' A3 - Approaches used in epidemiologic studies of environmental carcinogenesis are reviewed briefly. Some approaches, as with kepona, a chlorinated hydrocarbon insecticide, and with polybroininated biphenyls, start with exposed populations and ( measure disease frequency, the so-called prospective or cohort approach. Others, illustrated by vinyl chloride monomer studies, start uith cases of cancer (hepatic angiosarcoma) and measure the extent of toxic exposure! ie, the retrospecti'<e or case history (case-control) approach. Other studies describe patterns of cancer occurrence and then seek correlations with potentially related population characteristics. All of these approaches are part of epidemiologic methodology and all are predicated on the existence of prior human exposure or prior disease occurrence. In this regard, major limiting factors involve concepts of latency and exposure dose. Although in vitro and animal test systems will never fully supplant human studies, they represent the only means ( for detecting potential carcinogenicity before human exposure has become widespread or long-established. (17 Refs) 30 AU Frank AL (_ AO Mount Sinai Sch. Medicine, New York, NY TI OCCUPATIONAL LUNG CANCER. SI ICD3/79/13543 SO Pathogenesis and Therapy of Lung Cancer. Harris CC, ed. New York c. and Basal, Marcel Dakker, Inc., Lung Biology in Health and Disease, Vol. 10, 762 pp,, 1978. LA ENG AB An overview is presented of factors that contribute to lung c cancers associated with working areas. Major' occupational respiratory carcinogens discussed are arsenic, asbestos, chicromethyl ethers, chromium, carbon compounds including coke and tar', mustard gas, nickel and radiation. Additional agents are discussed with proven, suspected, or possible carcinogenic risk: beryllium, carbamates, chloropreno, fibrous glass, isopropyl oil, meThyiene-bi s-or tho-chloroanI 1 Ine and ni tr'osam 1 nes . Also discussed, in connection with luno cancer, are smelting cper a 11 Oris , various vegetable dusts, vinyl chloride and woodworking. The review concludes with a brief consideration of directions in occupational carelnopenesis. Despite the interest of various professional and legislative groups , it is pointed Out that there will still be a need for The astute clinician to note unexpected associations. (146 Refs) 00005746 VINYL CHLORIDE PAGE IS 31 AU AD TI SI SO LA A3 32 AU AD TI SI 50 LA AB Gideon J i Schoults K > Bochinski J Natl. Inst. Occupational Safety and Health, Cincinnati , OH ENGINEERING CONTROL TECHNOLOGY IN POLYVINYL CHLORIDE POLYMERIZATION PLANTS (MEETING ABSTRACT). IC03/79/11S73 Proceedings of the First Annual NIOSH Scientific Symposium held in Cincinnati i OH, 17-19 April, 1973 National Institute for Occupational Safety and Health, Cincinnati, OH, 1973. ENG The National Institute for Occupational Safety and Health, Division of Physical Sciences and Engineering has initiated a research program in control technology. Tha objective of this program is to facilitate the implementation of effective preventative measures in order to prevent occupational illness. The objectives of the plastics and resins industry control technology assessment were to document and evaluate effective control technology for plastics and resins polymerisation plants. Particular emphasis was given to polyvinyl chloride (PVC) polymerisation processes, since the relatively recant lowering in The personal exposure limit for vinyl chloride monomer (VCM) to an S-hr 1 ppm time weighted av has required the application of state-of-The art controls. The present paper contains a summary of The control technology that was found to be effective in controlling VCM in processes manufacTuring PVC bv suspension, bulk, and dispersion polymerisation. Controls necessary for VCM include process and equipment modification, isolation, local and general ventilation, work practices, personal protective equipment, workplace monitoring systems, empioyee/enployer education, and cn-qoing effort by both workers and management. All of these components must function together as an integrated coordinated system in order to assure Worker protection under normal operating conditions, (no Refs) Simmon VF t Tardiff PG Microbial Genetics Frogram, Stanford Res. Inst, International, Menlo Park, CA, 94025 THE MUTAGENIC ACTIVITY OF HALOGENATED COMPOUNDS FOUND IN CHLORINATED DRINKING WATER. CARC/79/02 700 Water chlorination; 2:417-431 1970 ENG The mutagenic activities of 22 halogenated compounds found in chlorinated drinkinq water were determined using the Ames Salmone11a/microsome procedure with S. typhimurium strains TA1535 and TA1C0. Two known carcinogens, carbon Tetrachloride and chloroform, were not mutagenic in this system, probably because mutagenic metabolites were formed m insufficient amounts or they were so unstable that they did not surwtve lonq enough To penetrate the bacteria and interact with the DMA. Known carcinogens That were mutagenic were vinyl chloride, vinylidine c'n lor i be , 1,2-d I ch loro ethane , 1,1,2 -1 r I c'nloroe thy iene , b i 3 - ( 2-chloroe t hy 1 )e th-sr > methyl iodide, and brouoform. Mutagenic 00005747 VINYL CHLORIDE PAGE 19 activity was alio observed with brcmodichloromethane* chlorodi bromomethane > methylene bromide* bromochloromethane , methylene chloride* methyl bromide* methyl chloride* 2-chlorcpropane, 1-chlorcpropens, bis(2-chloroisopropyl lether, n-butyl bromide* T-butyl bromide* and s-butyl bromide. The results indicate that the number and amount of alkyl halides in potable water should be reduced to lessen possible health hazards. (20 Refs) 33 AU - Sgybinski Z I Popiala T AD - Instytut Medycyny Wewnetrgnej AM, A1. Pokoju* Bocana 9* m. 7* 31-543 Krakow* Poland TI - MULTISTAGE STUOIES AIMED AT EARLY DETECTION OF CHRONIC EFFECTS OF VINYL CHLORIDE AND MERCURY VAPORS. SI - ICDB/79/10703 SO - (led Pr! 29(5)i 371-377 1976 LA - FOL AB - A total of 168 workers occupationally exposed to vinyl chloride (VC) vapors were subjected to multistage clinical investigations. Biochemical Tests were perfcrmed in 34 subjects* liver scintigraphy in 30, and liver bicpsies in 11. Of the 168 workers * 66 were exposed to an av concentration of 17,9 mg/m3 (36 of them for greater than 10 yr), and 102 to an av concentratien of 133 mg/m3 (49 of them for greater Than 10 yr). Hepatomegaly was found in 19/102 patients exposed To high concentrations and in 7/66 workers exposed to lower concentrations. Pathological liver encyme activities and bilirubin levels were found in 45 workers exposed to high concentrations and in 29 workers exposed to lower concentrations of VC. Angiosarcoma was not found, (no Refs) 34 AU - Lee CC ; Bhandari JC ; Winston JM ; House WB ; Oixcn RL ; Woods JS AD - Midwest Res. Inst., 425 Volker Bi'-d,* Kansas City, MO, 64110 TI - CARCINOGENICITY OF VINYL CHLORIDE AND VIMYLIDENE CHLORIDE. SI - CARC/79/02129 SO - J Toxicol Environ Health; 4(1)115-30 1978 LA - ENG AB - The effects of exposure to 50, 250, or 1,000 ppm vinyl chlcride (VC) cr 55 ppm winyiidene chloride (VDC) for 6 hr/day, 5/days/wk, wore studied in albino CD-I mice and CD rats. The animals were killed after 1, 2, 3, 6, 9, or 12 mo. Bronchioloalveolar adenomas developed in 12/63, 2/63, and 48/69 mice exposed to 50, 250, and 1,000 ppm VC, respectively. Bronchioloalveolar adenomas developed in 6/35 animals e:*posed To VDC. Three of 29, 23/63, and 31/69 mice exposed to 50, 250, and 1,000 ppm VC, respectively, developed hemangiosarcomas 0(5) in the liver. In the mice exposed to VDC, IIS developed in the livers of two males and one female. Mammary gland tumors occurred in 9/34, 3/34, and 13/36 female mice exposed to 50, 250, 1,000 npm VC respective ly, and Thev included ductular adenocarcinomas and scuamous and anaplastic cell carcinomas with metastasis to the lung. Malignant I'.vpromas were found in various organs of mice e>Posed to VC but net in any of the mice exposed To VDC. Twelve of 70 and 21/70 rats exposed To 250 and 1,000 ppm VC, respectively* developed HS in the liver! 00005748 VINYL CHLORIDE PAGE 20 35 AU AD II SI SO LA A3 36 AU AO TI SI SO LA AD 3/34 female rats exposed to 250 ppm VC and 13/70 rats exposed to ljQOO VC also developed HS in The lung. Two of 36 male rats exposed to VDC developed HS in the mesenteric lymph node or sc tissue. It is concluded that VC is highly carcinogenic in mice! the incidence and severity of the tumors increased wiTh dose and length of exposure. Rats were more resistant to the carcinogenic effects of VC and VDC. (26 Refs) Muller G ! Norpoth K Owzarski LI Institut fur Staublungenforscnung, Westring 10. 0-4400 Munster. W. Germany IN VIVO TRAPPING OF A VINYL CHLORIDE METABOLITE BY MEANS OF 3,4-OICHLCROBENZENETHIOL. CARC/79/01939 Int Arch Oscup Environ Health; 42(2 ):137-139 1978 ENG A method for trapping metabolites of vinyl chloride (VC) and 2>2'-dichlorodiethyleTher (DDE) is reported. Rats treated with VC and 3.4-dichlorobenzenethiol excrete S-2(3.4-dichlorothiophenyl lacetic acid in the urine. The structure of the compound was confirmed by gas chromatoqraphv-mass spectrophotometry. Similar results were obtained with DDE. Thus, the formation of ultimate carcinogens from nonelectrophi1ic precursors can be proved by the use of nucleophilic trapping agents both in vitro and in vivo. (9 Refs) MnTufuji H Occupational Health Service Center, Inst. Science Labor, Japan VINYL CHLCRI0E POISONING IN THE USSR: LITERATURE SURVEY. IC0B/79/C6137 Rodo Kagaku; 54t 11) '.505-592 1973 JPN Among workers exposed To vinyl chloride in western countries about 70 cases of hepatic angiosarcoma have been reported in Western countries, while none have been reported in the Soviet Union (USSR). However, many cases of chronic vinyl chloride poisoning have been reported in the USSR, while few have been reported in Western countries. The USSR requires poisoned workers to change to work unrelated to vinyl chloride and limited exposure time on The jcb. Tolerated limits of vinyl chloride are Set at 10.7 ppm in the USSR, while the limit has been 500 ppm (1959-1971) to 200 pprn (1971-1975) in the United States. Inspection of USSR factories between 1953 and 1969 revealed that unacceptable levels (greater Th.-n 10.7 ppm) occurred in 2-30/ of cases. Exposure regulations and The low tolerance limits in the USSR may explain why patients with chronic vinyl chloride poisoning with characteristic symptoms not progressed to the point of developing hepatic angiosarcoma. (42 Refs) ii c 00005749 VINYL CHLORIDE JO </> 03 03 03 C* PAGE 21 c c jf`wuLij *.*&{. L-lt 37 AU - Biran 0 5 Gilbert SG ; Giacin JR AO - Bait Yicchak, Israel TI - SORPTION OF VINYLCHLORIDE BY SELECTED FOOD CONSTITUENTS. SI - CARC/79/01526 50 - J Food Sci; 44( 1):56-53 1976 LA - ENG AB - The sorption of vinyl chloride monomer for selected food constituents (water, corn oil, oil-in-water emulsions, casein, and sucrose) was found to be affected significantly by the chemical nature of the food constituent, the initial concentration of VCM, and temperature. (12 Refs) 36 AU - Biran D ! Giacin JR J Hayakaua K i Gilbert SG AO ~ Bait Yicohak, Israel TI - VINYLCHLORIDE SORPTION BY DRY CASEIN PARTICLES! MECHANISTIC CONSIDERATIONS. 51 - CARC/79/01524 50 - J Food Sci; 44(1):59-61 1973 LA - ENG A3 - The amount of vinyl chloride monomer (VCfl) sorbed by dry casein particles increases with a decrease in temperature or a reduction in moisture content of the particles. Adsorption is presumed to take place on the casein surface and to involve two distinctly different modes of sorption: active site sorption in unich VCM molecules are attracted to the casein surface and an intermolecular attraction of VCM molecules, in uhieh there is clustering around initially bound VCM. (10 Refs) 39 AU - Ames BN AO - Berkeley, CA, 94720, Univ, California TI - SESSION II. CARCINOGEN SCREENING: C3STACLE5 AND OPTIONS. IN VITRO TESTING OF ENVIRONMENTAL MUTAGENS/CARCINOGENS. 51 - CARC/79/01094 SO - Structural Correlates of Carcinogenesis and Mutagenesis A Guide to Testing Priorities? Proceedings of the Second Food and Drug Administration Office of Science Summer Symposium held in Annapolis, 31 Auqust-2 September 1977. Office of Science, FDA, Annapolis, MO, HEW Publication Ho (FOA) 73-1046, 241 pp., 1973. LA - ENG A0 - The development, accuracy, and recent applications of the Ames Salmonella mutagenesis test are discussed. Chemicals tested fcr mutaasnieity and carclnogen Iclty have included flame retardants in children's pajamas, pesticides, vinyl chloride, and dibrcmo compounds in citrus-f1avcred soft drinks. (9 Refs) c c c c c ( c c c L L 000057S0 VINYL CHLORIDE PAGE 2 40 AU AD TI SI SO LA AB 41 AU AO TI SI SO LA AB Fis'nbein L Mall. Center Toxicological Res. . Little Rock, AR, 72207 STRUCTURAL PARAMETERS ASSOCIATED WITH CARCINOGENESIS (HALOGENATED OLEFINS, VINYL AND ALLYL ANALOGS AND EPOXIDES). CARC/79/01C92 Structural Correlates of Carpincgenesi s and Mutagenesis. A Guide to Testing Priorities? Proceedings of the Second Food and Drug Acini ni s tration Office of Science Su .-.mer Symposium hald in Annapolis, 21 August-2 September 1^77. Office of Science, FDA Annapolis, MD HEN Publication No. I FDA)73-1046, 241 pp., 1973. ENG A number of reportedly carcinogenic industrial compounds (including halogenatad olefins, vinyl and allyl analogs, and epoxides) were examined to determine if their structural, biological, and metabolic similarities could help predict thair carcinogenicity. The chlorinated olefinic derivatives of major concern are vinyl chloride, vinyliccne chloride, trichloroethylene, chloroprere, dichlorobutene, and perchloroeThylene 1 all of which have been proved to be carcinogenic To humans and/or laboratory animals. Evidence suggests that all chlorinated alhyien.es are n-eTabol 1 gad to oxiranes (epoxides) as a first step. The oxiranes, which are strongly electrophilic, may react directly with cell nucleophiles Or they may undergo intramolecular arrangements. No such structure-activity relationship has been demonstrated for the various vinyl and allyl analogs That are carcinogenic and/or mutagenic- In the case of the epoxides, the presence of a reactive functional group (as m eplchlorchydrin) or a double bond (as in glycidaldehyde ) near the epoxide appears to enhance care 1 nogenicitv by allouinq the chemical to act as a difunctional alkylating agent for macro,'oicucies , Greater reliance should be placed cn mutagenicity testing and on definitive metabolic and pharmacokinetic studies to augment struetura-act1v1ty predictions of carcinogenicity. (79 Refs) Simmon VF SRI International, Menlo Park, CA, 94025 STRUCTURAL CORRELATIONS OF CARCINOGENIC AND MUTAGENIC ALKYL HALIDES. CARC/79/01073 Structural Correlates of Caroinogenes 1s and Mutagenesis. A Guide to Testing Priorities? Proceedings of the Second Food and Drug f uni n i s t r a 11 on Office of Science Su .1-er Svmpesium held in Annapolis, 51 August-2 September 1^77. Office of Science, FDA Annapolis, MD HEN Publication Mo. (FDA 1 73-1046, 241 pp, , 1973. EMG The Ames Salmonella typh 1 mur'1 urn mleroscme assay, using strain TA100, was used To determine The mutagenicity of 23 alkyl halides, 10 of which were unknown carcinogens.' Twenty-one of these halides were mutagenic with and without S-9 liver uicrosome mix. The mutagenic CP.'pounds (c denotes proven carcinogen I included metra'l bromide, methyl chloride, methyl Iodide tc), ', >.r*',C-' - -- *-r-; W ^rr' < * .*Y., /.; ii c 00005751 VINYL CHLORIDE PAGE 23 c methylene chloride (c), bromochlorcmethane, methylene bromide, brcmoform (e), d i bromochloromethane , bromodichlcromethane, vinyl c chloride (c), vinylidene chloride (c)> 1 , 1.2-trichlcroethyiane (c), bis(2-chloroethyl ) ether (c). bis(2-chioroisopropyl) etheri 1-chlcrcpropene, 3~chloropropene, epichlorohydrin (c), hexachlorobutadiene, 3-bromoprcp) cni c acid, 3-i odopropi oni c acid and 3-chlcroprcpionic acid. Two known carcinogens, carbon tatrachloride and chloroform, were not mutagenic in the presence or absence of the S-9 mix. It is likely that an insufficient amount of the mutagenic form was produced cr that this form uas so unstable it was unaval labie to interact with the bacterial DMA. In general, the mutagenicity correlated with chemical reactivity. Of interest was the mutagenicity of methylene chloride, a widely used industrial chemical with broad environmental exposure (via paint removers and aerosol spray cans ). (17 Refs ) 92 AU - Weisburger EK ( AO - NCI, Eethesda, MD TI - CARCINOGENIC NATURAL PRODUCTS. SI - CARC/79/01070 SO - Structural Correlates of Carcinogenesis and Mutagenesis. A Guide to Testing Priorities? Proceedings of the Second Food and Drug Administration Office of Science Summer Symposium held in Annapolis. 31 August-2 September 1977. Office of Science, FDA Annapolis, MD HEW Publication No, (FDA 173-11096, 291 pp., 1978. LA - ENG AB - A review is presented of carcinogenic compounds occurring naturally in plants and funqi. Studies have shown tobacco to contain nitrosamine, hydrazine, vinyl chloride, benz(a Ipyrene, and polycyclic aromatic hydrocarbons, all proven carcinogens. The nut of the cycad plant, sometimes used as a source of starch, may contain cycasin, which is known to induce carcinomas of the liver, kidnev, and intestine in laboratory animals. Among fungal carcinogens, ethyl carbamate (urethane), a byproduct of food and \, beverage fermentation, has been shown to induce lung and liver tumors when adm i n i s t or ed to mice -and newborn rats, respectively. Mycotoxins, particularly aflatoxin B1 (and to a lesser extent B2, Gl, and G2 1 produced by the fungus Aspergillus flatus is an extremely potent carcinogen and readily contaminates many types v of grains and oilseeds. It is postulated that many other naturally occurring carcinogens are present in the envlronment but these are generally thought to be weak or adequately defended v,, against by normal detoxification mechanisms, repair enzymes, and natural protective substances in -sods (eg, indole derivatives in vegetables). (99 Refs) R&S 138843 00005753 VINYL CHLORIDE PAGE 34 43 AU - Chatter)! DC ', Greene RF ', Gallelli Jr AO - Pharmaceutical Development Service, Fharmacy Dept., Clinical Center, NIH, Bethesda, HD, 30014 TI - MECHANISM OF HYDROLYSIS OF HALOGENATEO NITROSOUREAS. SI - CATH/79/00538 SO - J Pham. Scii 67(111:1537-1533 1976 LA - ENG A3 - The hydrolysis of chlorozotocin (CZT), carmustine (BCNU). lomustine (CCNU 1. samuslina (methy1-CCNU1. 1,3-b i s ( 2-f luoroethy 1 )-l-n l trosourea , and streptozoTocin ( SZT 1 were inves T i gated using CZT as a mccal. Tha hydrolytic reactions of tha nitrosouraas at pH 3-8 represented a summation of ua'erand hydroxide ion-catalyzad reactions, Tha latar reaction was tha sum of two parallel reactions. Tha relative contribution of aach reaction dapandad upon pH, which resulted in different product distributions. Dianionic phosphate increased tha production of free chloride ion without causing a significant change in the hydrolysis rata. Tha active alkylating intermediate of tha chloroathylnitrosouraas under physiologic conditions has not yet been identified, but it may be The 3-chloroethyl cation or tha corresponding diazonium hydroxide. Tha increased chloride ion production caused by phosphate dlanion led to a proposed mechanism whereby the 2-cr.loroethylcarboniu... ion acts as a bifunctional alkylating agent of phosphate dianion. The 2-chloroethylcarbon1 urn ions derived from BCNU, CCNU, mathyl-CCNU, and CZT may act as bifunctional alkylating agents to form interor intrastrand nucleic acid cross-links. Tha inability of the non-haloganatad nitrosoureas (such as SZT) to form bifunctional reactive intermediates may account for Their lower activity. The higher activity of the haloggnated nitrosoureas may also be caused by siqnificant production of acetaldehyde and vinyl cation products at physiologic pH. (11 Refs) 44 AU - Curran KL ! Kupchella CE ; Sandcz J I Tamburro CH AD - Cancer Center and Div. Diqestive Diseases and Nutrition, Univ, Louisville Sch. Medicine, Louisville, KY TI URINARY GLYCOSAMINOGLYCAN PATTERNS IN HUMAN HEPATIC ANGIOSARCOMA, HEPATOMA, AND IN WORKERS AT RISK FOR ANGIOSARCOMA (MEETING ABSTRACT). SI ICDO/79/01166 SO Gastroenterology; 75(5) = 959 1978 LA ENG AB A previous stud'.' reported an aberration in qlycosaminoglycans (GAGs ) eluted from an 1 on-exchange columns with 1.25 and 1.5 M Ns Cl m The urine of patients tilth hepatic angiosarcoma. A controlled pilot study examined urinary GAG patterns in workers at risk for angiosarcoma. Six individuals with a history of nigh vinyl chloride exoosure and documented 11 ,'er disease were paired with individuals with a high 5'pasure index To vinyl chloride but no clinical liver disease. Similarly six persons with low exposure but abnormal liver function were paired with low exposure/normal liver function indlviduals, A 24-nn urine was 00005753 VINYL CHLORIDE ( PAGE 25 -_\4 c collected from each individual and the GAGs analysed by anion-exchange chromatography. Individuals with clinically active c liver disease at the time of this study were found to ha"e urinary GAG excretion patterns which were similar To those ^ described in angiosarcoma. No significant differences were found between high vs low vinyl chloride exposure or between those with inactive liver disease and those with normal liver function. GAG (.' excretion was also studied in an additional hepatic angiosarcoma and human hepatoma and confirm The reported urinary changes. These findings support the concept that urinary GAGs are 30 increased only in active hepatic disease and may be useful in evaluating The degree of activity at the various stages of liver (/) disease in humans, (no Refs) 45 AU AD Jones RN ; Neill H Tuiane Medical Center, New Orleans, LA W CO CD TI OCCUPATIONAL LUNG DISEASE. SI CARC/79/00464 cn SO Respir Care! 23(10)1989-998 1973 LA ENG AB Occupational lung disorders are reviewed with regard to their causative agents and the pathologic responses evoked, Oust macules (which are caused by inhaling tin, barium, iron, or coal ( salts), pulmonary fibrosis, hypersensitivity pneumonia, beryllium 1 lung disease, and obstructive airwavs diseases are discussed. Asbestos, arsenic, chromates, nickel radioactive inhalants, the halo ethers, and vinyl chloride monomer may induce respiratory tract tumors. Asbestos may also cause cancer of the larynx and carcinoma of the gastrointestinal tract, and brain Tumors and hemangiosarcoma of The liver may result from exposure to vinyl chloride. The diagnosis of occupational lung disease is discussed, as is the setting and enforcement of permissible dust exposure levels, (10 Refs) c 46 AU AO TI SI 50 LA AO Tamburro CH I Creech JL I Davis A I Greenberg RA Cancer Center, LViiv. Louisville Sch. Medicine, Louisville, KY INDOCYANINE GREEN CLEARANCE AS THE PROSPECTIVE INDICATOR OF HEPATOCELLULAR CHEMICAL TOXICITY (MEETING ADSTRACT). ICD3/79/00973 Gastroenterology; 75(5):989 1978 ENG Standard biochemical liver tests (alanine (SGPT) and aspartate am l r.otrans f erase , gamma glutamyl Transpopt l dase , alkaline phosphatase (AP ), bilirubin, lactic acid dehydrogenase, proThrombIn Time, albumin, and cholesterol) are The mainstay for clinical screening of liver injury, including cancer development, In industrial envIrenmgnts. Twelve-hundred chemical workers were Screened with physical examination, standard bIochemica 1 liver tests (S3LT) , liver-spleen scans and indocyanine green (ICG) clearance (0.5, 2.5, & 5.0 mg/kg doses) over a four-year period. Individuals with persistent abnormalltles received a liver biopsy. Every employee had a ranked ordered exposure work history for 22 chemicals used at 350 job classifications over The past 35 c. L L L 00005754 VINYL CHLORIDE PAGE 26 yr~. The frequency with which each S3LT and ICG could identify liver injury were studied. ICG was found to be the most effective in correctly identifying the presence of liver damage. Vinyl chloride workers also showed a progressively increased frequency of abnormal ICG clearances with progressive chemical exposure. The SGPT, AP> and other studies only show increased abnormalities late in the exposure, often concomitant with clinical manifestations of overt hepatic disease. This data illustrate th inability of SBLTs to detect early latent hepatic injury and the ability of ICG clearance to identify prospectively early. developing lesions and follow their progressive course, (no Refs 30 (Jo (/) 47 AU - Roche J I Fournet J ! Hostein J ; Panh M ; Bcr.net-Eymard JB AO - Clinique d'Heoatologie-Gastroenterologie, C.H.U. de Grenoble. Hopital des Sablonsi F 33700 La Tronche. France II - HEPATIC ANGIOSARCOMA DUE TO VINYL CHLORIDE. REPORT OF 4 CASES. SI - CARC/79/C0300 CO 03 00 O SO - Gastroenterol Clin Biol; 2(8/91:669-678 1978 LA - FRE A3 - Angiosarcomas of the liver developed in four men (aged 63. 43, 33, and 42 yr 1 who had worked in the production of vinyl chloride V (VC) for 12, 26, 10, and 12 yr, respectively. Initial symptoms were abdominal pain in three patients and back pain (due to metastases) in cne. The most constant laboratory indication was elevated serum alkaline phosphatase (55-77 ml 11 i (m )IU 1', ar.mma-glutamy 1 transpsp t i dases were markedly elevated (217 and 293 mlU) in the two patients in which they were measured. alpha-Fetoprotein was normal, and S30T and SGPT were close to normal. Two patients had hepatomegaly, which was the principal L clinical finding in the literature on other VC-induced angiosarcomas. Arterlography revealed the angiosarcoma in the four patients, although liver scans with Tc99,,, also indicated liver pathology in two patients. Gastrointestinal tract c hemorrhage occurred in two patients and hoivorrhaqe into the peritoneum in two. Survival was 2-13 mo. Clinical, biochemical and histological features of previously reported patients with VC-induced angiosarcomas are reviewed. (50 Refs) 48 AU AD TI 51 SO LA AB Green T I Hathuay DE Imperial Chemical Industries Ltd. Central Toxicology Lab. Aider-ley PsirK * Cheshire 5KI0 ATJ England INTERACTIONS OF VINYL CHLORIDE WITH RAT-LIVER DNA IN VIVO. CARC/79/Q0C07 Chem Biol Interact; 22( 2/3 ): 211-224 1973 ENG The reaction of vinyl chlcride (VC) with 1 i war DMA in Wistar rats and The reaction of chloroacataldehyde (CAA) and calf Thymus DNA wars lnwsfisated. 9b* Ta-D - 2 ' -Ceoxvr 1 bo f uranosy 1 imidazo-(2 1l J-cjrina (*Thsnodeoxyadenosins) and lbe T ci-D-2 *-deoxyrI bo furanosy1-1,2-d1hydro-2-cxo1 mldaso-(12-c) -py rimidine ( e Thonodeoxycy 11 d l n* ) uere identified in The enzyme hydrolysates obtained (1) from coif thymus DNA That had been L L L 00005755 VINYL CHLORIDE PAGE 27 modified by chemical reaction with CAA and (2) from liver DNA prepared from rats that had been exposed po to VC in their drinking water (250 ppm) for approx 2 yr. Thus> VC-derived cnloroethyiene oxide and/or CAA behaved as a bifunctional alkylating agent toward deoxyadenosine and deoxycytidine residues of DNA. It is concluded that modification of the DNA structure by VCi through imidaoo-cycliration of deoxyadenosine and deoxycytidine residues and through depurination of the resulting ethancdeoxyr.denosine residues, is related to the mutagenicity of VC. The carcinogenicity of VC in animals and in humans and its mutagenic properties after biotransfcrmation (by microsomal ensymes ) into the active metabolites chloroethylene oxide and CAA, which show electrophilic reactivity toward DNA, would appear to conform with the idea of a relationship between carcinogenesis and mutagenesis. (41 Refs) 49 AU - Cylwik B J Grabcwski H J Gula-Fietkiewicz E AD - Zaklad Anatomii Patoiogiconej , Instytut Biostruktury AM, ul. Kilinskiego 1, 15-230 Bialystok, Poland TI - PRIMARY MALIGNANT HEMANGIOENDOTHELIOMA OF THE LIVER WITH META5TASE5 TO THE LUNGS, ADRENAL GLANDS AND LYMPH NODES. SI - ICDB/78/30339 50 - Pol Arch Ned Uewnl 60(21:103-107 1973 LA - POL AB - Malignant hemanqioendotheiioma of the liver and metastases to the left lung, adrenal glands and lymph nodes were found at autopsy in a 69-yr-old man who died from brenchopneumonia with lung emphysema, circulatory insufficiency, chronic gastritis and cachexia. The patient had never been exposed to vinyl chloride, Thorotrast, or any other substance believed to induce such tumors. (11 Refs) 50 AU - Simmon VF ; Kauhanen K I Mortelnans K ; Tardiff R AD - Stanford Res. Inst., Menlo Park, CA TI - MUTAGEMIC ACTIVITY OF CHEMICALS IDENTIFIED IN DRINKING WATER (MEETING ABSTRACT). 51 - IC0S/73/30040 SO - MutaT Rest 53(2):262 1973 LA - ENG AB - Approx 300 chemicals have bean identified in finished drinking water in the US. Some of these chemicals are known to be carcinogens in rodents (eg, aldrin, carbon tetrachloride) and/or humans (benoopyrana ). Me ha'<e begun to analyse these chemicals for their mutagenic activity in microorgamsms. Of 123 chemicals that we hawe tested, 21 were mutagenic in preliminary spot tests on Salmonella typhi n-ur 1 urn TA100 (without metabolic activation). We have obtained dose-dependent mutagenic responses with 19 of these compounds (bincopyrene> brcmochlorcmethane, browodichlorowe thane bromoform , bromomethane ; n-butyl bromide, sec-butyl bromide, tert-butyl bromide, technical crade chlsrdane, ch1 orcd1bromomethane b1s(2-chlcroethy1 1 ether, dIbromomethane, 1,2-dlchloroethane, 1 ,1--d1 chiorca tny1ene, hexachloro-113-buTadiene> iodomethane , methyl chloride, methylene c c c 33 (/) eg 03 03 c c c L e L > w*v* c 00005756 C" VINYL CHLORIDE PAGE 23 ( cchloride and vinyl chloride) in strains of S typhinuriu. Additional mutagenicity assays using Escherichia coli KP2 and c Saccharomyces cerevisiae 03 are underlay, (no Refs) 51 AU - Rannug U ! Ramel C c AO - Environmental Toxicology Unit, Wallenberg Lab.. Univ. Stockholm, Stockholm, Sweden TI " THE MUTAGENICITY AMO METABOLISM OF 1,2-0ICHL0R0ETHANE (MEETING ABSTPACT ). c SI - ICD3/73/30026 SO - Mutat Res'. 53(21:251-252 1973 LA - ENG AE5 - The tar-like waste product from the vinyl chloride production has shown mutagenic properties in the Salmonella micrcsome test using 3J strain TA1535. Ethylenedichloride (1>2-dichloroethane ). one of the main components in the tar, was also mutagenic in the test (/) but cannot be responsible for the mutagenicity of the total tar. In both cases an increase in the number of mutants is seen when the metaboliping system is present, but the activation of the tar is NAQPH-dependent and the activation of 1,2-dichioroethaoe is NADPH-independent. The metabolism and mutagenicity of the latter was therefore studied in more detail with Salmonella and C*5 03 00 t* 00 different metabolising systems. From the results it can be concluded that the activation to a more potent mutagen is carried out by enpymes in the soluble fraction. This activation 13 further stimulated by addition of glutathione to the system, indicating a formation of a conjugate between 1, C-dichloroethane and glutathione. 1,2-0ichloroethane has also been tested on the same Salmonella strain (TA-1353) with perfused rat-liver as e metabolizing system. In this test the bile produced, within half an hour after The addition of 1,2-dlchloroethane, is strongly mutagenic, while no effect can be seen in The perfusate. A corresponding enhancement in The mutagenicity of 1 1>2-dlchloroethane was seen if the bacteria were incubated in the presence of enzyme preparations of glutathione S-Trans farases, glutathione and 1,2-dichloroethane. It can Therefore be concluded That one metabolic pathway of 1,2-dlchloroethane involves direct c conjugation with glutathione. This conjugate is excreted in the bile, where The mutagenicity is found. Normally the Conjugation with glutathione is regarded as a detoxication, but in this case the effect is quite the contrary. The substance is activated by L The conjugation. The results also illustrate the usefulness of the mu Tag-on 1 c 1 Ty test based on Salmonella and in vitro metabolism In Tracing metabolic pathways which could be more difficult to detect in vivo, (no Pet's) L L 00005757 VINYL CHLORIDE PAGE 29 .\A 52 AU AD TI SI SO LA AB 53 AU AO TI SI SO LA A3 > Ivanetich KM ; Kate: ID '> Aronson I Dept. Physiology and Medical Bi ochemi s Try > Univ. Cape Town Medical Sen., Capa Town, S. Africa THE METABOLIC ACTIVATION Or VINYL CHLORIDE IN VITRO (MEETING ABSTRACT). ICDB/73/30020 MutaT Ras", 53(2):209 1978 ENG In the presence of hepatic mlcrosomes . vinyl chloride produces a 'Type I` difference spectrum and stimulates carbon monoxide inhibitable NADFH consumption. Vinyl chloride> therefore, appears to bind to and to be metabolised by hepatic microsomal cytochrome P-950 in vitro. The Ks value for the binding of vinyl chloride to cytochromes P-950 in uninduced microsomes (00 mM) is decreased to approx 10 niM following phencbarbi tal or 3-mathylcholanThrana induction. The change in Amax and max velocity vaLues are not altered by 3-methyichoianthrene induction, but are enhanced 2-to 3-fold by phenobarbital induction. These resuts indicate that more one type P-950 cytochrome binds and metabolites vinyl chloride, but that the cytochrome P-950 induced by phenobarbital plays a major role in these processes. In the presence of NADPH and hepatic microsomes. vinyl chloride mediates the degradation of the heme moiety of cytochrome P-950. (Aider these conditions, the levels of other hepatic microsomal enzymes are not affected. The effect of vinyl chloride on The levels of cytochrome P-950 is slight in uninducad or 3-methvlcholanthrene microsomes but is striking in phenobarbital microsomes. The effect is abolished in the absence of NADFH or vinyl chloride and is diminished by reduced glutathione. The activated metabolite of vinyl chloride produced by cytochrome P-950 may in part mediate the mutagenic and carcinogenic effects of vinyl chloride, (no Refs) Drevcn C J Kuroki T ! Montesano R International Agency for Res. on Cancer, 150 cours Albert Thomas, 69000, Lyon, France MICROSCUE-MEDIATED MUTAGEMESIS OF A CHINESE HAMSTER CELL LIME BY VARIOUS CHEMICALS (MEETING ABSTRACT). IC0B/73/29991 Mutat Res; 53(2 ):101-102 1973 ENG A mlcrosome-mediated mutagenesis system for mammalian cells has been established using V79 cells, a Chinese hamster cell line. The cells, qrotin in monolayer, were treated with the chemicals to be tasted in the presence of a post-mitochondrial fraction (515) and cofactors for 1 hr or more (denendlnq on the chemicals), washed and incubated for 2-3 hr on fresh culture medium, and then the cells mere plated for Toxicity and mutagenicity assays. Mutation lias determined by resistance to 20 uq/ml 8-azagua.oine or 1 mlilitl ouabain. In our assay system. S15 ar.d cofactors were not found to be toxic to the Cells. The chemicals tasted included 12 niTrosamtnes , 3 chlorinated hvdrocarbons> seyeral polycyclic hydrocarbons and aflatoxln Bl. Dose-related mutation and c c c c c 30 <z> GO 03 03 > CO t c c L L ( c ( (. '1 '.'V', /*: J'-- '-'-X.'.Xr V. V E-SpEAv')'-'A-a -vi-c-s' -VV*'X\r-.-'-,Rn ,;^,A 1 C, ~ 00005758 VINYL CHLORIDE 33 99 (/> W oo oo ut o ( PAGE 30 cytotoxicity were induced after incubation wiTh dimetnylniTrosamine (DMN) only in the presence of both the S15 fraction of the livers of BD-V1 male rats and the cofactcrs. Pretreatment of rats with phenobarbital (PB) led to an approx E-fold increase in the mutation rate over thal uith the untreated rats are DtiN concentrations ranging from 2 to 50 millih. while aminoacetonitrile pretreatment reduced the mutagenic effect. Methylcholanthrene pretreatment resulted in an increase in The mutation frequency uith a higher concentration of CttN (50 milliM). A good correlation uas found between in vivo careinogenicity and this mutagenesis test: uith the exception of H-nl trosomethylphenyiamine i the carcinogenic nltrosamines (DilNi N-ni trosodiethylamine. N-nitrosodl-n-propylam 1ne> N-nitrosodi-n-butylamine> N-nitrosodi-n-pentylaminei N-nitrosamethy1-n-propylamine N-nitrosomorpholine > N-nl Trosopyrrolidin, N-nltroso-N'-methylpiperagine > N-nitrosomethyIphenylamine ) uere mutagenic to V79 Chinese hamster cells in the presence of the PB-pretreatsd 515 fraction and cofactors. The non-carcincgenic N-nltrosodiphenylamine and N-n l trosomethy1-1ert-buTyi-amine had no mutagenic effect. Vinyl .chloride i vinylidene chloride and 2-cnlorobutadi ene were tested) but only vinyl chloride uas mutagenic in the presence of FB-pretreated S15 and cofactcrs while the others uere found to be toxic but not mutagenic. The mutagenicity of polvcyclic hydrocarbons and aflatoxin 61 is now under investigation, (no Refs ) 54 AU - Leonard A ; Decat G ; Leonard ED AD - Mammalian Genetics Lab., C.E.N-S.C.K.. 6-2400 Mol) Belqium TI - CYTOGENETIC INVESTIGATIONS ON LYMFHCCYTE5 FROM WORKERS EXPOSED TO VINYL CHLORIDE (MEETING ABSTRACT). SI - ICDB/70/E9965 SO - Mutat Res) 53(2):219 1970 LA - ENG AB - Male Workers from the polymerigation department of a vinyl chloride (VC) factory, people employed in the laboratory of another VC plant and controls from outside the factory environment were examined for the presence of chromosome aberrations in blood lymphocytes. The incidence of chromatid aberrations (gaps and breaks) and of chromosome gaps was not significantly increased after VC exposure > but more severe chromosome anomalies such as chromosome fragments) rings and dicentrics were observed in most of the workers from the polymeriration department. The medical hlstorv of the workers shows that most people from the pol\n-er i ga t i on department received several radioqraohies. The conclusion that the chromosome fragments and chromosome dicentics result from VC exposure remains) Therefore) dubious. IT is much more probable that these anomalies originate from the diagnostic exposure to lonlolng radiation, (no Pefs) c c ( c c c ( c c c L L L 00005759 VINYL CHLORIDE PAGE 31 55 All AD TI SI SO LA A8 56 AU AD TI SI SO LA Fueerova M ; Polivkova Z Pediatric Dept., Postgraduate Medical Inst., Prague> Czechoslovaki a MUTAGENIC EFFECTS OF DIFFERENT MUTAGENS ON HUMAN CHROMOSOMES IN VITRO AND IN VIVO AS DETECTED BY CONVENTIONAL AND 'HARLEQUIN' METHODS (MEETING ABSTRACT). ICQ3/73/29960 Mutat Res; 53(2)=215 1973 ENG Ip vitro studies uere performed which considered the mutagenic effects of Mitomycin C, Aiaxan, triethylene thiopnosphorride (TEPA), Imuran i Vincristine and Vinblastine on peripheral human lymphocytes exposed for the last 29 hr of cultivation to 10**-3> 10**-9i 10*#-5j 10**-6 and lO***-? mg/ml concentrations of these chemicals. The lowest concentrations were ineffective when using conventional cytogenetic technique. The possible mutagenic effect of this lowest ccncentration of 10**-7 mg/ml was tested also by 'harlequin' method scoring the numbers of sister chromatid exchange (SCE). Oisly Mitomycin Ci Alexan, Imuran and TEPA were found to increase the number of SCE, while Vincristine and Vinblastine did not induce any significant chances. In vivo studies dealt with patients treated with Imuran, with children vaccinated against variola and with workers occupationally exposed to vinyl chloride. Again both conventional and 'harlequin' techniques were used, comparing the relationship between the number of gross chromosome aberrations and The number of SCE induced by in vivo exposure to these Three muTagens. The results detected by conventional and 'harlequin' cytogenetic methods have revealed a highly specific susceptibility of human peripheral lymphocytes to different types of mutagens after in vitro and m vivo exposures, (no Refs) Barb in A ; Planche G ; Croisy A ; Malaveille C ; Bartsch H Unit Chemical Careinegen-esis, International Agency for Res. On Cancer, 150 cours Albert Thomas, 69003 Lyon, France DETECTION OF ELECTROPHILIC METABOLITES OF HALOGENATEO OLEFINS WITH Q-(9-MITR03ENZYL1PYRIDINE (NOP) OR WITH SALMONELLA TYPHIMURIUM (MEETING ABSTRACT). ICDB/73/29930 Mutat Res) 53( 2)1150 1973 ENG Metabolic conveneion of volatile substances can be assayed by passing a gaseous mixture of The test compound and oxygen (air) through a mouse liver microsomal swstem and bv trapping volatile aklylatlng metabolites by reaction with excess N3P. Using this system, epoxide formation from vinyl chloride or vinyl bromide was demons trat ed', 2-chloro-I,3-butadiene ( chloroprene ) yielded an alkylating intermediate although, 1,1-difluoroethylene , 1,1-dichi orcethylene and trichloroethylene did not. ChlorceThylene oxide, perhaps the ultimate carcinogenic metaboilTe of vinyl chloride, showed potent biological activity in various short-tern. Tests for the detection of potential 00005760 VINYL CHLORIDE PAGE 32 carcinoqens, In all the in vitro assays used> the color reaction ui th H3P snowed The highest sensitivity for detecting chloroethyLena oxide at a 2 uM concentration. S Typhimurium TA100. in The presence of a 9000 x g superernatant of PB-Treated mice> was exposed to gaseous mixtures of the following test compounds/air. Mutation rates (hi$ + rewertant coionies/umol/hr/plate) taken from the linear region of Time and dose-dependent assays either with or without NADP+> were as follows - vinyl acetate) 1(l-dlfluorethylene and trlchloroethylene 0 (0); vinyl chlo-ide 6 (2); 1.1-dichloroethylene 15 (1); vinyl bromide 26 (91`, 2-cnlcro-l.3-butadiene 51 (9); 1-chloro-l>3-butadiene 157 (31); 3.9-dlchlorobutene-1. 990 (395). 1>9-Dichlcrcbutene-2 (77X trans-isomer ), whan incorporated in the soft agar layer) showed a mutagenic effect in TA100, Microsomal fractions from mouse and human liver enhanced The mutagenicity three-fold. The putative synthetic metabolite 1>9-dichloro-Z>3-epoxy butane was> however) four times less mutagenic in TA100 than in The parent olefin, (no Refs) 57 All - Carere A Ortali VA ; Cardamone G : Morpurqo G AD - IcTituto Superior" di Sanita. Ifni vers i t a dl Rcma> Rome > Italy TI - MUTAGENICITY OF DICHL0RV05 AND OTHER STRUCTURALLY RELATED PE5TICIDES IN SALMONELLA AND STREPTCMYCE5. SI - ICOB/73/29793 SO - Chem Biol Interact: 22(2/3)1297-303 1973 LA - ENG AB - The following pesticides! apinphosmethyl, diallate> dichlorvos> EPTC (5-ethyld)propyl thiol + carbamate)) fenchlorphos > mevinphoS) monocrotophos> noruron > parathionmethyl, TriallaTe> tr i chlor-phon and vegadex were tested for the ability to induce his + rovertants in four h1st1dine-reouiring strains of Salmonella t vph i mur l um > TAI 535 (mlssense)> TAI 5I6> TAI 557 and TAI 553 (frame-shift). and resistance to low levels of streotomycin in Streptomyces coelicolor. Dichlorvos, which is a phosphoric ester with a dichiorovlny1 group as side chain, and tr1chlorphon , which is known for its spontaneous conversion in dichlcrvos> are both mutagenic in Salmonella (strain TAI 535) and StreoTomyces. Five organophosphorus pesticides similar to dichlorvos but devoid of the vinyl group are not mutaqenic. Three carbamates i diallate) triallate and veqadex, which contain a chloroallyl qroup similar to the vinyl group of dichlorvos are mutaqenic in StrepTomvces) triallate and veqadex are powerful mutaqens also in Salmonella (strain TAI 535 1; two oTher carban'aies devoid of the chlorinated group are not mutaqenic. The results Suoqest that the presence of a vinyl chloride or aliyl chlo-ide q-oup in The molecule of these pesticides is responsible for the ability to Induce point mutations in Salmonella and 51reotemyces . (Author abstract) (27 R&S 138853 j3 l.. 00005761 VIHYL CHLORIDE PAGE 33 58 AU - Ungvary G ; Hudak. A ; Tatrai E ; Lorlnc; M ; Follv G AO - Dept. Experimental Pathology, State Inst. Occupational Health Budapest, H-1550 Budapest P.O.B. 22, Hungary TI - EFFECTS OF VINYL CHLORIDE EXPOSURE ALCNe'aND IN COMBINATION WITH TRYPAN BLUE--APPLIEO SYSTEMATICALLY DURING ALL THIRDS OF PREGNANCY--GN THE FETUSES OF CFY RATS. SI - CARC/73/07366 50 - Toxicology; 11(11:45-55 1578 LA - ENG AB - The teratogenic and embryotoxic effects of vinyl chloride and/or trypan blue were investigated in CFY rats. VC was found in the fetal and maternal blood as well as in the amniotic fluid of pregnant CFY rats exposed to an atomospheric concentration of 5,500, 13,000, or 33,000 mg/m^*3 VC for 2.5 hr on gestation day 18, indicating the permeability of the placenta to the agent. Investigation of the offspring of oregnant rats exposed Continuously to A ,000 mg/mh*3 VC curing the first, second, cr last trimester showed that VC has no teratologlcal or embryotoxic effects when applied during the second or last Trimester. However, exposure to VC during the first trimester resulted in an increased fetal mortality and in the manifestation of embryotoxic effects. Fetal losses and the induction of CN5 maiformaticns due to trypan blue (50 mq/kq SC on gestation days 7 and 8) were not potentiated by 4,000 mg/m#*3 VC. Occupational exposure of women of childbearing age may be hasardaus. (34 Refs) 59 AU - Thomassen MJ ; Buoen LC ! Brand I ; Brand KG AD - Dept. Pediatrics, Case Western Reserve Univ., Cleveland, CH, 44106 TI - FOREIGN-BODY TUMORIGEHESIS IN MICE: DMA SYNTHESIS IN SURFACE-ATTACHED CELLS DURING PRENEOPLASIA. 51 - CARC/73/07817 SO - JNCI; 61(21:359-363 1978 LA - ENG AB - DflA synthesis throughout the stages of foreign body (FB) Tumor i genes i s was investigated to provide insight into the role of macrophages in The development of neoplasia. Four una 1 as 11 c I red vinyl chlor i de-'11 ny 1 acetate copolymer films (15 X 22 mm) were implanted sc into The flanks of (CBA/H x C3A/H-T61F1 mice. The animals were pulsed with <I"3!I-Thymi di re at various times durlnq the next 15 mo. DNA synthesis occurred consistently in Tile film-attached cells, predam i nan t iy macropr ages , throughout the preneoplastic phase in both male and female mice. The iabelinq rate was calculated To be 5-15 cells/1,CD0, The cell turnover- rate to be 1.5X-5.5//daw, and tne mitotic rate To be less Than 3 cells/10,000. Giant cells with less Tran 10 nuclei were labeled synchronously end as1, nch'-cnously . No DNA synthesis was detected in giant cells with greater than 10 nuclei. The results show that the macrophages were not dormant with respect to DMA synthesis, (16 Pefs ) - -:y n vv'-;g -j :rj7A 00005762 VINYL CHLORIDE PAGE 34 60 AU AO TI SI SO LA AB 61 AU AD TI SI SO LA AB 62 AU AD TI SI SO LA AB Delorme F Centre Hospitalier Regional de la Hauricie, C.P. 1130, Shawini gan-Sud, Quebec, Canada TEN CASES OF ANGIOSARCOMA OF THE LIVER IN VINYL CHLORIDE WORKERS IN CANADA. CARC/73/07702 Ann Anat Pathol (Paris); 23(2)=97-104 1978 FRE Ten cases of hepatic angiosarcoma were found among employees of a vinyl chloride plant in Shawinigan, Canada. All patients had been exposed To vinyl chloride vapors. The av age of the patients Was 50 yr (41-61 yr)", the length of occupational exposure to vinyl chloride averaged 16 yr 10 mo (ranging from 5 yr, 3 mo To 26 yr); and the time lapse between first exposure and diagnosis was 20.5 yr (11-13 yr). Survival after diagnosis averaged 4.4 mo (1-8 mo). The risk of hepatic angiosarcoma appears To be highest among vat cleaners, pipe fitters, and polymerigation workers. (16 Refs ) Delorme F Centre Hospitalier Regional da la Mauricie, C.P. 1130, Shawlnigan-Sud, Quebec, Canada ASSOCIATION OF AN ANGIOSARCOMA OF THE LIVER WITH A HEPATOMA IN A VINYL CHLORIDE WORKER. CARC/78/0 7701 Ann Anat Pathol (Paris); 23(2):105-113 1973 FRE A 51-yr-old man who had been exposed occupationally to vinyl chloride vapors for 23 yr, 4 mo died in a coma with jaundice. Autopsy revealed the association of a hepatic angiosarcoma with a hepatoma. Alcohol consumption by The patient was negligible. The association of the two tumors is the first ever to be reported in tlie literature. This case raises doubts about the theory That suggests that vinyl chloride induces vascular Tumors in humans. (22 Refs ) Vainio H Dept. Industrial and Toxicology, Inst. Occupational Health, Haartman 1nkatU 1, SF-00290 Helsinki 29, Finland VINYL CHLORIDE AND VINYL BENZENE (STYRENE)--METABOLISM, MUTAGENICITY AMO CARCINOGENICITY. CARC/73/07652 Chem Biol Interact; 22(11=117-124 1973 ENG The metabolism, mutagenicity, and careinoqenicttv of vinyl chlorida, (VC ) and winv/i b'Sn^sn* ( j T y r "A? ) are reviewed briefly, VC and styr-isn* are mutagenic in bacterial test systems, Oro seph 1 1 a yeast, and mammalian cells. The muT aqen 1 c 1 ty o* VC in bacterial test systems decends , at least partially, on me'cbollc activation by microsomal ercvmes. Chicroethylene oxide, the primary bioTrans formaT1 on product of VC, is a potent mutagenic and alkylating agent. Styrene is mutagenic to Salmonella 00005763 VINYL CHLORIDE PAGE 35 Typhimuriurn. but only after metabolic activation, whereas styrene oxide, its primary biotransformat1 on product, 13 mutagenic to Salmonella uithout activation. In several studies, an exce33 of chromosome aberrations (compared in th controls) was found in the lymphocytes of workers exposed to VC monomer. In addition, an excess fetal loss occurred among women whose husbands are heavily exposed to VC. Workers exposed To styrene also had increased chromosome aberrations in their lymphocytes. Eoth chloroethylene oxide and styrene oxide bind covalently to cellular macromolecules. VC is carcinogenic in rats (skin, lung, bone, liver) and humans (liver, brain, lung, and lymphatic tissue). Styrene oxide was a weak carcinogen when applied to mouse skin. Styrene is currently being tested in animals. These findings raise concern about the possible genetic risks of VC and styrene to humans, (55 Refs) 63 All - Neumayr A AD - I. Nedicinische Abteilung, KrankenanstalT Rudoltstiftung, Juchgasse 25, A-1033 Wien, Austria TI - HEW DEVELOPMENTS IN HEPATOLOGY. SI - IC03/73/27763 SO - Therapiewcche; 23(34 ):5996-5993,6000,6003-6007 1973 LA - GER AB - Recent findings in the study of liver disease are reviewed. Viral hepatitis, the hepatorenal syndrome, environmsntally induced hepatic tumors, vinyl chloride and resulting hepatic angiosarcoma, recent advancements in portal vein surgery and scmtisplencportography, and new application methods of the Chiba needle in percutaneous transnepatic cholangiography are discussed. (53 Refs) 69 AU - Matos EL i De Lustig ES AD - Departamento de Investigaciones , Instituto de Oncologia Angel H. Koffo, Av. San Martin 5931, 1917 Buenos Aires, Argentina TI - THE ROLE OF CHEMICAL CARCINOGENS IN ENVIRONMENTAL'CONTAMINATION. SI - ICC3/73/27729 SO - Medicina (B Aires); 33(2)1200-203 1973 LA - SPA AB - Known carcinogens present in the environment are reviewed. The principal fixed sources of carcinogens contaminating the atmosphere are domestic and industrial i nc i net-a t or s , in addition to petroleum refineries which emit volatile and highly carcinogenic substances. Airborne carcinogens (automobile pollutants) are considered more danserous as Thov have easier access to human repiratory passages. Solid phase aerosol carcinogens include polycyclic and heterocyc1lc aromatic nvdrocarbons aromatic amines and inorganic substances including nickel, beryllium, arsenic and asbestos. Liquid areosol carcinogens consist ..ainly of beneene compounds, biscnloromathviether, haioqenated compounds , nitrosamines and their precursors, sulfated compounds, and nitrogenated precursors of nitrous acid and nitrosamines. Gas phase carcinogens include anhydrous oxidants such as nitrogen dioxide and sulfurous 30 B9 CO CO 00 00 cn o 00005764 VINYL CHLORIDE PAGE 36 anhydride, formaldehyde, halogenated carbon compounds! and vinyl chloride. Benzopyrene and asbestos are considered to represent the greatest risk due to their high conentration and diffusion in the environment. An increase of 1 uq benzopyrene/1i000 meter*#3 of air can result in a 57. increase in tumors. Large asbestos fibers carry a greater carcinogenic risk as their ability to absorb hydrocarbons, metal particles, viral particles and other carcinogens from the air is augmented by their size. Cancer due to asbestos inhalation is greater among smokers than non-smokers. Water contamination is principally by hydrocarbon derivatives such as 3.4-dibenzanthracene. 1..5.6-dibenzantracene. 7.12-methylbenzanthracene and 20-r.iethylcolonthrene . Alimentary contamination is mainly by nitroso compounds. natural carcinogens such as aflatoxin. cycasine. arsenic, molybdenum, and food dyes. 65 AU - Rail OP AD - Natl. Inst. Environmental Health Science, Research Triangle Park, HC, 7709 TI - VALIDITY Or EXTRAPOLATION OF RESULTS OF ANIMAL STUDIES TO MAN (MEETING A3STRACT ), SI - ICD3/73/27370 SO - The Scientific Basis for the Public Control of Environmental Health Hazards, held by the New York Academy of Sciences in New York, 1-30 June, 1978. The Hew York Academy of Sciences, New York. New York, 1978. LA - ENG AB - To prevent exposure of human populations to chemical carcinogens, laboratory or experimental animal systems must be used that ulll predict human carcinogenicity. Until recently control has rot followed until epidemiological evidence of carelnogeniclty has been developed. Whether or not to institute control measures V based on laboratory evidence or on human evidence is a public policy decision. This decision must be based on good scientific evidence. The critical question is: Do tests in laboratory / animals predict for cancer in man? Attempts to correlate L. quantitative aspects cf carcinogenic!ty between laboratory animals and man are difficult. An NA5/NRC panel on pesticides attacked this problem. Six compounds, benzidine, chlornaphazineI (. aflatoxin B1. d1ethystilbestrol (DES), vinyl chloride and cigarette smoke, were reviewed. For benzidine, chlornaphazine and cigarette Smoke the mg/kg lifetime exposures estimated for man and for the mo s t sensitive animal species were close. With The other compounds the differences appear greater but with DES and vinyl chloride the human population is still at risk. Other data also suggest That the results of tests in laboratory animals can predict for the human population and therefore can be used to prevent human exposure and disease, (no Pefs) 00005765 VINYL CHLORIDE PAGE 37 66 AU - Cottine BR AD - U.S. Occupational Safety and Health Review Commission! Washingtoni DC TI - FU3LIC" HEALTH DECISION-MAKING AND THE LEGAL FROCESS IN THE UNITED STATES: THE REGULATION OF VINYL CHLORIDE (MEETING ABSTRACT). 51 - ICDB/73/27368 SO - The Scientific Basis for the Public Control of Environmental Health Hazards i held by the New York Academy of Sciences in New Yorki 21-30 Junet 1973. The New York Academy of Sciences! New York, New York, 1976. LA - ENG AB - Public health decision-making on the hazards of vinyl chloride exposure occurred in the legal process of the United States through two functional systems. At a federal level 1public-ordering' was accomplished prospectively through authority delegated by Congress to several administrative agencies including the Consumer Product Safety Commission and the Occupational Safety and Health Administration. Investigatory hearings, rulemaking action, and enforcement actions were commenced. Public ordering also occurred retrospectively through State worker compensation systems. However, the retrospective systems do not integrate with, or provide data for, prosoective action. Moreover, retrospectivs ordering has a limited sensitivity and field of view due to statutory limitations on the compensability of occupational disease, variable latency periods, access controls on the system, and data visibility. Though limited retrospective data were available on vinyl chloride, prospective regulatory actions necessarily relied on experimental and epidemiological data. Frivate ordering also occurred on a limited basis, (no Refs) 67 AU - Norpoth K AD - Munster, W. Germany TI - SAFEGUARDING THE QUALITY OF MICROBIOLOGICAL MUTAGENICITY TESTING OF FOREIGN SUBSTANCES IN ROUTINE LABORATORY. SI - CARC/73/07321 SO - Staub-Re1nhalt LuftI 33(6 ):235-239 1970 LA - GER A3 - General methodological and statistical questions relevant to the use of bacter'ia in mutagenicity tests of eny i ronmen Tal comoounds are discussed. The probability of carcinogenic effects can be assessed from the results of mutagenicity tests cn mlcrocrqanlsms such as Salmonella Typhimurlum. the development of routine bacterial mutagenicity tests requires standardization, quality , control, and statistical validation of the results. The prerequisites include positive and negative controls, continuous checks on the indicator bacteria, constant activity of the mammalian oxygenase used, species- specificity of the oxygenase, arid attention to the influence of the solvent, 3,9-benco(a Ipyrene, aflatoxin B1, vinyl chloride, diaminotoiuene, known care i nogens , and b 1 s ( chi oroe t hy 1 )e t her ,' a suspected carcinogen, were found to induce mutations in mlcroorgantsms. (10 C.C."*;. V' .-1 33 & w 00 00 ui oo c 00005766 VINYL CHLORIDE PAGE 38 /A c Refs ) c c 68 AU - Zeuthen J AD - No affiliation gi van TI - EVALUATING THE RISK OF CHEMICAL MUTAGENS. c SI - ICC3/73/Z5732 SO - Ugeskr Laeger; 190(131:728-730 1973 LA - DAN AB - Recent studies on mutagenic chemicals are c carcinogenic substances but only feu non-carc i nogen i c substances are mutagenic. Most mutagenic carcinogens cause frameshift mutations. DDTi dieldrin, aldrin, vinyl chloride and many hair dyes are mutagenic, (no Refs) c 69 All - Popper H 5 Thomas L3 ; Telles NC I Falk H ; Selikoff IJ AD - Stratton Lab. Liver Disease) Mount Sinai Sch. Medicine, City Unlv. Hew York, Mew York, NY TI - DEVELOPMENT OF HEPATIC ANGIOSARCOMA IN MAN INDUCED BY VINYL CHLORIDE, THCROTRAST, AND ARSENIC. COMPARISON WITH CASES OF UNKNOWN ETIOLOGY. SI - CARC/73/07005 SO - A.., J Pathol; 92(E):349-376 1973 LA - ENG AS - Human hepatic angiosarcomas that occurred following exposure to vinyl chloride, Tncrotrast, or arsenic (medicinal and industrial) and cases, including those in children, of unknown etiology were studied to establish diagnostic criteria and evolutionary features. The uniform evolution suggests that there is also an environmental factor in the cases of unknown etioloay. The precursor stage is charactericad by areas of combined hyperplasia of hepatocytes and a variety of sinusoidal and perisinusoidal cells associated with an excess of reticulin and with sinusoidal dilatation. Silver stainings indicated reticulum formation by the perisinusoidal cells, presumably the lipocytes. The hepatocvtic proliferation suggested a hopatocarcinogenic, but usually not fully expressed, potential. The mixed hyperplasia of the various sinusoidal cells proceeded to an overgrowth of angiosarcoma cells, presumably derived from endothelial cells. In early stages they were usually in contact with hepatocyte ( i n tralobula.r growth). A trabecular arrangement resulted from loosening of the lobular plate arrangement by dilatation of sinusoids, leading To primary peliosis. With di sappearance of the hepatocytes, va.rious growth patterns developed, terminating in nodular, solid angiosarcoma composed of either sp1ndle-shaped or polyhedral cells that underwent necrosis or hemorrhage (secondary peliosis). The interaction between hepatocytes a.nd sinusoidal cells reouires elucidation. (110 Refs) c c L L L *, 00005767 VINYL CHLORIDE PAGE 39 70 AU - Uatanabe PG ; Zempel JA ; Pegg OG I Gehring PJ AD - Toxicology Res. Lab., Health and Environmental Res. > 1503 Building. Dow Chemical Co.t Midland, MI, 48640 TI - HEPATIC MACROMOLECULAR BINDING FOLLOWING EXPOSURE TO VINYL CHLORIDE. SI - CASC/73/06973 SO - Toxicol Appl Pharmacol! 49(3)1571-579 1978 LA - ENG AB - Male Sprague-Oawley rats were exposed by inhalation to 1, 25, 50, 250, 1,000, or 5,000 ppm **14C-labeled vinyl chloride (VC) for 6 hr, and covalent binding of VC to hepatic macromolecules and nucleic acids was studied to determine if VC-induced carcinogenesis might be related to electrophilic alkylation of macrcmoiecules in vivo. The total amount of VC metabolized and hepatic glutathione (GSH) content were also measured. The total amount of radioactivity bound to hepatic macromolecules did not increase propertionately to the increase in the exposure concentration of VC, but it was related directly to the total amount of VC metabolized. At exposure concentrations greater than 50 ppm, the total metabolism of VC and covalent binding appeared *o correlate with the induction of hepatic anglooarcinomas in the rats. Isolation of RNA and DMA by a nondigestive procedure from the liver of rats exposed to 1, ICO, 250, and 1,000 ppm VC failed to reveal any detectable radioactivity. Hepatic GSH was depressed significantly only at greater than or equal to 100 ppm, suggesting that VC carcinogenicity is related to a decreased ability to detoxify the reactive metabolites of VC. The results do not associate the carcinogenic affect of VC with a disproperticnate increase in binding of electrophilic metabolites of VC to hepatic macromolecules as the exposure concentration is increased. Moreover, the lack of preferential binding of the metabolites to the hepatocyte nucleic acids suggests that the careinogenicity of VC may not be associated directly with this commonly accepted mechanism of careinoqenes1s. (27 Refs) 71 AU - Fleiq I ; Thiess AM AD - Dept. Occupational Medicine and Health Protection, BASF Akt i enqesel Iscnaf t , 6700 Ludwi gs'naf an , W. Germany TI - MUTAGENICITY OF VINYL CHLORIDE. EXTERNAL CHROMOSOME STUDIES ON PERSONS WITH AND WITHOUT VC ILLNESS, AND ON VC EXPOSED ANIMALS. SI - CARC/70/06937 SO - J Occup Med; 20(8)1557-561 1978 LA - ENG AB - Chromosome analysis was performed on lymphocyte cultures from 6 workers with an estimated degree of exposure to vinyl chloride (VC), 4 workers whose degree of exposure was monitored, 20 workers showing symptoms of VC illness after unknown degrees of exoosu-e, and 1 patient with VC-induced angiosarcoma. Bone marrow cells from Chinese hamsters exposed to VC by inhalation (2,500 or 5,000 ppm for 4 hr/day x 5) cr ip injection (300 or 600 mq/kq/day x 5) were also analyzed. The frequency of chromosome aberrations was not increased relative to controls in the exposed workers i-s-* 00005768 VINYL CHLORIDE PAGE 60 C ( (. ( (. (, A-: - with no signs of VC illness. The frequency of aberrant metaphases in the workers with VC illness was 5.2k excluding gaps and 11.2k including gapsi these values were significantly higher than the control values of 2.1'/. and 5.5k, respec T i wely. The rate of aberrant metaphases in the angiosarcoma patient was 7.3k excluding gaps and isogaps and 16.6k including gaps and isogaps. The frequency of structural abnormaliTies in the VC-Treated hamster cells was also signiflcantly higher than that in the control colls, inclusive and exclusive of gaps. (15 Refs) 72 AU - Hans teen IL ; Hillestad L ; Thi i s-Evensen E Heldaas SS AD - Lab. Genetics. Telemark Central Hosp.. Olavsgt. 26. 3900 Porsgrunn, Norway TI - EFFECTS OF VINYL CHLORIDE IN MAN. A CYTOGENETIC FOLLOW-UP STUDY. SI - CARC/73/06925 SO - Hut at Res; Sit 2 ) 271-273 197S LA - ENG A3 - For ccmoarison. a second cytogenetic study was made of 37/39 polyvinyl chicride workers 2-2.5 yr later, during which time the workers had minimal exposure to vinyl chloride monomer (VCM1. The second studv was performed with 32 matched controls selected from office employees at the same factory. Of The original 39 workers. 16 had bean chosen at random. 13 because they had heavy exposure to VCM for years. and 12 because of abnormal clinical findings that later proved to be normal. Sreaks. gaps, and stable rearrangements were scored as 100 metaphases/person from 63-hr lymphocyte cultures. In the first study, the mean number of chromosome breaks was significantly higher for the workers (3.61kl than for the controls (1.79k). No significant difference was found in the second study. In addition, there was no significant difference In mean number of breaks between the first control qroup and both groups of The second studv. The results of the two studios provide evidence That VCM was The cause of the chromosome damage found in the first study. In the Second study, the mean number of sister chromatid exchanges per cell was The same (7.6) for both workers and controls. Studies of bone marrow samples from four workers revealed that these samples had a higher mean number of chromosome breaks (6.2k) than normal bone marrow (literature values. 0.2k-1.7k) or The corresponding lymphocyte cultures. (19 Refs) 73 AU AD TI SI SO LA AB - Blendls LM I Smlthe PM ; LawrIe DU ; Stephens MR ; Evans WD - Room 112. tdiiv. Wing, Toronto General Hasp., University Ave., Toronto, Ontario. Canada MyG 1L7 - PCRTAL HYPERTENSION IN VINYL CHLORIDE MONOMER WORKERS. A HEMODYNAMIC STUDY. - ICCD/70/26126 - Gastroan*erology ; 75(2)1206-211 1973 - ENG - Hemodynamic studies were performed in five vinyl chloride monomer workers in whom splenomegaly or thrombocvTopen 1 a was detected during a screening program at a major chemical plant. Three patients had portal hypertension and collateral venous 00005769 VINYL CHLORIDE PAGE 91 circulations> with intrasolenic pressure between 20 and 29 mm Hg and normal wedged hepatic venous pressuresi but the gradient between the wedged and free hepatic vein pressures was also increased. Splenic blood flows ware increased in both hypertension and normotensive patients. There was no correlation between the splenic blood flow and the portal pressure or the presence of the portal fibrosis. The portal hypertension associated with vinyl chloride exposure is mainly presinusoidal in t'/pei and may be attributed To an abnormality of the portal vein radicles, or hepatic sinusoids. (Author abstract) (23 Refs) 79 AU - Gehring PJ ; Uatanabe PG Park CN AD - Health and Environmental Res., Dow Chemical USA, Midland, MI, 90690 TI - RESOLUTION OF DOSE-RESPONSE TOXICITY DATA FOR CHEMICALS REQUIRING METABOLIC ACTIVATION: EXAMPLE--VINYL CHLORIDE. SI - CARC/78/06903 SO - Toxicol Appl Pharmacol; 99(3):531-591 1970 LA - ENG A3 - The concept that the toxicity of many chemicals may not be a function of exposure to the chemical per se but rather to a blotransformation product is illustrated with vinyl chloride (VC). In such a case, it is necessary to determine the amount of the chemical undergoing biotransformation as a function of dose or exposure before a meaningful dose-response relationship can be established. Male Sprague-Dawley rats were exposed via inhalation to 1.9-9,600 ppm VC for 6 hr, and the total amount of VC metabolised was determined. Activation to the toxic form followed apparent Ml chael i s-f'en t an kinetics. A logarithmic probability plot of the incidence of hepatic angiosarcoma vs the amount of VC transformed, rather than the exposure conccntration of VC, was linear. Assuming no threshold dose, extrapolation of the data below the ranqe of doses causing experimentally observable responses predicted a 0.01X hepatic angiosarcoma incidence in rats exposed to 9.6 ppm VC. Theoretical extension of the extrapolation to humans exposed dailv for 8 hr to 1 ppm led to a predicted incidence of 1.5/100,000,000. This incidence, although likely an overestimate in the light of evidence for at least a practical threshold in both rats and humans, is less than that expected to occur spontaneously. Although this method of estimation is not without flaws, the rationale involved represents a new approach that utilises more logic than current extrapola11 on methods. The concepts that evolved from this analysis re"oal why pharmacok I ne t i cs must be considered in designing toxicology experiments as well as in interpreting the resulting data, (22 Peis) 00005770 VINYL CHLORIC PAGE 42 75 AU - Purchase IF ; Richardson CR ; Anderson D ; Paddle GM ; Adams UG AD - Central Toxicology Lab. > Central Medical Group and Mond Div., Imperial Chemical Industries Ltd., Alderley Park. Haeelesfield, Cheshire. England II - CHROMOSOMAL ANALYSES IN VINYL CHLORIDE-EXPOSED WORKERS. SI - CARC/78/06359 50 - Mutat Res; 57t3):325-334 1978 LA - ENG A3 - The chromosomal morphology of cultured peripheral lymphocytes from 81 men C57 employed in plants manufacturing vinyl chloride (VC) or polyvinyl chloride (FVC). 19 on-site controls, and 5 off-site controls] was studied. There was a significant increase in chromosomal abnormaliTies among the VC/PVC-exposed workers compared with the controls. Total 0 cells (those with a chromatid break or gap or a chromosome gap), total Cu cells (those with larger unstable chromosomal abnormali ties). and total Cs cells (those with larger unstable chromosomal abnormalities) showed the greater increases in autoclave operators, with smaller increases in the other five job categories. The increase in chromosomal aberrations was correlated with length of exposure and with a history of exposure to excursion levels of VC during the year prior to sampling (1973-1974). There were no correlations between results of liver function tests and chromosome aberrations. Quantity of tobacco smoked 13 mo after blood sampling was correlated with total C cells, as was smoker vs nonsmoker status at 18 mo postsampling. It was not possible to determine whether smoking history, length of employment. or exposure to excursion levels of VC was the most important variable in determining C-cell abnormalities. (15 Refs) 76 AU - Magnusson J ; Ramel C AO - Environmental Toxicology Unit. Wallenberg Lab.. Univ. Stockholm. Stockholm, Sweden TI - MUTAGENIC EFFECTS OF VINYL CHLORIDE ON DROSOPHILA HELANOGASTER WITH AND WITHOUT PRETREATMENT WITH SODIUM PHEN0BAR8ITURATE, 51 - CARC/78/06790 SO - Mu Tat Res! 57(3)1307-312 1978 LA - ENG AQ - Exposure of wild-type Karanas 60 Drosophila males (0-2 days old) to 10,000, 100,000 or 200,000 ppm vinyl chloride (VC) gas increased the number of complete and mosaic sex-linked recessive lethals. A Threshold effect was observed that may be due to a limit of the mixed-function oxidase activity. In additional experiments, Drosophila were pretreated with a IX soln of phgnobarbital sodium ( P3 ) dissolved In water containing IX sucrose for 2A hr, followed immediately by exposure to 1,000 or 100,000 ppm VC gas ( C-rouo 1). Group 2 tias treated with either concentration of VC alone, and Group 3 was not treated. PB pretreatment enhanced the number of recesslve ` 1eThais over the numbers produced by Groups 2 and 3. Compared with Groups 2 (corresponding group) and 3, the Total number of recessive lethals produced by F3 + 10,000 ppm VC was significant, but not 00005771 VINYL CHLORIDE PACE 43 the number* produced by PB + 100,000 ppm VC. In Groups 1 and 2> The higher VC dose did not produce a higher frequency of recessive lethals Than The lower dose; again. There uas a lack of a dose-response effecT. The resulTs indicale That the in i xad-f uncT i on oxidase system can be induced in Drosophila in The same uay as in mammals. (12 Refs) 77 AU - StuTTe HJ ; Heusermann U AD - Kiel, U. Germany TI - THE CONDITION OF THE SPLEEN DURING VINYL CHLORIDE DISEASE (MEETING ABSTRACT). SI - ICDB/78/23190 SO - Zentralbl Allg Pathol; 122(3) = 234 1973 LA - GER A3 - Contact with vinyl chloride during The production of various synthetic substances is unavoidable and may lead To severe organ alterations. The most frequently observed being splenomegaly uiTh clinical signs of portal hypertension. Morphological examination indicates That the spleen is the target of fibrotic lesions with characterlstic types, location, and dissemination. These parameters allow for successful histological confirmation of a clinically occult splenomegaly and tr.a differentiation of a portal occluded spleen in case of hepatic cirrhosis. The most significant differential diagnostic criteria are presented in tabular form. With respect to these criteria, it is thought that the splenic alterations observed during vinyl chloride disease uere not caused by portal hypertension due to vinyl chloride induced hepatic alterations, rather by a direct fibrotic process in the red and unite pulpa and connective tissue of the spleen induced by vinyl chloride or its metabolites, (no Refs) 73 AU - Sucuki T AD - Environmental Science Lab., Mount Sinai Sch. Medicine, Fifth Ave. and 100th St., Nau York, NY, 10029 TI - PULMONARY TUMORS INDUCED IN MICE BY VINYL CHLORIDE MONOMER. SI - CARC/73/06720 SO - Environ Res! 16(1/3 ):235-301 1970 LA - E ),u AB - The incidence of lung Tumors due to vinyl chloride (VC) inhalation was studied in 27 CD1 Charles River male mice, and precancerous changes and the resulting Tumor uere characterised u11ras trueturally . The mice were exposed to 2,500 or 6,000 ppm VC 5 hr/day, 5 days Aik, for 5 or 6 mo and then sacrificed 2, 6. cr 37 days later. Pulmonary tumors were found in 26/27 mice but in none of the 16 controls. The tumors were round, whitish, multiple, and variable in sice from 1 to 5 mm in diameter. The Tumors uere arranged in t u'ouloneo 111 ary or adenomatous formations. There were no met astases to reqional lymph nodes or other organs, parenchymal fibrosis, or fibrotic adhesions of the pleura, although occasional mitotic divisions and 1nvaginat1ons into the bronchiolar lumen were noted. Under The electron microscope, the characterlstic features of The neoplastic cells were short microvilli, tight junctions between two adjacent R&S 138864 s' ' 4 00005772 VINYL CHLORIDE PAGE 44 cells, csmi op'ni 1 i c lamellar bodies, large irregularly shaped mitochondrial wel1-developed Golgi complexes, continuous or discontinuous basement membranesi occasional appearance oi sequestration and of crystalloi ds> and a lack of cilia and mucous secretory granules. Some of the cells were poorly differentiated and were equipped with poorly developed organoidsi without the formation of osmiophi1ic lamellar bodies. The gross anatomical and histological aspects of the tumors indicated that they were alveologenic tumors. The neoplastic cells were assumed to have been transformed from type II alveolar epithelium via its hyperplastic torTM, because of the ultrastruetural similarities between normal type II cells and the neoplastic cells. It is concluded that the mouse lung is a sensitive indicator of the oncogenicity of VC. (40 Refs) 79 AU - KiIson R AD - Dept. Physics, Harvard Univ.i Cambridgei HA, 02138 TI - RISKS CAUSED BY LOW LEVELS OF POLLUTION. SI - CARC/78/06623 JSO - Yale Biol Med; SHI): 37-51 1973 LA - ENG AB - The theoretical and experimental evidence for the concept that pollutants in almost any concentration cause a small risk of death is reviewed. The hypothesis that cancer incidence is linear at low doses with applied dose of pollutant originated with radiation carcinogenesis. Accordinq to the linear theory, if the quantity of a carcinogen is constant and randomly distributed throughout the environment, the total number of cancers produced will be constant to within the square root of that number, Although there are various theoretical reasons for expecting to find a deviation from linearity, taking a linear dose-response relationship is recommended by most regulatory bodies. Data on cancers produced in humans by chemical carcinogens reveal few wall-measured dose-response relationships, but there is a considerable amount of data on chemical cancers induced In animals. Many carcincqens such as vinvi chloride (VC) are indirect, and they only become carcinogenic as a result of the production of metabolites m the liver. The linearity of effect vs dose actually applies to the dose presented to the cell. The metabolic production of carcinogens in the liver r.uqht not be linear with the VC concentrat1cn. However, prudent public policy demands the assumption of linearity for exposure to the general public until further information Is available. (50 Refs) 80 AU - Watanabe FG ', Zempol JA I Genrinq PJ AO - Teleology Res. Lab., Health and Environmental Res., Dow Chemical USA. Midland, MI, 48640 TI - CCMPAPISDN OF THE FATE OF VINYL CHLORIDE FOLLOWING SINGLE AND REPEATED EXPOSURE IN RATS. SI - ICDS/78/22165 so - Toxicol Appl Fharmacol; 44(2)1391-399 1973 LA - ENG AB - The metabolic fate of vinyl chloride (VC) in rats exposed by 00005773 VINYL CHLORIDE PAGE 45 61 AU AO TI SI SO LA A3 67 AU AD TI SI SO LA AO inhalation onc or repeatedly. The activities of the microsomal enzymes (aniline hydroxylase and p-nitroanisole-O-demethylase) was essentially the same in both groups as well as nonexposed control rats. Repeated exposure to VC did not induce its biotransformation since covalent bonding to hepatic macromolecules was greater in rats repeatedly exposed. (17 Refs) Muller G ; Narpoth K ; Kusters E I Herweg K ; Vers in E Institut fur Staublungenforschung und Arbeitsmedi=in. Westfahliche Wi lhelms-Uni vet's l tat , D-4400 Munstert W. Germany DETERMINATION OF THIODIGLYCOLIC ACID IN URINE SPECIMENS OF VINYL CHLORIDE EXPOSED WORKERS. ICD3/73/21017 Ini Arch Occup Environ Health; 41(3>:199-705 1973 ENG Tniodiglycolic acid (TDGA) content was measured in the urine of workers exposed to varying amounts of vinyl chloride (VC) > and an improved analytical method for these determinations was described. The analytical procedure used made it possible to distinguish between normal values (in 70 ncn-exposed men) and values obtained from 13 slightly exposed worker's (0.14-7.0 ppm VCU measured by personal air samplers) at the IX significance level. In all cases TDGA concentrat1ons exceeding 2.1 microg/ml Urine can be distinguished from normal concentraticns with a 99X probability of confidence. Mean values obtained from the normal group and two exposed groups suggested a correlation between the extent of exposure and the amount of TOGA excreted. Increasing metabolite concentrations were found in the urine with increasing exposure. The correlation was tested by a distribution free statistical procedure and was confirmed at the level of p less than 0.01. The increase in metabolite excretion began shortly after the initiation of exposure each day and reached a peak in The first or second urine samples obtained after the highest possible VC-uptake. Significant increases in metabolite excretion Were observed even at VC-concentratlons below 5 ppm. The Usefulness of usinq this analytical procedure for monitoring VC concentration in work places is discussed. (36 Refs) Du JT ; Tamburro CH Digestion, Disease and Nutrition Section, Dept. Medicine, Cancer Center', Ltniv. Louisville Medical Sen., Louisville, KY. 40737 ELEVATED GLUTATHIONE CONTENT, GLUTATHICNE-S-TRANSFERASE AND GLUTATHIONE REDUCTASE IN LIVER OF RATS EXPOSED TO VINYL CHLORIDE (MEETING AD5TRACT). ICDS/7G/70956 Fed Proc; 37(6): 1545 1973 ENG Vinyl chloride (VC) is believed To be metabolized to chloroetnylene oxide (CEO) and ch 1 ore aceta idehyde and detox!-led by way of glutathione. Pats were e-pcsed To 73,000 ppm VC, 7 hr/day, 5 davs/wk for a 4 and 6 wk, the activity of glutathione eoox1de-S-transferase (GEST) was elevated 30 to 54X over normal control and air control (9.71 *- 0.63 vs 7.52 0.97 and 6.30 +- R&S 138866 c 00005774 VINYL CHLORIDE PAGE 46 c 0.68) respectively. However, the activity of glutathione aralkyl-S-Transferase (GAST) was not significantly elevated until c 6 wk of exposure to VC. The content of reduced glutathione was also elevated 45X in the VC treated group and the activity of the glutathione reductase, the enzyme to regenerate glutathione from the oxidized form was elevated 50X. These results demonstrate that VC exposed rats have the capacity to maintain glutathione ( reductase activity and glutathione concentration for detoxification. Further, it suggests that the primary route of VC metabolism is initial oxidation to CEO and then detoxification by GE5T directly. With longer exposure and probable saturation of the direct route, there is greater rearrangement of CEO to chloroacetaldehyde, and detoxification with glutathione as supported by the delayed induction of GAST. 83 AU - Filser JG ; Bolt Ht1 AD - Institut fur Tcxikologie, Universitat Tubingen, Wilhelmstrasse 56, 0-7400 Tubingen, W. Germany TI - FHARMACCKINETICS"OF HALOGEHATED ETHYLENES (MEETING A3STRACT). SI - ICD3/73/2 0 792 SO - Naunyn Schmi edebergs Arch Pnarmakol; 30Et Suppl ) :R22 1978 LA - ENG A3 - The present discussion of toxic effects of vinyl chloride raises the question of interpretation of toxicological data. Evidently, biochemical and mechanistic concepts of action of healogenated ethylenes can only be correlated wi th Toxiclties observed in vivo, if differences in pharmacokinetics are taken into account. This consideration led to the present investigation. Rats were exposed in a closed system to atmospheric concentrations of fluoroethylene (vinyl fluoride) 1,1-difluoroethvlene (vinvlidene fluoride), chloroethylene (vinyl chloride), 1,1-dichloroeThylene (vinylidene chloride), trans-1,2-dichloroethylene and cis-1,2-dichloroethylene , tricnlorcethylene, and bromoethylene (vinyl bromide). Pharmacokinetlc analysis was done as previously described. The following principles could be derived. (1) 'Non-linear1 (dose-dependent) pharmacokinetics may apply if the organism is exposed to higher concentrations of halogenated ethvlenes. This is consistent with The concept of Watanabe. Young and Gehring, In the case of vinyl chloride, it refers to ( atmospneric concentratlons higher Than 2S0 ppm. (2) The equilibrium constant of distribution of the non-metabolized compound (concentra11on in the an 1mal/concentration in the gas piiase) increases from vinyl fluoride to vinyl bromide. (3) The rate of metabolism depends on The structural properties of the individual compound, Trans-1,2-dich1 orcethylene and vinylidene fluoride are extremely slowly metabolized, con parable to the rate of metabolism of 1 ,1,1-1richloroethane (methyl chloroform) which was used as a reference compound. rj>r, - ; VvsV--.c ... , n (' . h> 7:>_I; -. , 00005775 VINYL CHLORIDE PAGE 67 c 86 au Laib RJ i Ottenualber H AD InsTitut fur Toxikologie, UniversitaT Tubingen, Uilhelmstrasse ( 56i D-7600 Tubingen, U. Garmany II ALKYLATION OF DMA AND RNA BY NETAS0LITIES OF VINYL CHLORIDE AND VINYL ERCNIDE (MEETING ABSTRACT). SI ICD3/73/20791 SO Naunyn Schmiedebergs Arch Pharmakol", 302(Suppl ) :R21 1978 ( LA ENG AB If rats ara exposed to 16C-vinyl chlorida. radioactivity is incorporated into nucleic acids of the liver. In previous investigations we showed incorporation of radioactivity from I6C~vinyl chloride into the physiological bases of RNA. In addition, alkylation of adenosine and cytidine moieties occurred leading to formation of radioactive 1 ,N**i>6-ethanoadanosina and 3 ,N**6-eThenocy t i d i lie . The time courses of 1 ,M*#6-eThenoadenos ine and 3,N"*6-eThenOcy t i dir.e in rat liver RNA after vinyl chloride inhalation are dissimilar: 92 hr after ending exposure the ethenoadanosine is only 1/5 of its original value whereas the content of ethanocytidine persists. This ought to be indicative for the relative importance of cytidine alkylation. Formation of labeled ethono derivatives of adenosine and cytidine was also observed if rats were exposed to 16C-vinyl bromide. To establish possible changes in DMA due to alkylation by vinyl chloride ( metabolites, OIIA was incubated with rat liver microsomes, NADPH and lAC-vlnyl chloride. Re-isolation of the DMA, hydrolysis and separation of the nucleosides on Aminex-A-6 showed that small amounts of radioactive 1 Nlf'fb-etheno Z ' deoxyadanos i ne and 3,N*6-a Thano 21deoxyeyIldine were formed. In addition, a major alkylation product, presumably of 2' deoxyquanosine was isolated which, on Aminex-A-6-columns , shewed the same chromatograchic behavior as a compound which was obtained from chemical reaction of 2'deoxyquanosine with chloroacetaldehyde . 05 AU Veltman G I Lange CE ] Stein G AO Uni.-Hautk1inIk Bonn-Venusberg , D-5300 Bonn 1, U. Germany (., TI TOXIC EFFECTS OF VINYL CHLORIDE. SI CARC/73/05367 SO Hsu Tar = t; 29(61:177-132 1978 LA GER c.. AB The toxicological aspects of vinyl chloride (VC) are reviewed on the basis of examinations of workers occupationally exposed to VC over long periods of time. The liver histology revealed periportal, septal, and intralobular fibrosis: fecal and reticular collaqenl~ n tI on of the sinusoid walls) hepatocyte daceneration ; and activation and proliferatI on of the sinusoid cells, with cell aiypla and transition into angiosarcoma occurring in cone cases. The meteonase analysis revealed no remarkable pathological changes; le, no mutagenic effect of VC. (35 Refs ) R&S 138867 c c ( V; i. V vyr- - ; ". -s\i\ :.. i :=;";sv, a*.^; a 00005776 VINYL CHLORIOE PAGE A3 86 AU AO TI SI SO LA AB 87 AU AO TI SI SO LA AB Ehrenberg L i Holmberg B apt, Radiation Biology, Wallenberg Lab., Univ. Stockholm, Stockholm, Sweden EXTRAPOLATION OF CARCINOGENIC RISK FROM ANIMAL EXPERIMENTS TO MAN. CARC/73/06300 Environ Health Perspectl 2133-35 1978 ENG The hypothesis that one or more mutational events are involved in tumor initiation is supported not only by the strong, qualitative correlation between mutagenic and carcinogenic activities of chemicals, but also by certain reaction-kinetiC considerations. Experiments with microorganisms, plants, and animals suggest that limiting step in tumor origin is one mutational event in one cell and that the dose-response curve is linear from dose gero onuard. An inverse relationship between dose and latency time has been observed frequently and has been taken as an indication that it should be possible to extrapolate to such a low dose that the mean latency time would exceed the expected lifetime of the species studied. However, a small dose may give individual latency times within the expected lifetime, even though The mean latency time for a group exceeds the life span. The most important contribution of dose-response studies is in the application of mathematical models to epidemiologic data. It should be remembered, however, that a deviation from the linear dose-response relationship, with a higher effectiveness at lower doses, may occur for radiation, urethane, and vinyl chloride. (23 Refs ) Laib RJ I QTtenualder H `, Bolt HM Inst. Toxikologle, Univ. Tubingen, Wilhelmstr. 56, D-7A00 Tubingen, W. German'/ FORMATION OF ETHENO DERIVATIVES OF NUCLEIC ACID BASES IN VIVO BY META50LITES OF VINYL CHLORIDE (MEETING ABSTRACT). ICQ3/73/1C83A Hoppe Sevlers Z Physiol Chemi 359(3):293 1970 ENG The detection of mutagenic and carcinogenic effects of vinyl chloride greatly stimulated research on the molecular mechanism of vinyl chloride disease. Rat liver microsomes were incubated with NADPH, Cl>2-IAC]wlnyl chloride and polyadenylic acid or polycytidylic acid. The latter were re-isolated from the incubation mixtures and hvdrolv'Ped. The radioactivity originating from ClACIvtnyl chloride, which was Irreversibly bound To the polyadenylic or polvcytidyllc acid, was confined to 1 , N'lw6-e tnenoadenos i ne or 3 , M'9-e T henoc y 11 d i ne . When rats were exposed to [ 1,2-1AC1viny1 chloride, part of The radioactivity was incorporated Into the liver RMA. Analysis of hydrolysates of liver RMA showed that all natural nucleosides of RMA were labeled. Besides, small amounts of radioactivity could be detected which were confined to 1 ,NJ*6-etnenoadenos1ne and 3 , It* * A-e t hcnocy t i d l n e . DMA from livers of rats exoosed to Cl,2-lAC]vinyl chloride also contained significant amounts of ( (' c c / V. (., J3 & U) co 00 00 o (> 00005777 VINYL CHLORIDE PAGE 49 radioactivity. When DMA was incubated with rat liver microsomes NADPH and C14C)vinyl chloride, radioactivity was also incorporated into the DMA. Re-lsolaT)on of the DMA, hydrolysis and separation of the nucleosides showed that radioactive 1,N*#6-etheno-21-ceoxyadenosine and 3>N'fV4-etheno-2 1-deoxycyt i dine were formed. The experiments support the theory that vinyl chloride metabolites react with adenine or cytosine moieties of nucleic acids to form etheno analogues. 63 AU - Cowles SR AD - Occupational Medicine Branch. Naval Regional Medical Center, Bremerton, UA, 96314 TI - CANCER lit THE N0RKPLACE--PERCIVALL POTT TO THE PRESENT. SI - CARC/73/06242 50 - Milit Med! 143(6)1395-400 1976 LA - ENG AB - Known and susoected carcinogens commonly found at Naval installations, particularly shipyards, are reviewed, and methods of controlling hu>'an exposure to these substances are outlined, "the carcinogens include physical agents (cigarettes, asbestos), metals (Ml, As), and hydrocarbons (ethvlenethiourea 4,4'-methylenebis(C-chlonoani1ine ), vinyl chloride, and polychlorinated biphenyls). 69 AU - Bolt KM AD - Inst. Toxicology, Univ. Tubingen, Wilhelmstrasse 56, D-7400 Tubingen 1, W, Germany TI - PHARMACOKINETICS OF VINYL CHLORIDE. 51 - CARC/78/06214 SO - Gen Pharmacol; 9(2)191-95 1973 LA - ENG AS - Data cn The pharmacokinetic behavior of vinvl chloride (VC), all of which have been obtained from studies with rats, are reviewed, Consistent evidence shows That, above a saturation concentration! which on inhalation exposure is reached at 250 ppm VC, nonlinear (dose-dependent) pharmaeokinetics apply. Two different models describing the pharmaeokinet1cs of VC have been published. They show that VC can leave the body very rapidly via expiration by The lungs. However, special conditions apply if rats are exposed to atmospheric VC: the compound equilibrates with the organism within 15-30 min and is removed from this equilibrium me t abol i c a 11'/, probably by formation of (he reactive epoxide. The rapid elimination of VC and its,major metabolites from the orcanism ag-ees with The current theory that a reactive, snort-lived metabolite, which occurs in low concentrat 1ons only, may be responsible for The Toxic effects of VC. (25 Refs) 00005773 VIMYL CHLORIDE PAGE SO 90 AU AD TI SI SO LA AB 91 AU AD TI SI SO LA AB Spirtas R Kaminski R Illness Effects Section. SB/DSHEFS/NIOSH, Robert A. Taft Labs., 4676 Columbia Parkway, Cincinnati, OH, 45226 ANGIOSARCOMA OF THE LIVER IN VINYL CHLCSIOE/POLYVINYL CHLORIDE WORKERS: 1977 UPOATE OF THE NIOSH REGISTER. CARC/78/06177 J Oocup Ned; 20(6):427-429 1973 ENG Data cn 64 cases of angiosarcoma among vinyl chloride (VC) polymerication workers reported as of October 1977 are Summarized. The material comprises 23 US and 41 foreign cases from 11 different countries. The age at diagnosis ranged from 37 to 71 yr, with a median of 49 yr. The latency period ranged from 9 to 33 yr (median of 21 yr ), duration of exposure from 4 to 31 yr (median of 18 yr). The data suggest that the reported VC-induced angiosarcoma cases gradually increased over time. The 20-to 30-yr lag between the growth of the industry after Korld Liar II and the increase in the number of diagnosed angiosarcomas among VC/polvvinvl chloride (PVC) workers during the 1970's roughly coincides with the median latency period of 21 yr. Recent studies have also found VC to be associated with excesses in brain cancer and neoplasms of the respiratory and lymphatic systems . (6 Refs) Preussmann R Institut fur Toxikologie und Chemotherapie, Deutsches Krebs forschungszenirum, Im Neuenheimer Feld 230, D-6900 Heidelberg 1, H, Germany ENVIRONMENTAL CARCINOGENS: MECHANISMS OF ACTION AND OCCURRENCE. CARC/7C/06160 Zsntralbl Bakteriol tOrig B); 166(2/3)=144-158 1978 GER The mechanism of action of known environmental carcinogens is described. These compounds are not carcinogenic per se, but are metabol1 cally bioactivated To electrophilic reactants by chemically reactive intermediates. The electrophi1ic reactants Then form covalent bonds with nucleic acids. This change in the genetic code is in agreement with the mutation hypothesis of carcinogenesis. The bioactivation of aflatoxin B1 (AFB), N-nitroso compounds, and benzo (aIpvrene (DP) is presented to illustrate this mechanism. Threshold levels (no-effect levels) determined by animal experiments are compared with data on human exposure to BP, AFB, N-ni troso compounds> and vinyl chloride. The difficulties involved in risk evaluations are discussed. 00005779 VINYL CHLORIDE PAGE 51 c 92 AU - Hoffmann D t Uynder EL AO - Naylor Dana Inst. Disease Prevention! American Health Foundation! c Valhalla, NY, 10595 TI - IDENTIFICATION AND REDUCTION OF CARCINOGENS IN THE RESPIRATORY ENVIRONMENT. SI - CARC/7S/06155 SO - Zentralbl EJakteriol (Grig B]; 166(2/31:113-135 197S LA - ENG A3 - The three major factors responsible for the overall increase in lung cancer (tobacco, air pollution, and industrial chemical exposure 1 are reviewed. Concerning industrial carcinogenesis, ' particular attention is focused on bis(chioromethyl )ether , vinyl chloride, bengene, coke owen effluents, asbestos, and n;trosamines . Sources of atmospheric carcinogens and their reduction are outlined. The tumor)gemc agsnts m cigarette smoke are being studied so that a less harmful cigarette can be developed. 93 AU - Guess HA t Crumo KS c AD - Envlronmentai Biometry Branch, Natl. Inst. Environmental Health Sciences, Research Trianqle Park, NC, 27709 TI - BEST-ESTIMATE LOW-DOSE EXTRAPOLATION OF CARCINOGENICITY DATA. c SI - CARC/7S/06074 SO - Environ Health Perspectt 22:149-152 1970 LA - ENG A3 - A low-dose extrapolation technique was developed for dichotomous data and used to analyze carelnogenicity data for vinyl chloride, diel drin , 1,1,1-trichloro-2,2-bis-(p-chlorcpheny1)ethane (DDT), dimethyinitrosamine, and ionizing radiation. The results suggest that when the very flat and the gradually sloping (linear or nearly linear) dose-response curves are considered together, it is extremely difficult on mathematical grounds to reject the hypothesis that the dose-respense curve is nearly linear in the dose ranqe correspond Inq to increased risks 0"er a background of less than or equal to 10*#-6. These results have implications both for test design and for risk assessment. They suggest that If the hypothesis of a nearly linear dese-respense curve in the low-dose ranqe cannot be ruled out by assumption, then it seems questionable that it can be rejected by the data, even in cases V. in which it may be false, (no Refs) 94 AU AO TI SI SO LA AB - Delorme F ', Theriault G - Dept. Pathology, Centre Hospitaller Regionale de la Maurice. Shauinigan, Quebec, Canada - TEN C a j Li o OF AhGlOGAHCCttA OF THE L. IV E R IM SHAVJXHItjAM, QtJ E D E C . - CARC/73/05915 J O-cuo M.-d; C0(S):333-340 1973 - EKG - Of The 10 cases of anoio5srco`'ia of The liver diagnosed in Shouil n 1 qan, Quebec since 1955, till occurred in m-sn who worked in i\ vinyl chloride (VC) polymerizing plint All 10 men w*r? vary light drinkers, and only 4 moked cna cr more pc*ic<s of ciq;ir*Ttes 00005780 VINYL CHLORIDE PAGE 52 per day. The time between the first exposure of VC monomer and the diagnosis of angiosarcoma ranged from 11 to 29 yri with an av of 20.5 yr. Exposure to VC monomer in the plant, although not documentedt is believed to have been very high in the past. The benign 1iver lesions found in these workers included portal and perisinusoidal fibrosis. (15 Refs) 95 AU - Miller EC AD - McArdle Lab. Cancer Res., Dniv. Wisconsin Medical Center. Madison, WI, 53706 TI - SOME CURRENT PERSPECTIVES ON CHEMICAL CARCINOGENESIS IN HUMANS AND EXPERIMENTAL ANIMALS: PRESIDENTIAL AOORESS. SI - CARC/73/05656 SO - Cancer Res) 33(61:1679-1696 1973 LA - ENG AD - Current ccncepts of chemical carcinogenesi3 in humans and experimental animals are reviewed. Topics discussed include: tumor induction as a multistage phenomenon; electrophi1icity as a common property of ultimate carcinogens; examples of the metabolic activaticn and reactivity of chemical carcinogens, possible molecular mechanisms of chemical careinogeneslsI prevention of the promotion of initiated cells; and extrapolat i on of the basic knowledge of chemical careinogenesis To the prevention of human cancer. Recarding The molecular mechanism of careinogenesis , examples are cited to illustrate that metabolic activation is an essential step in the induction of neoplasia by most chemical carcinogens. The electrophilic ultimate carcinogens can react, probably more or less indiscriminately, with a number of nucleophilic sites in DNA, RMA, and proteins. Thus, the strong elec t i'oph i 1 i c nature of ultimate carcinogens is consistent with both genetic and epigenetic mechanisms of careinogenesis or with mechanisms That include both genetic and epigenetic events. These mechanisms may or may not involve the expression of oncogenic viral information. Chemicals qensrallv recognized as being carcinogens in humans include: 2-naohthylamine, benzidine (6,61-dI aminobiphenyl ) , 6-aminebiphenyl, 6-m trebiphenyl , bis(chloromethy 1 ) ether, b1s(2-chloroethy1 ) sulfide, vinyl chloride, certain soots, tars, and oils, chromium compounds, nickel compounds, asbestos, cigarette smoke, betel nut or tobacco quids, N,N-bis(2-chloroe thy 1 ) -2-naph thy lamine, and diethyls tilbestrol. 96 AU - Kravbill HF AD - Dlv. of Cancer Cause and Prevention, NCI, Bethesda, MD TI - CARCINOGENESIS INDUCED BY TRACE CONTAMINANTS IN POTABLE WATER. SI - CARC/73/05662 SO - Bull NY Acad Med; 56(61:613-627 1973 LA - ENG AB - The following are some recognized and suspect 'carc1 nogens in US drinking water and Their eoncen'raI Iens (In uq/liter, when given): aldrin (5.6), benzene (50), benzo(a Ipyrene ( 0.0002-0.002), b)s(2-chloroethy 1 letner (0.62), lindane, carbon tetrachloride (2.0-3.0), chiordane (0.1), chloroform (0.1-311), ,-flj c ( '-X---'' _ '- -' . ' ' X; .. V. ;r. l r,,` ;~?}p>>'?r'f ". V N : >-;'*$ 00005781 VINYL CHLORIDE PAGE S3 97 AU AD TI SI SO LA AB 98 AU AD TI 51 SO LA AB 1,2-dibromoethane, dieldrin (8.0)> dichlorodipheny1trich1oroethane t DDT ) , dichlorodiphenyldichloroetnylene (DDE) (0.05), 1,9-dioxane (1.0)i endrin (0.009), heptachlor, trichloroethylene, and vinyl chloride (10.0). Of these compounds, benzo(a Ipyrene and vinyl chloride are the only recognized carcinogens. Only volatile organic compounds have been identified in US drinking water, and a much larger component of nonvolatile substances remains to be identified or quantified. In city water in the Netherlands and Germany, concentration ranges of inorganic contaminants such as arsenic, cadmium, chromium, and selenium are 1.0-8.1, 2.0-9.0, 9.5-10.0, and 3.1-6.0 ug/liter, respectively. Asbestifcrm materials or asbestos particles have been found in many river systems at concentrations greater than 10 ug/gallon. In a study of cancer mortality in 10 river basins in the US, nickel concentrat1cns appeared To correspond with oral and intestinal cancer death rates, arsenic with cancer of the eye and larynx and myeloid leukemia. Beryllium correlated with bone cancer and with mortalities from breast and uterine cancer. Lead was associated with leukemia and lymphoma and with kidney, stomach, intestinal, and ovarian cancer. The results of various epldemlological studies throughout the US are reported. The need for in vitro bioassays to augment in vivo procedures in determining carcinogenicity is stressed. (30 Refs) Maqoner JK Office Assistant Secretary for OSHA, COO Constitution Ave., Room U3660, Washington, DC, C0C10 VINYL CHLORIDE AND PULMONARY CANCER (LETTER TO EDITOR). CARC/7C/053I1 J Environ Pathol Toxicol; 1( 3)'-361-362 1978 ENG In a previous article, the development of an undifferentiated adenocarcinoma of the bronchus in a 95-vr-old organic chemist was attributed to a 2-yr exposure to bis(chloromethyi lether. This claim was made in spite of the patient's long-term involvement in vlnvl chloride (VC) research. Since numerous animal and human studies have indicated a link between VC exposure and pulmonary cancer, it is suggested that VC was the agent that caused the t u.nor, Infante PF Industry-Wide Studies Branch, Dlv. Surveillance, Hazard Evaluations and Field Studies, Natl. Inst. Occupational Safety and Health, Center Disease Control, Dept. Health, Education and Welfare, Cincinnati , C'.i, 95202 MUTAGENIC AND CARCINOGENIC RISKS ASSOCIATED WITH HALOGENATED OLEFINS. CAPC/73/05319 Environ Health Perspect; 2H251-2S9 1973 ENG The mutagenicity and care 1nogenlcity of vinyl chloride (VC), vinvlldene chloride, tr1cnloroethylene, percnloroethylene , and 33 (/) c C*. C ( c. ( ( V 00005782 VINYL CHLORIDE PAGE 54 chloroprene are reviewed. Of The first four compound:, all except perchloroeth'/lsne have been shown to be mutagenic in test systems, and all have induced tumors in experimental animals. Studies with chloroprene have indicated that it causes sterility in male mice and rats. Rat studies have also indicated that concanTrations ranging from 0,04 to 1.0 ppm result in a dominant lethal effect, affect sperm, cause testicular atrophy, and cause chromosomal aberrations in bone marrow Cells. Human studies have indicated both an increase in chromosomal aberrations and a decrease in mobility of the sperm of exposed workers. Several studies have indicated an excess of lung and skin cancer in exposed workers , and one report confirmed a case of angiosarcoma of the liver in a worker with extensive exposure to finished polychloroprene. with VC have indicated that in addition to angiosarcoma, there appears to be a dose-response relationship between exposure and the induction of mammary cancer in rats. A study of women employed in the VC industry indicated a 33k excess of breast cancer in those exposed. These findings could indicate another site of VC carcinogenesis. (29 Refs) 99 AU - Reynolds ES ", Moslen MT AO - Dept- Pathology, Univ, Texas Medical Branch, Galveston, TX, 77550, 77550 TI - DAMAGE TO HEPATIC CELLULAR MEMBSANES BY CHLORINATED OLEFINS UITH EMPHASIS ON SYNERGISM AND ANTAGONISM. SI - CARC/78/05306 SO - Environ Health Perspect', 21:137-147 1973 LA - ENG AQ - The biochemical mechanisms responsible for the toxicity of vinyl chloride (VC), 1,1-dlchloroetnylene (1,1-DCE), trichloroethylene ITCH), and perchloroethylene (PCE) were investigated in male Spraque-Dawley rats pretreated with pncnobarbital, 3-methylcholanthrene, hexachlorcbengen-o , spironolactone, or pregnenolone-lbalpha-carbonitr1le. The most nonsvmmetrical 1V depolarised compound, 1,1-DCE, was the most hepatotoxic and caused a unique pattern of hepatocellular injury involving mitochondria, plasma membranes, and chromatin. The injury induced by the other chloroethylenes appeared to affect the structural integrity of the endoplasmic reticulum profoundly, with the toxic potential in the following order! TCE greater than VC greater than PCE. PreTreaTments That increased the cytcchrome P-450 Content (increased metabolic activation) enhanced or were synergistic to the hepatotoxic potential of TCE, VC, and FCE, but they were protective or antagonistic to 1,1-DCE hepatotoxicity. This suggests That the biologic response to 1,1-DCE may be expressed by a different metabolic pathuav. Glutathione appears to be involved in the biologic response to all ncnsymmetric ch1 oroethy1enes and To act as an antagonist against injury. Marked differences in The patterns of injury and the biologic responses suggest that more than one mechanism is involved in the production of injury by chloroethylenes. (17 Refs) f *rr*#t c ( (' ( 00005783 VIHYL CHLORIOE PAGE 55 100 AU AD TI SI SO LA A3 Fprtwenqler HP ', Dever ME ; Tamburrp CH ", Espinosa E Univ. Louisville Sch, Medicine, Louisville, KY, 40201 LYMFHOCYTE TRANSFORMATION TESTS IN VINYL CHLORIDE tVC) UCRKERS (MEETING ABSTRACT). ICD5/7S/14653 Fed Proc", 37( 3) = 362 1973 ENG Previous reports have shown circulating immune complexes in vinyl chloride (VC) workers and a tumor-associated antigen in VC-related liver angiosarcoma. This suggests immune stimulation by a tissue of plasma antigen induced by or conjugated with VC or a metabolite. In this work, the in vitro lymphocyte reactivity for such antigens was tested in 79 VC workers including 25 with 1iver abnormalities, and 20 normal Individuals having no exposure to VC. The liver angiosarcoma antigen preparation included the tumor-associated antigen and other tissue antigens as shown by immunodiffusion. Stimulation indices (SI) were calculated from cellular incorporation of tritiated thymidine. Mean SI in the normal individuals for antigens of angiosarcoma and normal liver tissues were 4.7 (SE+-1.7) and 3.3 (+-0.9) and in VC workers, 1.8 (+-0.2 ) and 2.5 (+-0.3) respectively. Mean SI for phytchemagglutinin and concanavalin A in the normal individuals were 235 (+-35) and 209 (+-30 ) and in VC workers 201 (+-23) and 180 (+-19) respectively. Thus, these results suggest that VC workers have a decreased lymphocvte response to antigens of liver angiosarcoma and normal liver tissues rather than the hypothesised increased reactivity. This appears to be due to a lower overall lymphocyte responslveness in these chemical workers. 101 AU AD TI SI SO LA AB Heuse A Laboratoire de Medecine du Travail at Hvqlene du Milieu, Unlversite Libre de Bruxelles, Brussels, Belgium TOXICOLOGY OF VINYL CHLORIDE. CARC/78/05111 Eru:< Med; 53(1)113-34 1978 FRE A review of the literature on vinyl chloride (VC) traces the hi s `cry of the toxicity of the compound. Also reviewed are the toxic effects of polyvinyl chloride (PVC ) , relative risk of industrial exposure to VC and PVC, and potential danger of exposure of the general population to PVC. (196 Refs) 102 AU - Buffler PA ; Wood SM ", Suareq L I Kilian DJ AD - Dept. Preventive Medicine and Community Health, 140 Kedler . Building, Univ. Texas Medical Branch, Galveston, TX, 77550 TI - MORTALITY FOLLOW-UP OF WORKERS EXPOSED TO 1,4-DIOXAtlE. 51 - CAPC/7C/04960 50 - J Oocup Msd; 20(4)1255-259 1973 LA - ENG A3 - The carcinogenic effect of 1,4-diovane was studied in 100 workers In the manufacturirg area and 65 workers in the processing area of a dloxane manu f ac tur I r.g plant. The workers had been employed 00005784 VINYL CHLORIDE PAGE 56 between April 1954 and June 1975 end had served aT least 1 mo in the given areas; the exposure in the areas was determined to be less than 25 ppb. There were seven deaths among the manufacturing area workers and five among the processing area workers. Of the formeri one died of carcinoma of the stomach (23 mo exposure) and one of alveolar cell carcinoma (33 mo exposure); of the latter, One died of a malignant mediastinal tumor with generalised metastases (12 mo exposure). This total of three deaths from malignant tumor was not significantly greater than the 1.7 expected. A comparison of workers with intermittent exposure and those with continuous exposure revealed nearly identical incidences of mortality. The seven deceased persons in the manufacturing area also had exposure to other chemicals, and the five in the processing area were also exposed to vinyl chloride. These observations were based on small numbers of deaths of employees who were apparently exposed at low levels and for relatively short exposures. (12 Refs) 103 AU - Ott MG ", Townsend JC ; Fisnbeck WA ! Langner RA AD - Dow Chemical Co., Midland, MI II - MORTALITY AMONG INDIVIDUALS OCCUPATIONALLY EXPOSED TO BENZENE. SI - CARC/73/04391 SO - Arch Environ Health; 33(1) = 3-10 1978 LA - ENG AB - The long-term mortality experience among 594 individuals occupationally exposed to bencene was studied using a retrospective cohort design. Excluding 53 individuals who were also exposed to arsenicals, asbestos, or vinyl chloride, no statistically significant increases over US white male mortality rates were found among the benccne workers in any cause "-of- death category. When the 53 patients were included, there were higher than expected incidences of anemia (2 vs 0.2 expected) and leukemia (3 vs 0.8). The records of these fivo decedents were examined in detail. One Of those who died of leukemia had also been exposed To nitrobenzene, bromine, and vinyl and vinylidene chloride, another had been employed previously in the manufacture of veneer, and the third had probable exposure to p-chloroohenol, ethyl chloride, phenetldlne, acetic anhydride, and phenacetin dust. Therefore, although The observed incidence of leukemia in the study group significantly exceeded the expected incidence, a retrospectlve assessment of The possible relationship to benoene exposure is difficult. (11 Refs) 104 AU - Rudolph RH AD - Mason Clinic. P.0. Box 900, Seattle, U'A, 90111 TI - BENIGN AND MALIGNANT LIVER NEOPLASMS. SOME NEU ETIOLCGIC ASSOCIATIONS. SI - CARC/73/04717 SO - Postgrad Med; 63(3)156-60,62,65 1973 LA - ENG AB - Recent studies of benign and malignant hepatic neoplasms have suggested associations between these tumors and oral contraceptives, androgens , hepatitis virus, and vinyl chloride. 00005705 VINYL CHLORIDE PAGE 57 It is suggested that hepatic artericgraphy is the best method for diagnosing hepatic adenomas in women using oral contraceptives. (20 Refs ) 105 AU - Conolly RB t Jaeger RJ ; Scabo S AD - Dept, Physiology, Harvard Sch, Public Health, Boston, HA 02115 TI - ACUTE HcPATOTOXICITY OF ETHYLENE, VINYL FLUORIDE, VINYL CHLORIDE, AND VINYL BROMIOE AFTER AROCLOS 1254 PRETREATHENT. 51 - CARC/78/04565 SO - Exp Hoi Pathol; 23(l):25-33 1978 LA - ENG AB - The hepatotoxicity of ethane, vinyl ethylene, fluoride monomer (VFN)i vinyl bromide monomer (VEM), and vinyl chloride monomer (VCM) was determined in male Holtzman rats pretreated with Aroclor 1254. All compounds except ethane caused degeneration and necrosis of the liver. Ethylene, VFH, and VGH should be evaluated for chronic effects in view of their similarity of acute action to VCM, a known carcinogen. (20 Refs) 106 AU - Laib RJ ; Bolt HH AD - Institut fur Toxikologie, Universitat Tubingen, Hilhelmstrasse 56, 0-7400 Tubingen, U, Germany TI - FORMATION OF 3,N**4~ETHENDCYTIDINE MOIETIES IN RNA BY VINYL CHLORIDE METABOLITES IN VITRO AND IN VIVO. SI - CARC/73/043S1 SO - Arch Toxicol (Berl); 39(3)1235-240 1970 LA - ENG AB - Rats were exposed to #14C-vinyl chloride, and the in vivo liver metabolites were examined. In addition to RNA and 1,N't*6-e thenoadenos i ne , 3,N*#4-e thenocy t i di ne was also radioaetlvely labeled. In vitro experiments using vinyl chloride-exposed liver microsomes and NA0PH produced the same results. These alkylation mechanisms are consistent with the mutagenic and carcinogenic properties of vinyl chloride. (22 Refs) 107 AU - Sharma RP Gehrinq PJ AD - Utah State Unlv., Logan, UT, 84322 TI - VINYL CHLORIDE EXPOSURE INDUCED LYMPHOCYTE TRANSFORMATION IN SPLENIC CULTURES (MEETING ABSTRACT). SI - ICDB/7S/10225 SO - Fed Pr-oc; 37(3): 502 1973 LA - ENG A3 - V'nvl chloride (VC) disease has been suggested as an immune complex disorder. The influence of VC exposure on selected Immunologic parameters of mice and rabbits was studied. In male mice, inhalation of VC ( 10,000 and 1.000 ppm for' 6 hr/day 5 davs/wk) for up to 8 wk caused no toxic effects, as indicated by body wt gam, clinical hematology, or organ ul , with the exception of an increase in spleen wt at the hiq-est exposure le-'el. After 2 wk of exposure to 1,000 ppm and after 4 and 8 uk to all levels , cultured splenic lymphocytes showed an increase In DMA svnthesls (as measured by H3-thym1d1ne uptake by cells in culture). The response of splenic lymphocytes To phyTomitcgens c m&r c c 33 </> 03 CO 00 ^1 00 00005736 VINYL CHLORIDE PAGE SO (phytohemagglutinin and pckeweed mitogen) at the above levels of VC exposure was increased several fold. In rabbits* exposure to 1*000 ppm VC caused a slight but inconsistent rise in serum immunoglobulin levels. Rabbits immunized with tetanus toxoid and Freund's adjutant revealed no VC-related changes in serum antitetanus Titers, skin reactivity to tuberculin, or The number of plasma cells in popliteal lymph nodes. There was no increase in immunization induced lynr.'hccvte Trans f ormal J on in either mice or rabbits. The results indicated an increase of lymphocyte transformat ion in splenic cultures That may be related To the immune complexes observed in VC syndrome. 103 AU - Laumbach AD \ Lee S ; Wong J ; STreips UN AD - Dept. Microbiology and Immunology* Univ. Louisville Sch. Medicine, Louisville. KY, 40201 TI - STUDIES CM THE MUTAGENICITY OF VINYL CHLORIDE METABOLITES AND RELATED CHEMICALS, SI - CARC/79/06491 SO - Prevention and Detection of Cancer, Part I, Prevention. Vol. 1. Etiology. Proceedings of The Third Internatlcoal Symposium on Deduction and Prevention of Cancer held 26 April - 1 May 1976 New York NY, Nieburgs HE. ed.New York, Marcel DeKKer, Inc,, 1193 pp., 1977. LA - ENG AS - The mutagenicity and potential mechanisms of action of several vinyl chloride (VC) metabolites Cchloroacetaldehyde (CAA) monomer hydrate, CAA dimer hydrate, and CAA trimerj and epichloronydrin (ECH* a carcinogenic chlorooxirane homolog) were studied. Indirect mutagenicity assays using repair-defic1enl Bacillus subtilis strains and direct mutagenicity assays using Salmonella t'`phi mur i uni were performed. The mutagenicitw of CAA and chioroo.vi ran* was confirmed and that of the VC metabolites and ECH was found. Neither acetaldehyde chloroacetic acid, nor chlorceThano1 showed a sicnificanT lewel of mutagenicity. There may be a molecular relationship involving The proximity of the chloride group To the aldehyde moiety for mutagenicity. RecombinaTion repair appeared to be The mechanism for correcting VC metabolite-elicited damage. CAA decreased the biological activity of Transforming DMA only if the Cells were treated with the mutagen prior to DMA extraction. In vitro studies showed no such effect. The mode of action of ECH differed from that of the VC monomer metabolites. Although It caused similar base-substitution mutations in Salmonella strain TA100, it was a ccmpara 11 v.^ly weaker alkylating agent, ECH also exhibited lower toxicity lewel Than VC monomer metabolites and thus demonstrated (Mutagenicity Through wider range of concen *r a 11 ons . ECH produced higher levels of mutation m Salmonella cultures that were actively replicating DMA than in cultures that were arrested in DMA replication. (29 Pefs) 00005787 r> VINYL CHLORIDE PAGE 59 c 109 AU Espinosa E AD Dept, Pathology, Univ. Louisville Son. Medicine, Louisville, KY TI IMMUNOPATI 10LOGIC OBSERVATIONS IN LIVER ANGIOSARCOMA. ( SI CARC/79/06971 SO Prevention and Detection of Cancer. Part I. Prevention. Vol. 1. Etiology. Proceedings of the Third Internatianal Symposium on Oectection and Prevention of Cancer held 26 April - 1 May 1976 ( New York NY. Mieburgs HE, ad.New York, Marcel Dakker, Inc., 1193 pp., 1977. LA ENG AB To develop a more sensitive liver function test for the early detection of vinyl chloride liver disease, an attempt was made to discover antigenic changes in anglosarcomatous tissue and to test for the presence of an antibody response in the host. Serum, liver, and adjacent tissue samples were obtained at autopsy from 2 individuals with vinyl chloride-associated angiosarcoma and 10 control individuals with normal liver function and at bicosy from 10 patients with liver dysfunction with fibrosis. Immunodiffusion studies of angiosarcomatous tissue revealed the presence of an antigen not found in normal liver or kldnev, but found in normal lung and spleen. This protein was inactivated bv Pronase and trypsin, was heat- and acid pH-labile, and was found to precipitate at concentrations of 20-30K saturated ammonium sulfate and 30-70/1 ethanol. Immunoelec trophore t i c assays of angiosarcomatous tumor extracts revealed the absence of one normal tissue antigen characteripad as an entity unaffected by Pronase, trypsin, and heat treatment, inactivated by periodate and acid pH, and which precipitated over a wide range of conditions. Additionally, immunofluorescence assays of ang I osarcoma t ous tissue indicated the presence of bound IcG. Further studies are necessary, to determine whether- this Tumor-bound IgG represents specific antitumor antibody or antibody fixed by the tumor tissue nonspecifically. (29 Refs) 110 AU AD TI SI SO LA AB Kupchella CE t Tamburro CH Cancer Center, Dept. Medicine, Univ. Louisville Sch, Medicine, Louisville, KY, 90201 URINARY AND TISSUE GLYC0SAMIM0GLYCAM PATTERNS IN HEPATIC ANGIOSARCOMA. CARC/79/069 70 Prevention and Detection of Cancer. Part I, Prevention. Vol. 1. Etiology. Proceedings of the Third Inter-national Symposium on Oectection and Prevention of Cancer held 26 April - 1 May 1976 New York MY. Mieburgs HE, ed.New York, Mar-cel Dekker, Inc., 1193 pp., 1977. ENG To evaluate the use of glycosaminoqlycan (GAG) patterns as an earlv indicator of vinvl chloride (VC)-induced 1iv^r injury or angiosarcoma (AS), GAG patterns were determined in urine samples of 9 patients with histories of exposure to VC and who had abnormal liver biochemistry, 6 with 'other' cancers prior to surgery, 3 ui T'n AS, 8 with viral hepatitis, 6 with cirrhosis, 2 00005703 VINYL CHLORIDE PAGE 60 uith lung-liver mat as tases i and A uit'n metabolic liver disorders. Determinations of GAG were carried out by creatinine and uronic acid assays. Additionally! tissue samples taken at autopsy from 2 patients uith ASi 2 uith cirrhosis, and 3 controls (uho had gun-shot wounds ) were similarly analysed. Results shoued that AS. hepatitis, cirrhosis, and liver metastases all involved elevated GAG excretion. Tissue data indicate that these elevated levels reflect GAG elevation in the liver. Furthermore, results disclosed that the chondroltin sulfates are the primary urinary GAG in both normal controls and in patients, uhile chcndroitin sulfates and heparin are the dominant GAG present in flbrotic. nontumor portions of AS livers and tumor tissue, respectively. It is concluded that the increases in liver and urinary GAG levels may uell reflect an important role of these substances in the process of f1brogenesis and tumor grouth. (31 Refs) 111 AU - Krces R AD - Lab. Pathology. Natl. Inst. Public Health, P.0. Box 1, Biltnoven, Netherlands TI - FOOD'- A CARCINOGENIC HAZARD? SI - CARC/79/06A5A SO - Prevention and Detection of Cancer. Part I. Prevention. Vol. I. Etioloqy. Proceedings of the Third International Symposium on Dectectlon and Prevention of Cancer held 26 April - I May 1976 Maw York NY. Nieburgs HE. ed.Neu York, Marcel Oekker. Inc,. 1193 pp., 1977. LA - ENG AB - Information on the possible carcinogenic hagard of food is reviewed. Natural components of food that pose a carcinogenic threat include nitrate (in spinach, leeks, and purslane), fats, and proteins. Natural contaminants of food that are carcinogenic include aflatoxln, cycasin, safrole. sterigmatocystin , peniclllic acid, patulin, luteoskyrin, eyelochlcrotine. and pyrrolip1dine alkaloids. Manmade chemicals that contaminate foods come from a wide range of sources. The food additives butter yellou, ponceaux SX and 3R> guinea green, fuchsin, amaranth fur fury 1furamlde> and dulcin are non legislatively prohibited, based on recent findings that they may be careinogen Ic. Contamination can occur from food packaging chemicals! le. vinyl chloride, a proven carcinogen that is now federally regulated. Various agricultural chemicals still in use and under suspicion include dibromoethane. dibromochloropropane, aramlte, chlordecone, lindane, DDT, aldrin, dieldrln, and nitrogen fertilisers. In addition, potentially carcinogenic substances used for dlsinfection , grouth promotion, weed and insect control, and chemical synthesis reach food as a result of environmental pollution. The last source of carcinogenic contam Ination is from food processing! smoke cu-inq introduces polycyclic aromatic hvdrocarbons, nitrate and nitrite curinq introduces nitrosam1nes, and processing through the use of fungi introduces mycotoxins into the dieT. t25 Refs) 00005789 VINYL CHLORIDE PAGE 61 112 AU - Lehmann P AD - New York Acad. Sciences, 2 East 63rd ST., New York, NY, 10021 TI - CANCER ANO THE WORKER. SI - ICD5/79/16563 SO - Cancer and The Worker, New York, New York Academy of Sciences, 77 pp., 1977. LA - ENG A8 - Volume 271 of The Annals of The New York Academy of Sciences, 1OccupaTional Carcinogenesis', has been rewriTTen for The general public. Basic cancer terms are defined, Cancer hazards To The worker are reviewed, The prevention of occupational cancer is discussed, and The social issues involved are considered. Some of The specific hazards discussed are chemicals (vinyl chloride, anesthetics, bls(chloromothyllether, coke-oven emissions and coke by-products, benzene, rubber industry chemicals, chloroprene, benzpyrene, and lubricating oils), metals (arsenic, cadmium, lead), and dusts and fibers (asbestos, fibrous glass, radioactive dusts, wood dust, textile industry dusts). The effects of smoking on the risk of cancer among workers is briefly considered. Hazards to the communities surrounding industrial sites are discussed. Government regulations on occupational exposure to hazardous substances are reviewed. (4 Refs) 113 AU AD TI SI so LA AE3 - Otsuki M ! Maeda M ; Yuu H ! Baba 5 - Second Dept, of Internal Medicine, Koba Univ. Sch. Medicine, Kcbe, Japan - THE NATURE OF HYPERAMYLASEHIA IN PRIMARY LUNG CANCER! DEMONSTRATION OF A PRECURSOR OF THE SALIVARY TYPE ISOAMYLASE (MEETING ABSTRACT). - ICDB/78/26400 Summary Program and Abstracts of Papers> Proceedings of the 3rd Asian Cancer Conference Held by the Philippine Cancer Society under the Auspices of the Asian Federation of Organisations for Cancer Pesearch and Control in Manila, 26-30 September, 1977. Philippine Cancer Society, Manila, Philippines., 184 pp., 1977. - ENG The nature of the amvlase in serum, pleural fluid and tumor extracts in patients with primary lunq cancer was investigated. There seemed to be no correlation between histoloqical structure of the tumors and The attendant hvperamvlasemia. High amylase activity in The extracts of the diseased lunq Tissue has been found in pneumonia and tuberculosis* (chiefly salivary type isoamylases). Moreover, elevated amylase activity of the salivary type was observed in serum specimens sampled from the left atrium at autopsy, though there was no possibility of contaminaIion of the salivary amylase durinq passage through The lunq. In The extracts of primary arid metastatic tumors of lunq cancer and inflammatory lunq tissues from a patient who died of vinyl chloride monomer poisoning, a peculiar isoamylase snowing cathodic mobility on S'/, polyacry 1 am 1 de gel at pH 8.8 was found, in addition to the increased salivarv Type isoamylases. While in the extracts of metastatic liver nodules, only this peculiar ' j'. i'-z. . yi!& t . C ' -,Y 3J fio cn w 00 00 00 to !'-? c c c (. /' (. (. 00005790 VINYL CHLORIDE PAGE 62 isoamylase was found. We herein demonsTrate That The salivary Type hyperamylasemia in primary lung cancer may be due To an increase in The amylase contained in normal lung Tissues resulting from activation and release inTo the blood stream by some infla.nmatory process. Ectopic production of amylase was also suggested in a particular case with primary lung cancer by findings of high amylase contents and a precursor of isoamylase both in the primary and metastatic lesions, (no Refs) 114 AU - Wagoner JK I Infante PF AD - Industry-wide Studies Branch) Div. Surveillance> Hazards Evaluations and Field Studies) Natl. Inst. Occupational Safety and Health, Cincinnati, OH, 45202 TI - VINYL CHLORIDE: A CASE FOR THE USE OF LABORATORY BIOASSAY IN THE REGULATORY CONTROL PROCEDURE. SI - CARC/73/07396 SO - Human Risk Assessment, Proceedings of the Cold Spring Harbor Conferences on Cell Proliferation. Vol. 4 (Book C), Hiatt HH, Watson JO, Uinsten JA, ed. Cold Spring Harbor, Cold Spring Harbor Laboratory, Origins of Human Cancer., 583 pp., 1977. LA - ENG AB - The need for laboratory bioassays in the regulatory control of chemicals is illustrated using vinyl chloride (VC) as an example. The induction of skin, lung, and bone tumors in rats exposed by inhalation to high VC levels (levels not infreguently approached in the industrial setting) was first reported in 1971, 40 yr after VC's commercial introduction but 3 yr before Three cases of liver angiosarcoma were reported among workers at a VC polymerisation facility. A follow-up study, initiated as a result of these initial angiosarcoma cases, showed a significant excess of deaths from malignant neoplasms among VC workers , compared with US white male death rates. Excess cancer mortality was found for four organ systems: brain and CNS, respiratory system, hepatic system, and lymphatic and hematopoietic system. The cancer risk increased with increasing year's of exposure. In the follow-up study, 11/14 confirmed cases of biliary or liver cancer were hepatic angiosarcoma. Among 8 bronchogenic carcinomas, 5 were large-cell und i f f er'en t i a t ed and 3 were adenocarcinomas, which is not consistent with distributions previously reported for inhaled car'c I noqens. A recent bioassay was predictive not only for the careinogenicity of VC but also fon several of the tarqet organs. VC is mutagenic In microbial test systems, and VC metabolites hawe induced mutations in mammalian cells. Wives of VC-exposed men ha'-e a significantly high risk of fetal loss. Thus, both mutagenic and carcinogenic assays predicted The potential hazards of VC. (34 Refs) c c c c ( c c L L L 00005791 VINYL CHLORIDE PAGE 63 115 AU AD TI SI SO LA AB 116 AU AD TI SI SO LA AB Popper H *, Maltoni C ; Squire RA ; Thomas LB Stratton Lab. Study of Liver Diseases) Mount Sinai Sch. Medicine> City Univ. New York. New York, NY, 10029 COMPARISON OF NEOPLASTIC HEPATIC LESICMS IN MAN AND EXPERIMENTAL ANIMALS. CARC/78/07373 Human Risk Assessment, Proceedings of the Cold Spring Harbor Conferences on Cell Prolifera!ion, Vol. 4 (Book C), Hiatt HH, Watson JD, Winsten JA, ed. Cold Spring Harbor, Cold Spring Harbor Laboratory, Origins of Human Cancer., 583 pp., 1977. ENG The induction of hepatic tumors in animals and clinical observations of hepatic tumors in humans are compared. The progression from fibrotic lesions to angiosarcoma in man following exposure to vinyl chloride (VC), inorganic arsenicals, and Thorotrast is almost identical to changes observed in rodents treated with VC. This similarity in the evolution of hepatic lesions supports the predictive nature of animal experimental studies for human careinogenesi3 . The major difference between the species was the greater fibroplastic reaction in man. The development of hepatocellular carcinoma in human and rodent nodules supports the concept of multiple cell populations in hepatccarcinogenesls. In the VC-assoclated lesions, the simultaneous proliferation of hepatoevtes and sinusoidal cells, the latter potentially terminating in angiosarcoma, is stressed. The metabolic processes underlying this evolution remain to be established, (77 Refs) Infante PF '> Waqoner JK J Young RJ Industry-wide Studies Branch, Div. Surveillance, Hazard Evaluation and Field Studies, Natl. Inst. Occupational Safety and Health, Cincinnati, OH, 45202 CHLOSOPRENE: OBSERVATIONS OF CARCINOGENESIS OF MUTAGENESIS. CARC/70/0 7215 Incidence of Cancer in Humans, Proceedings of the Cold Spring Harbor Conferences on Cell Proliferation. Vol. 4, Hiatt HH, Watson JO, Winsten JA, ed. Cold Spring Harbor, Cold Spring Harbor Laboratory, Origins of Human Cancer., 602 pp., 1977, ENG Observations of excessive lung and skin cancer associated with chlorcprene production were reported in the Russian literature in 1972. However, it was not until 1974, when an epidemic of liver, brain, and lung cancer a.monq vinyl chloride (VC) po lymer i cat I on workers was identified, was attention in the US focused on the carcinogenic potential of chloroprena. Chioroprene is mutagenic in bacteria, causes recessive lethality In Drosophila, causes dominant lethality and chromosome aberrations in rat bone narrow cells, and lias been associated with sterility in mice and rats. A significant excess of chromosome aberrations and a reduction in the numbers and motilitv of soerm have been reported in chioroprene workers, and a threefold excess of miscarriages has been reported among their wives. In The absence of adequate data, .ak-sp).if ^ >) r" c c r \ ( 00005792 VINYL CHLORIDE PAGE 6A a final "valuation of The carcinogenicity of chloroprene cannot be made. However* given its other effects* the possible careinogenieiTy of chloroprene may be only of academic interest from a public health point of view. The data for VC anc chloroprene may serve as the basis for a more aggressive role by genetic toxicologists in the assay of industrial chemicals. (35 Refs ) 117 AU - Gehring PJ ; Watanabe PG I Young JD AD - Toxicology Res. Lab.* Health and Environmental Res.* Dow Chemical, Midland. MI, A86A0 TI - THE RELEVANCE OF DOSE-DEPENDENT PHARMACOKINETICS IN THE ASSESSMENT OF CARCINOGENIC HAZARD OF CHEMICALS. SI - CARC/78/0721A SO - Incidence of Cancer in Humans* Proceedings of the Cold Spring Harbor Conferences on Cell Proliferation. Vol. A, Hiatt HH, Watson JD, l-linsten JA* ed. Cold Spring Harbor, Cold Spring Harbor Laboratory, Origins of Human Cancer., 602 pp.* 1977. LA - ENG AB - The use of data obtained after the lifetime daily administration of max tolerated doses of an agent to animals (usually rats or mice) to predict the hazard of low-level exposure to the agent is not justified. Changes in the fate of the chemical or in the metabolic status of the animals preclude the use of routine statistical processes to predict hazards from low doses. Metabolic Thresholds may lead to a disoroportionate increase in toxicity, including carcinogenesis. This concept is illustrated by pharmacokinetic studies with l,A-dioxane and vinyl chloride (VC). The marked dose-dependent fate of dioxane and the strong metabolic induction by high doses, together with toxicologic data, negate extrapolation of high-dose carcinogenesis to predict the hazard of low doses. In rats, cancer induction occurs only at doses sufficient to cause marked pathology, metabolic alteration, and even death. These effects, including careinoqenesis , are correlative with the dose-dependent fata of dioxane. In light of this correlation, the hazard of low-level exposure To dioxane appears to be nil. Studies indicate That VC is metabolized bv at least Two different pathways. The fate of VC changes with dose because the primary pathway for its metabolism is saturated at hiqh doses or exposures. However, both pathwavs for the metabolism of VC produce reactive metabolites that lead to the same end products. A correlation appears to exist between coses of VC that cause tumors and those That saturate metabolic cr detoxifying pathways. There is a threshold of exposure in rats. in which the physioloqlc defense mechanisms remain fully operative. Thus, dose-dependent alterations in the fate of chemicals must be considered when using toxicioloq1 cal or carcinogenic data obtained at high doses To assess The hazard of low doses. (21 Refs) 31 (n 03 CO CO CO cn ii 0Q0Q5793 VINYL CHLORIDE PAGE 65 rx 1 ( 118 AU - Maltoni C c AO - Inst. Oncologyi Bologna, Italy 40138 TI - VINYL CHLORIDE CARCINOGENICITY: AN EXPERIMENTAL MODEL FOR CARCINOGENESIS STUDIES. SI - CARC/73/07128 c SO ~ Incidence ot Cancan in Humans, Proceedings of The Cold Soring Harbor Conferences on Cell Proliferation, Vol. 4, Hiatt HH, Watson JO, Winsten JA, ed. Cold Spring Harbor, Cold Spring Harbor Laboratory, Origins of Human Cancer., 602 pp., 1977. LA - ENG c A3 - The carcinogenicity of vinyl chloride (VC) uas evaluated in Sprague-Dauley rats, Wistar rats, Sulss mice, and golden hamsters. In inhalation studies, 50-30,000 ppm VC produced Zvmbal c gland carcinomas, nephroblastomas, hepatic angiosarcomas (HAS) and angiosarcomas of other sites, sc angiomas, skin carcinomas, hepatomas, brain neuroblastomas, and mammary carcinomas in adult Sprague-Dauley rats after 52 uk of exposure. Rats exposed to only c 25 ppm VC for 87 uik developed HAS. Reducing the length of treatment sharply reduced the onset of several tumor Types, parTicularly HAS: when rats uere treated for 5 wk at 10,000 and 6,000 ppm, no HAS were observed. VC also had a transplacental effect: exposure of pregnant rats to 10,000 or 6,000 ppm VC on days 12-18 of pregnancy produced VC-dependent tumors in the offspring. Newborn rats Were also more susceptible to VC careinogenesis Than older ones. Exposure of Wistar rats to varying VC concentrations for 52 uk resulted in basically the same tumors as those produced in Sprague-Dauley rats. Exposure of Swiss mica to 50-10,000 ppm VC for 30 uk resulted in lung Tumors, mammary carcinomas, HAS, vascular tumors of other types and/or sites, and epithelial tumors of The skin. In golden hamsters, the same VC concentrations resulted in HAS. skin trichoepitheliomas, melanomas, and forestomach epithelial tumors. In addition, the latency Time of lymphomas uas decreased from 82 uk (in controls) c. to 48 uk. IngesTion of 50, 16.65 or 3.33 mg/kg/dav VC by Sprague-Dauley rats, 4-5 days/uk for 52 wk produced essentially the same spectrum of tumors as the inhalation studies. One nephroblastoma and one sc anqlosarcoma wore found among 240 c Sprague-Dauley rats that had received one to four ip injections of 4.25 mg VC, and one nephroblasToma was found among 75 animals that had receiued the same dose sc. It is concluded that the neoplastic response to VC depends largely on the species and c. strain of animal and that age is also important with respect to tumor incidence and d1stribution. (5 Refs) 119 AU AO TI SI so Fonseca JJ ; Pena FM Catedra de Patologla, Facultad de Mediclna, Universldad de Costa Rica, Costa Rica PRIMARY HEMANGIOSARCOMA OF THE LIVER ASSOCIATED WITH MICROANGIOPATHIC HEMOLYTIC ANEMIA AND THROMBOCYTOPENIA (KAS3ELBACH-MEPPITT SYNDROME). REPORT OF TWO CASES. ICDB/7S/2 34 73 Acta Med Costarrlct 20(31:273-285 1977 L L 00005794 VINYL CHLORIDE PAGE 66 LA A8 120 AU AD TI SI SO LA AD 121 AU AD TI SI SO LA A3 SPA Abnormal hematologic findings are resorted in two cases of primary hemangiosarcoma of the liver: microangiopathic hemolytic anemia and thrombocytopenia in one case and chronic hypofuremic anemia in the other. Doth patients succumbed to massive intraperitoneal bleeding, in one patient following a needle biopsy, in the other because of spontaneous rupture of the tumor. Both cases were diagnosed at autopsy. Exposure to thorium dioxide, arsenical solutions or vinyl chloride was denied. (47 Refs ) Henschler D Institut fur Pharmakologie und Toxlkologie, Univ. Wurzburg, D-S7 Wurzburg, W. Germany METABOLISM OF CHLORINATED ALKENES AND ALKANES AS RELATED TO TOXICITY. CARC/76/06409 J Environ Pathol Toxicol; 1(2):125-131 1977 ENG Chlorine substitution in aliphatic compounds results in a destabilization in alkanes and a stabilization in alkenes. With alkanes, therefore, the main pathways of metabolic transformation to reactive intermediates are radical formation by a C-C break and dechlorination or dehydrochlorinat1 on. In the chlorinated ethylenes, the first metabolic trails format i on step is oxidation to electrophi 1 ic oxiranes. These con-pounds may be nydrolized enzymatically or nonenzymaticallv, react with cellular nucleophiles, or rearrange to either chlorinated aldehydes or acyl chlorides. With tetrachloroethylene, 1,2-cis-dlchloroethylene, trans-dlchlcroethylene , 1,1-dichloroethylene, and vinyl chloride, the metabolies identified in in vivo experiments are identical to the thermal rearrangement products of the respective oxiranes. An exception is trichloroethylene, whose thermal rearrangement product is dichloroacety1 chloride; its metabolites in ivo , however, are entirely derived from trichloroacetaldehyde. Mutagenic and carcinogenic activities in the chlorinated ethylenes are determined by the stability of their chlorine substitution compounds : the relatively unstable and unsymmetric oxiranes of trichloroethylene , 1,1-dichloroethylene, and vinyl chloride are mutagenic in the Ames test, but the more stable asymmetric oxiranes of tetra-, 1,2-cls-, and trans-dichoroethvlenes are inactive. (20 Refs) Holn-berq B J Kronevl T ; Uinell M Section Occupational Toxicology, Natl. Board Occupational Safety and Health, Stockholm, 5weden SOME ASPECTS ON D05E-PESFCN5E IN VINY L-CIILCR IDE - INDUCED LIVER INJURY AND TUMORS IN MICE (MEETING ABSTRACT). 1003/70/19650 Scand J Clin Lab Invest; 37( Suppl 147 ): 74 1977' ENG Vinyl chloride monomer (VCM) induces liver injury and liver 00005795 VINYL CHLORIDE PAGE 67 22 AU AD TI SI SO LA A3 03 AU AD TI SI SO LA AD hemangi O3.'.rcoms in PVC workmen end is also carcinogenic in rodents. Nice were exposed by inhalation to 50 and 500 ppm VCN during 12 and 6 mo respectively. Blood samples were Taken every 6th wk for analysis of glutamic pyruvic transaminase (GPT), glutamic oxalacetic transaminase (GOT), acid phosphatase (AP), and total lactic dehydrogenase (LDM) as well as LDH isoenzymes. Some mice were sacrificed for histepathoiogical examinations after 6 mo and the rest when dead Or moribund. AP and total LDH activities were elevated in VCN exposed mice. The percentage of N form was also increased in exposed animals. The transaminases were not elevated. Enzyme activities were, however, increased after the appearance of tumors. A tendency to a dose-dependency was observed in Total LDH activities as well as in The frequency of tumour-bearing animals. The signif1cance of The data will be discussed with reference To possible early' detectability' of VCN induced tissue injury and with reference to current knowledge of dose-response relationships for chemically induced tumors. Nelson N Inst, Environmental Medicine, New York Univ. Medical Center, New York, NY, 10016 INHALATION CARCINOGENESIS. CARC/73/05362 Ecotoxlcol Environ Safi 1(3)1239-295 1977 ENG A limited review of the care inoqen i c i Ty' of various inhaled substances is presented. Chemical hazards in The workplace include benzene, nickel carbonyl, mustard gas, vinyl chloride, chloroprene, and bis(chioromethyl)ethen (BCNE). To date, at least 35 cases of lung cancer in the U5 have been attributed to BCNE. Several methods for The safe and controlled inhalation of experimental animals To carcinogenic material are outlined. Van Duuren BL Lab. of Organic Chemistry and Care I nogenesi3, Inst, of Environmental Medicine, New York Univ. Medical Center, New York, NY, 10016 CHEMICAL STRUCTURE, REACTIVITY, AND CARCINOGENICITY OF HALOHYDRCCARBCNS, CARC/73/05433 Environ Health Perspect) 21:17-23 1977 ENG The structural and carcinogenic properties of halohydrocarbcns are reviewed, with particular emphas 1 S on tr i chici-oethy'len: (TCE). Based on studies of the chemical structure, reactivity, and possible metabolic pathwa\s of TCE, The compound was predicted To be carcinogenic, par t i cular ly, to The liver. These studies also suggested that TCE is metabolized To an epoxide and that This epoxide may be the activated carcinogenic intermediate of TCE in liver care 1 nogenes i s . The binding of TCE To liver microsomal proteins of male E6C3F1 hybrid mice, which are susceptible To TCE-irduced live- Tumor i genes I s , uas found to be significantly higher than the binding of TCE to microsomal 9P (P C 00005796 VINYL CHLORIDE PAGE 68 c proteins of mala Osborne-Mendel rats, which are resistant To TCE-indueed hepaTocallular carcinoma. Also, The in vitro binding of TCE To liver microsomal proteins was hlqher for male Than c female 86C3F1 mica; females ha>'e been reported To show a lower incidence of TCE-induced hepatocellular carcinoma than males. The results of carcinogenicity assays of vinyl bromide and polyvinyl bromide are also given. Neither compound appeared to be ( carcinogenic when injected sc or when applied to the skin of mice. The carcinogenicity of other chlorinated hydrocarbons That are widely used in The chemical industry and that are structurally analogous to TCE and vinyl chloride is discussed briefly. 129 AU - Lee CC J Bhandari JC ; Winston JM J House WB i Peters PJ AU - Dixon RL I Woods JS r AO - Pharmacology and Toxicology. Midwest Res. Inst-. 925 VolRer Blvd., Kansas City, MO, 69110 TI - INHALATION TOXICITY OF VINYL CHLORIDE AND VINYlIOENE CHLORIDESI - CARC/78/05937 SO - Environ Health PerspectJ 21:25-32 1977 LA - ENG AD - Experiments on the inhalation toxicity and careinoaenicity of vinyl chloride (VC) and vinylidene chloride (VOC) in mice and ( rats are reported. The exposure of mice to 1,000 ppm VC for 6 hr/day, 5 davs/wk caused some acute deaths with toxic hepatitis and marked tubular necrosis of the renal cortex. During the sixth month, mice exposed To 1,000, 250, or 50 ppm VC became lethargic, lost weight quickly, and died; only a few mice exposed to 50 ppm Survived for 12 mo. In mice exposed To 50, 250, or 1,000 ppm VC, there was a high incidence of bronchioloa1veolar adenoma, mammary gland tumors (including ductular adenocarctnoma ), squamous and anaplastic cell carcinomas with metastasis to The lung, and hemanqiosarcoma (HS) in the liver and, to a lesser extent, in other organs . The incidence and severity of these Tumors were proportional To the levels and duration of exposure. Malignant lymphoma involving various organs was observed in a few mice. Rats were more resistant To the toxic effects of VC, and exposure to 1,000 ppm slightly depressed the body wt of females. Exposures of 250 and 1,000 ppm VC caused a number of deaths and hepatic HS during the 9th mo. Most rats with hepatic IIS also developed HS in the lung. HS occasionally occurred In other tissues, including omentum, mesentery, or' sc Tissue, of rats exposed to 50, 250, or 1,000 ppm VC. The exposure of mice to 55 ppm VDC also caused a few acute deaths and a feu hepatic H5. Inflammatory, degenera t i ve, arid mitotic changes occurred in the liver. Ho mouse exposed to VDC developed any mammary gland tumors. Several mice had a bronchioloalveolar adenoma. The exposure of rats to 55 ppm VDC slightly deorpssed body wtl HS occurred in The mesenteric lymph node or sc Tissue of two rats. 00005797 VINYL CHLORIDE PAGE 69 125 AU - Hathway DE AO - Imperial Chemical Industries Limited' Central Toxicology Lab., Aldarley Park i Cheshire SK10 4TJ, England TI - COMPARATIVE MAMMALIAN METABOLISM OF VINYL CHLORIDE AND VINYLIDENE CHLORIDE IN RELATION TO ONCOGENIC POTENTIAL. SI - CARC/78/05A 3A SO - Environ Health Perspect; 21:55-59 1977 LA - ENG AO - Possible mechanisms for the mammalian metabolism of vinyl chloride (VC) and vinylidene chloride (VDC) are discussed in relation to the oncogenic potential of these agents. Studies in rats indicate that VC probebi'.' yields chloroethylene oxide (CE0)> union is then transformed spontaneously into cnloroacetaldehyde (CAA). Since CAA and CEO are mutagenic in the Ames test and in Chinese hamster V79 cells> thev may be relevant to VC carcinogen)clty. Observations in rats exposed to VC indicate that a degree of DMA depurination occurs. The alkylation that produces imldr.Zo- derviative formation ui th DNA labiiizes the N9-purlne beta-glycoside linkage, which leads to depurination. The gap so produced might then be filled by various bases, resulting in mispairing during DNA replication. In general, there is excellent agreement between the severe damaging effect of DNA depur Ination and mutagen!city. Thus. VC would be considered mutagenic/carcinogenic. Experiments with rats exposed to VDC indicate that chloroacetic acid (CA), which is a VDC metabolite per se. lies on a major metabolic pathway for VDC. There is a strong supposition that CA is detoxified through a glutathione S-aoyitransferase-catalyzed reaction process and ensuing degradative sequence for the resulting carboxymethylglutathione and that this represents the principal metabolic pathway for CA and a major one for VDC. Thiodiglycol1ic acid (TDC) is the ultimate de to.x i f i ca t i on product. Comparative studies of the processing of VDC in mice and rats show that in mice, the metabolic pathway from CA to TDC seens to be readily saturable, possibly on account of an inadequacy in the reaction catalyzed by glutathione 5-acyltransferase. Under these clrcumstances . detoxification of 1.1-dichloroethylene oxide by clutathlone S-epoxide transferase and the modification of DNA by 1,1-dichlorcethylene oxide or cnloroacetyl chloride would be expected to be more significant in mice than In rats. This diagnosis of species susceptibility agrees wiTh the discovery of VDC oncogenicity in the kidneys of mice. Overall, VDC emerges as an agent of low oncogenic potential that is likely to be damaging only under special biological circumstances . (26 Refs) 00005798 VINYL CHLORIDE PAGE 70 126 AU - Mai Toni C AD - Inst. Oncology and Tumor Centeri Bologna> Italy TI - RECENT FINDINGS ON THE CARCINOGENICITY OF CHLORINATED OLEFINS. SI - CARC/73/05401 SO - Env/iron Health Penspect; 21:1-5 1977 LA - ENG A3 - Major factors affecting the carcinogenic)ty of vinyl chloride (VC) and vinylidene chloride (VDC) are discussed. Although the two compounds have Very similar molecular structures? they have widely different biological effects. VS is a multipotentioi carcinogen, but VDC has produced tumors only in the murine kidney. Dose? ccncentration? length of treatment? route of administration? and animal species? 3train? sex, and age also significantly affect the neoplastic response. These factors may alter the metabolic pathway of the test compounds. The careinogenicity of VC and VDC is due to their active metabolites? probably epoxy derivatives. Animal species? strain, and sex greatly affect the production of active metabolites of VDC. In Swiss mice and Spragug-Dawloy rats? there is a parallelism between the toxic and carelncqenic effects of VDC in relation to species and sex. Confirmation of this parallelism in other strains would indicate new routes for establishing experimental animal models? and for understanding the mechanisms of action of many organic carcinogens. 127 AU AD TI SI SO LA AB - Anderson D ; Hodge MC ; Purchase IF - Central Toxicology Lab.? Imperial Chemical Industries, Ltd.? Alderley Park nr. Macclesfield? Cheshire SKIO 9TJ, England DOMINANT LETHAL STUDIES WITH THE HALCGENATED OLEFINS VINYL CHLORIDE AND VINYLIDENE DICHLORIDE IN MALE CD-I MICE. CARC/73/05317 Environ Health Perspect; 21:71-73 1977 ENG Vinyl chloride (VC) and vlnylidene dichloride (VDC) were assessed by The dominant lethal test for mutagenic activity in fertile male CD-I mice. Compared with control males exposed to air, VC and VDC did not cause dominant lethal mutations at 3,000, 10,000, and 30,000 ppm and at 10, 30, and 50 ppm, respectively. 128 AU AD TI SI SO LA AB Radike MJ t Stemmer KL I Brown PG I Larson E ; Bingham E Univ. Cincinnati, Inst. Environmental Health, Kettering Lab., Cincinnati, OH, 95267 EFFECT OF ETHANOL AND VINYL CHLORIDE ON THE INDUCTION OF LIVER TUMORS: PRELIMINARY REPORT. CARC/78/05303 Environ Health Penspect; 21U53-155 1977 ENG A preliminary report of the effect of ethanol on vinyl chloride (VC) careinogentcity in 320 male Sprague-Dawley rats is presented. Eoual numbers of rats were divided into four groups. Group 1 received a normal diet and breathed filtered air fer life. Group 2 received a normal diet plus 5V, ethanol In the 00005799 VINYL CHLORIDE PAGE 71 c drinking water and breathed filtered air fcr life. Group 3 received a normal diet but breathed 600 ppm VC 4 hr/das'i 5 days/uk, for 1 yr. Group 4 received a normal diet plus ethanol c starting At wk before VC exposure. The ethanol exposure lasted until the animal died or was sacrificed. Sixty weeks after the first exposure To VC, 55 rats had died or had been sacrificied. No tumors were noted in eight Group 1 animals that had died. Of c six dead Group 2 animals, one had a kidney tumor. Of 13 dead Group 3 animals, 5 had liver tumors (2 of them being angiosarcomas) and 2 had lung tumors. Of 28 dead Group 4 animals, 21 had 26 liver Tumors (5 angiosarcomas ) and 2 had kidney tumors. These preliminary findings suggest a synergism between VC inhalation and ingested alcohol in tumor 1 genesis. (6 Refs) 129 AU AO TI SI SO LA A3 Bolt HM ; Filser JG Inst. Toxicology, Univ. Tubingen, Uilnelmstrasse 56, D-7400 Tubinqen-1, W, Germany IRREVERSIBLE BINDING OF CHLORINATED ETHYLENES TO HACROMOLECULES. CARC/73/05301 Environ Health Perspect; 21:107-112 1977 ENG The binding of vinyl chloride (VC) and Trichloroethylene (TCE) To male Wistar rat macromolecules was investigated and compared to that of carbon teTrachloride (CC14). Saturation of the rat metabolizing systems was achieved aT 250 ppm VC, 150 ppm TCE, and 250 ppm CC14. Data on The uptake of the compounds, the urinary excretion of metabolites, and exhalation after exposure indicated that the chlorinated ethylenes were metabolized much fasTer than CC14. The metabolites of all Three compounds bound irrewersibiy to tissue proteins, mainly in the liver. Other sites of binding included the kidneys, small intestine, lung, and spleen. Irreversible binding of these compounds ranged within the same Order of maqnitude when related to The amount of the compound That had been absorbed. No differences in the relative portico of irreversibly bound metabolites were found after exposure of the rats to different atn'OSpheric concentra t i ons of The three Compounds. In vitro studies indicated That TCE metabolism by rat liver tuicrosomes l n The presence of an NADFH-reqeneraT ing system leads To Irreversible protein binding, mainly to albumin! similar findings ha>'e been reported for VC. lAslike VC, however, TCE metabolites also bind to non-5H proteins such as g.nmma-ql obul i n and concanavalin A. Thus, TCE metabolites irreversibly bind not only to 5H groups of a protein, bur also To NM2 groups, (23 Refs) 130 AU AO TI SI SO LA A3 Henschlcr 0 Institut fur Toxikologie und Pharmakoloqie> Universltat Wurzburg, D-8700 Wurzburg, U. Germany METABOLISM AND MUTAGENICITY OF HALCGENATEO 0LEFINS--A COMPARISON OF STRUCTURE ANO ACTIVITY. CARC/73/05133 Environ Health Perspect! 21:61-64 1977 ENG The metabolism of various halogenated olefins was studied in 00005800 VINYL CHLORIDE PAGE 72 vivo and their mutagenicity was investigated in vitro in a modified Ames testing system. The results of the mutagenicity test were compared with in vivo carcinogenieity findings reported previously. In mammals, chlorinated athylenes are first metabolized to epoxides, which may then undergo intramolecular rearrangement. This reaction has been studied in the entire series of chlorinated epoxyethanes. The rearrangement products found were acyl chlorides (tetracnlcro-, trichlcro-, and 1,l~dichloroethylenes ) or chlorinated aldehydes (cis- and trens-1i2-dichloroethylenei vinyl chloride). In vivo experiments yielded products that were further derivatives of these rearrangement products! except that with trichloroethylene> the only rearrangement product was chloral. Tetracnloroethylene, trIchloroethylene, cis-1,2-dichloroethyIene. Trans-1,2-dichloroethylene, 1,1-dichloroethylene> and vinvl chloride were then tested for mutagenicity in the Salmonella typhimurium assay. Vinyl chloride, trlchloroethylene, and 1.1-dichloroethylene were mutagenic, suggesting that asymmetric chlorine substitution renders the epoxides unstable and mutagenic. High electrophi1icity may be a prerecuisite for the mutagenic and carcinogenic activity of these chlorinated ethylenes. (20 Refs) 131 AU - Watanabe PG I Young JD I Gehring PJ AD - Health and Environmental Res. Toxicology Lab.. Dow Chemical Co.. Midland, MI, 48640 TI - THE IMPORTANCE OF NON-LINEAR (DOSE-DEPENOEHT) PHARMACOKINETICS IN HAZARD ASSESSMENT. SI - CARC/78/05009 SO - J Environ Pathol Toxical; 1(2):147-159 1977 LA - ENG AB - The importance of dose-dependent or nonlinear pharmacokinetics in interpreting animal toxicity data at high dose levels for subsequent assessment of the hazard of exposure to humans is illustrated by two examples, 1,4-dioxane and vinyl chloride. The biotransformation , excretion, and protein binding of many chemicals are eapacity-11mI ted processes, and the probability of encountering saturable processes in animal toxicity tests is high. Toxicity at high doses may be due to saturated de t ox 1 f i cat i on or excretion mechanisms that, when full'/ operative at lower doses, do not result in the same toxic response. Knowledge of the pharmacokinetics of a chemical, therefore, is essential m evaluating animal toxicity tests. Pharmacoklnetic data can also be used to assist in dose selection for chro-.ie toxicity studies. In both cases, max informalion is obtained from a well-defined dose-response re latIonsnIp , Massive doses that result in nonlinear' pharmacok i ne 11 cs should be avoided unless they approximate human exposure levels. (20 Pefs) 30 <S> t*J 03 03 CD 03 00005301 VINYL CHLORIDE PAGE 73 132 AU - Graim H i Bimboes D i EgerT G i Gogqelmann U i Kramer H AD - Abteilung Toxikologie, GesellschafT fur STrahlen-und Unweltforschung Munchen, IngoisTadtsr LandsTrasse 1> D-S0A2 Neuherbarg, W. Germany TI - MUTAGENICITY AND CHROMOSOMAL ABERRATIONS AS AN ANALYTICAL TOOL FOR IN VITRO DETECTION OF MAMMALIAN ENZYME-MEDIATED FORMATION OF REACTIVE METABOLITES. SI - CARC/7S/0A097 50 - Arch Toxicol (Dari); 39(1/21:159-169 1977 LA - ENG AB - The mutagenic activity of various chemicals was tested in bacterial and mammalian assay systems. Trichioroethylane, 1>1-dichloroethylenei vinyl chloride, tatrachlorocyclopentadiene. and The nitroso derivatives of the pesticides Carbaryl. Prometryn, and Dodin were mutagenic To Escherichia coli K12 and/or Salmonella Typhimurium in The presence of metabolically active mouse liver microsomes. Under the same conditions, tetrachloroethylene. 1.2-cis- and trans-dichioroeThylene. hexachlorocyclopentadiene. carbon tetraehlorlde. chloroform, haioThr.no . tr i chlorof luoromo Thane . and styrene were not activated to mutagenic species. Incubation of human lymphocytes with dime thyInitrosam1ne in the presence of mouse liver microsomes induced chromosomal aberrations: There was a significantly increased number of gaps . but crossovers or translocations and breaks were less frequent. It is concluded that human lymphocytes can be successfully used in metabolizing TesT systems in Combination with mouse liver microsomes to activate potential mutagens. 133 AU - Henschler D I Bonse G AD - InsTitut fur Toxikologie. Univers 1 tat Wurzburg, Versbacher Landstrasse 9, D-3700 Wurzburo. W. Germany TI - METABOLIC ACTIVATION OF CHLORINATED ETHYLENES: DEPENDENCE OF MUTAGENIC EFFECT ON ELECTROPHILIC REACTIVITY OF THE METABOLICALLY FORMED EPOXIDES. 51 - CARC/73/0A032 SO - Arch Toxicol (Berl); 39( 1/2 ):7-12 1977 LA - ENG AB - Investigations of The chemical reactivity, blotransformat ion, and ToxiciTy of the chloroethylenes are reviewed. In chlorinated ethylenes, the chlorine susbsTitution exerts, by its elecTron-uithdrawal effect, a stabi11zaTion of the molecule that increases with the number of chlorine residues. Epoxides are short-lived metabolic intermediates that rearrange to qlve two possible products: acylchlorides (as with Tetra-, Tri-, and 1.1-dichloroethylenes ) or aldehydes (1,2-cis- and 1.2-trans-dichloroethylenas and vinyl chloride). The aldehydes Subsequently undergo reduction and oxidation to alcohols and acids, respectively. The chlorinated ethylenes were Tested for mutagenic potential in a modified Ames system, and Three members of The qroup were active: l'invi chloride, "inylidene chloride, and TrlchloroeThylene. The molecular feature common To The active ( c c ( ( c c e L L 00005302 VINYL CHLORIDE PAGE 74 R&S 138894 molecules is an asymmetric chlorine substi tution, but in the inactive compounds There is a symmetric distribution of the chlorine residues. It is hypothesised That The increased electrophi1icity caused by the asymmetrical chlorine substituth otters an enhanced chance for alkylating reactions of the epoxides, which overpower The deactivation mechanisms of conjugationi rearrangement, and hydrolysis. The three mutagenic cnloroethylenes have also produced carcinogenic effecTs in animaIs - 134 Alt - C'nuoy JC i Crozby NT AD - Dept. Industry, Lab. Government Chemist, London SE1 9NQ, Englan, TI - SOME OBSERVATIONS ON THE DETERMINATION OF MONOMER RESIDUES IN FOODS. SI - CARC/73/03995 SO - Food Cosmet Toxicol! 15(6 ) :547-551 1977 LA - ENG AB - Parameters that might affect the headspace gas chromaTographic (HSGC) determination of vinyl chloride (VC) and acrylonitrile (AN) residues in foods were 1nvesTicated. They included solvent type, monomer distribution between The headspace and the liquid, and storage duration and temperature. Samples of oranqe drink, wine, olive oil, and water, which previously had not been in contact with polyvinyl chloride (PVC), were poured into PVC bottles so that a mini mum air space was left above the liquid and then sealed, AT monthly intervals, 5-ml portions were removed and analyzed by HSGC. For VC, equilibrium was attained mere rapidly in methyl ethyl ketone (MEK) than m water. At 30 C, full eoui1ibrium was attained only after 2 hr! at 40 C, the equilibrium time was as short as 30 min. AT 30 C, VC was 10 times more soluble in MEK than in water. After equilibrium was attained. The VC content of the headspace was sTable for at least 5 hr. For AN, eoui1ibirum was achieved in less than 30 min in water or dimethylformamide and at 60 or 80 C, and little change was observed over 7 hr. When dimethylaceTami da and a storage Temperature of 00 C were used, however, the AN cencentration in the headspace fell rapidly for 2 hr, beginning 1 hr after equilibrium was reached. The reason for This is not clear. The concentration of VC in The headspace qases at different headspace volumes rose markedly at volumes greater than 13 ml. There was a clear distinction between The aqueous and organic solvent systems, a fact That may be important in the desiqn of a standard method for the analysis of VC in foods, Migration of VC from the container into the fluids increased during the first 3 mo, followed by a leveling off and, in some cases, a slow decay. When the same four fluids, to which varying wts of VC had been added, were kept in open glass Jars, the VC content fell to half its original value within 2-4 hr. (9 Pefs) c 00005803 VINYL CHLORIDE ( PAGE 75 c 135 AU Libeskind M ; Lugagne F ! Malbran J I Villemant JF c AU Guyet-Rousset P AD Service da GasTroenterologie. Centre Hospitaller de Gonesse, F c 95500 Gcnesse, France TI HEPATOSPLENIC ANGIOSARCOMA. REPCRT OF A CASE AND REVIEW OF THE 3] LITERATURE. SI CARC/78/03553 (\ SO Gastroenterol Clin Biol; 1(12 ):1027-1036 1977 LA FRE CO AB Primary angiosarcomas of the liver and spleen were diagnosed in a W 37-yr-old man who had never been exposed to vinyl chloride. (8 03 00 Refs ) (D cn 136 AU Ungvary GY ; HudaK A ; Tatrai E ; Lorincc M ! Folly G AD Orscagos Hunka- es Uaemegesasegtan Interet> Budapest) Hungary 1 TI STUDY'OF THE TERATOGENIC AND E3RY0T0XIC EFFECT OF VINYL CHLORIDE IN CFY RATS. X. SI CARC/78/03599 SO Egesgsegtudomany; 21(9):363-369 1977 LA HUN A3 Inhalation of vinyl chloride (9)000 mg/m#3) between the 8th and c 19th days of pregnancy increased the absolute and relative wt of The liver of pregnant CFY rats significantly) but there was no significant increase in resorption, embryonal mortality) and developmental anomalies. In addition, vinyl chloride was found in the maternal and fetal blood and amniotic fluid following exposure of the mothers to 5.500-33.000 mg/m**3 vinyl chloride c( for .5 hr on the 18th day of pregnancy. (31 Refs) 137 AU Short RD ; Minor JL I Winston JM ; Lee CC AD Pharmacology and Toxicology. Midwest Res. Inst.. 925 Volker c\ Blvd., Kansas City. MO. 69110 TI A DOMINANT LETHAL STUDY IN MALE RATS AFTER REPEATED EXPOSURES TO VINYL CHLORIDE OR VINYLIDENE CHLORIDE, SI ICD3/73/00967 ( SO J Toxicol Environ Health; 3(5/61:965-968 1977 LA ENG c AO Germinal mutations, as manifested by a dominant lethal effect, in male rats exposed to 0. 50, 250, or 1000 ppm vinyl chloride or 55 ppm vinylidene chloride (6 hr/day for 5 days/uk) were studied. The males were mated tJi tin untreated females after 11 wk of L exposure. No evidence of pre- or postimplantation loss in the pregnant females was observed. (9 Refs) 133 AU AD TI SI SO LA AB Reynolds ES Dept. Pathology. Univ. Texas Medical Branch. Galveston, TX, 77550 ENVIRONMENTAL ASPECTS OF INJURY AND DISEASE: LIVER AND BILE DUCTS. CARC/73/03279 Environ Health Perspect; 20:1-13 1977 ENG Mechanisms by which environmental agents interact with the liver (_ L and cause liver and biliary damage are surveyed. Known :v' C..-.. . 00005804 VINYL CHLORIDE PAGE 76 c hepatotoxins (vinyl chloride, CCl4)i potential hepatotoxins cohepatoxins, miNad-function-ox Idase inducers. and potential c hepatoxins that could be encountered in various environments are listed. (27 Refs ) 139 AU La tarjet R AO Foundation Curie - Instltut du Radium. 26 Rue de Ulm. 75231 Paris (' Cede* 05 France TI POLLUTION BY CHEMICAL MUTAGEN'S AN0 THE RAD-EQUIVALENT SYSTEM. SI CARC/78/03092 SO EnTrcpm; 13(73):6-11 1977 LA FRE AB A rad-equivalent system applicable to pollution by chemical mutagens such as vinyl chloride and methyl methane sulfonate is described. The system is based cn internationally accepted rules for radiation exposure, and it uculd permit calculation of the total mutagenic risk of exposure to radiation and chemicals. (11 Refs ) v. 140 AU Fuecn AM ; Fcurnet A i Laulhere L ; Faure J ! Cau G ; Mailion JM AD Labcratoire de medecine legale, medeclne du travail, Textcologie . La Merci, 38700 La Tranche. France TI INCLUDING AMGIOSARCGMAS, HEPATIC LESICNS IN FIVE SU3JECTS EXPOSED ( TO VINYL CHLORIDE. SI CARC/78/03037 SO Arch Mai Frof; 38( 9 )'787-795 1977 LA FRE (. AO Five wen uho uere occupationally exoosed to vinyl chloride for 10-26 yr developed lesions of The liver (3 anqiosarcomas, 1 adenosarcoma plus cirrhosis. 1 portal sclerosis). The patients ranqed in age from 38 to 63 yr, and They had been employed in various aspecTs of polymer production (solution preparation, pal ymer I pa 11 on i filtration, d''inq, etc). 1,'orK conditions were conducive to intoxication, since the men ate at their place of work and The factories were pcorlv wentila ted. The three angiosarcoma patients died within 4 mo of diagnosis despite hepatectomy and/or chemotherapy. The patient with portal ''em sclerosis was not treated but was followed regularly without evidence of change In his symptoms. The last patient died of pulmonary metastases from hepatic adenocarclnoma 1 yr and 4 mo after liver biopsy revealed widespread cirrhosis, (0 Refs) 141 AU A0 rr si so LA AO Curran KL ", Kupchella CE Tamburro CM Cancer Center, UnIv. Louisville. Louisville. KY 40201 URINARY GLYCGSAMINOGLYCAN PATTERNS IN ANGIOSARCOMA OF THE LIVER. CARC/78/03036 Cancer; 40(61:3050-3053 1977 ENG The urinary ehondroitin sulfate fraction was examined in a 46-yr-oid man with advanced hepatic angiosarcoma who had worked in a vinyl chloride plant for 13 yr, a 54-yr-old man with moderately advanced hepatic angiosarcoma uho had worked in a vinyl chloride plant for 28 yr, and two normal controls. The j4 ( V 00005305 VINYL CHLORIDE c PAGE 77 A-'* R&S 138897 c c e ( ( V ;a -y -v/up, : - y > -`.../'j 142 AU AD TI SI SO LA AS 14 3 AU AU AD TI SI SO LA AO specimens were separated into hyaluronic acid, chondroitin 3ulfate> and heparin fractions. Anion exchange chromatography of The hyaluronic acid and heparin fractions revealed no qualitative differences between controls and patients. The chondroitin sulfate fraction of The patients had an increased total amount of Uronic acid in a hyaluronidase-resistant fraction and a decreased amount in a fraction susceptible to hyaluronidase digestion. These changes appeared to become more pronounced with advancing disease. The resistant fraction was heparin sulfate and the susceptible fraction was either chondroiTin-4-sulfate and/or chondroitin-6-sulfate, These tests could be useful in The detection of vinyl chloride-induced liver disease, (22 Refs I Schmahl D Institut fur Toxikologie und Chemotherapie am Deutschen Krebsforschungsoentrum, Im Ngvenheimer feld 280 69 Heidelberg, W. Germany TOXICOLOGY IN CANCER RESEARCH. CARC/78/02S93 Interdisclp Sci Rev; 2(4):3C5-311 1977 ENG The role of Toxicology in cancer research is reviewed. A study of occupational and geographic cancers indicated that there is a high prevalence of gastric cancer in Japan and a dietary 'f;!cfor in the etiology. IT also implicated vinyl chloride in hemanglosarcoma induction and halcethers In The development of carcinomas of the bronchi. Natural products may also be carcinogenic. Certain or probable natural carcinogens include aflatoxins, arsenic, asbestos, betel nuts, Cycas circinalis, PTeris aquilina. pyrrolicidin alkaloids, Streptccotocin, and tobacco. In testing substances for carcinogenicity, species with responses similar to those of humans must be -found. In addition, prenatal Toxicological effects must be considered. An example of This is diethyIsTIlbesTrol-inducod vaginal adcnocarcinemos in daughters of women who Took the drug. Various drugs used in cancer therapy are also known carcinogens (alkylating agents, arsenic, diethy1$tilbesTrol , and procarbag Ine ), but in many cases their benefits outweigh their adverse effects. Future toxicological research should focus on measures of reducing the toxic side effects of many cancer therapy drugs. IT is generally thought that chemical carcinogens work by attacking genetic material. Carcinogens differ with respect to their dose-effect and dose-time relationships. (37 Refs) Oiersack MJ ! San Luis T I Lange CE ,' Thelen )l ; Veltman G Winkler C Inst, for Clinical and Evper I i,,en * al Nuclear Medicine, 5300 Bonn-Venusberg , W. German'/ SCINTIGRAPHY OF LIVER AND SPLEEN IN VINYL CHLORIDE WORKERS. ICOB/73/06726 H'patogastroenterol (STuTTy); 24(5 ):3S7-36I 1977 ENG In 152 vinylchloride(VC )-exposed, workers of whom 124 were ^ ( l c L L C c 00005506 VINYL CHLORIDE c PAGE 75 c(' employed in The polyvinylchloride (PVC) production and 28 in VC-proeessing plants> liver and spleen imaging ua3 performed c cusing Tc99m-sulphur colloid and Hgl97-BMHP. In 101 (312) of the 124 workers of the PVC-production plant and in IS (642) uorkers of PVC-processing factories pathological liver and spleen scintigrams were found. The most frequent pathological change in the scintigraphic image was an increase in splenic colloid accumulation, when compared with the liver uptake. Three angiosarcomas of the liver were detected through circumscribed c defects of colloid accumulation. Sequential liver scintigraphy was done in 15 cases. In 7 patients with esophageal varices considerable decrease in portal venous blood flow was demonstrated . Scintigraphically detectable changes are sensitive JO indicators of VC-induced lesions of the liver including li'-er fibrosis, portal hypertension and angiosarcoma. (Author abstract! 03 (22 Refs ) 144 AU - Radwan 2 I Henschler D AD - Inst. Toxicology, Uni". Wurzburg, Versbacher Landstrasse 9, D-3700 Wurzburg, W, Germany TI - UPTAKE AND RATE OF METABOLISM OF VINYL CHLORIDE BY THE ISOLATED PERFUSED RAT LIVER PREPARATION. SI - CARC/73/02725 SO - Int Arch Arbeitsmed; 40(21:101-110 1977 LA - ENG AB - The metabolism of vinyl chloride (VC) under controlled, steady-state exposure conditions in varying concentrations uas examined in the isolated perfused rat liver. The solubility of VC in the RBC perfusion medium at 37 C was constant from 50 to 25,000 ppm. The amount metabolized, (14.62) as determined by the difference between VC concentrations before and after passaqe of the liver, was also constant throughout this concentration range. This indicates that there is no saturation of those enzymes That initiate metabolic conversion of VC. Ethanol (constant addition to 12 mtl 1 and pyrazole (single addition to COO ufl 1 reduced VC metabolism by 12.72 and 31.62, respectively. Bromobenzothiazole also inhibited metabolism (43.92), SKF 525A was inactive, and phenobarbital pretreatment increased the conversion rate bv 20.92. Fasted animals showed a 31.22 increase in the metabolic conversion rate. Detormina11 on of GGOT, SGPT, and the lac tate/pyruvate coefficient revealed no VC-induced changes, even at The highest concentration tested (24,000 ppm), but slight liver damage was detectable after increased metabolic VC transformatI on. This suggests the formation of a reactive intermediate, an epoxide, as a result of The first-step oxidation. The epoxide would be expected if The oxidation were catalyzed by cytochrome P-450. Trie involvement of other oxidases, hcwewer, cannot be ruled out. (19 Refs) CO 00 00 CD 00 c c L C L 00005807 VINYL CHLORIDE PAGE 79 145 AU - Basuk J ; Nichols A AD - Science Council Canada i Ottawa, Canada TI - AN OVERVIEW OF THE VINYL CHLORIDE HAZARD IN CANADA. SI - CARC/73/02459 SO - Chem Can! 29(7):24-38 1977 LA - ENG AB - The effects of occupational exposure to vinyl chloride monomer (VCM) ere emphasised in this review, uhich also includes a discussion of the properties and processing of VCM. VCM came to attention as a health hazard in 1973i when three cases of a rare form of liver cancer, angI osarcoma, were reported in workers from a VCM factory. Since then, 43 victims have been identified; others who may have died from angiosarcoma are unknown because of difficulty in diagnosing the disease. VCM has chronic effects on human beings at high levels of exposure. It causes a specific occupational disease known as acroosteolysis, in which there is both Raynaud's syndrome and sclerodermiform lesions. In animal studies VCM has produced a wide range of tumors in rats, mice, and hamsters: Zymbal gland carcinomas, nepnrcblastomas, angiomas and angiosarcomas of the liver and other sites, trichoepithelIomas, hepatomas, lung adenomas, mammary adenomas and carcinomas, and lymphomas. Recent findings suggest that mammary carcinomas can be Induced in laboratory animals at less than or equal to 1 ppm. Efforts to control the adverse health effects of VCM include the setting of standards for occupational exposure to VCM, improved manufacturing techniques to minimize VCM exposure and residual VCM in polyvinyl chloride resin, and increased research on the epidemiology of VCM-related diseases and on diagnosing pr-eang i osarcoma tumors , (65 Refs) 146 AU - Nicholson WJ AD - Dept. Community Medicine, Mt. Sinai Sch. Medicine, New York, NY 10029 TI - CANCER FOLLOWING OCCUPATIONAL EXPOSURE TO ASBESTOS AND VINYL CHLORIDE. SI - CARC/78/99910 SO - Cancer [Suppll I 39(4 1:1792-1001 1977 LA - ENG AB - A review is presented of occupational cancer caused by exposure to asbestos and vinyl chloride (VC). Tile population at risk for several asbestos-related cancers includes those handling the mineral directly, those working near the application or removal of asbestos materials, and these living near an asbestos operation or in the household or" an asbestos worker. Asbestos exposure has been connected with death from lunq cancer, gastrointestinal cancer, and mesothelioma. The interval from first exposure to cancer development is at least 20 yr. A synergistic effect has been demonstrated for' lung cancer in asbestos workers who smoke cigarettes. Exposure to VC has caused hemangiosarcoma of the liver in addition to excess mortal I tv from tumors of the brain, lung, and lymphatic and hematopoietic systems. Exposures in the polyvinyl chloride processing industry 00005803 VINYL CHLORIDE PAGE 80 147 AU AD TI SI SO LA AB 148 AU AD TI SI SO LA A3 149 AU AD TI SI SO LA AB have been reduced significantly by alteration of production methods to minimise residual VC monomer in the resin. Attempts t control asbestos exposures hav3 not been os successful i partly a a result of significant differences between the Two industries, new standard for occupational asbestos exposure of 0.1 f/cm**3 has been proposed, which if adopted and enforced will greatly lower the human risk from asbestos exposure. (39 Refs) ( 30 CO Legrand J ; Puech AM No affiliation given VINYL CHLORIDE: HEPATIC ANGIOSARCOMA ASSOCIATED WITH ACRCOSTEOLYSIS. CARC/73/02430 Arch Mai Prof; 33(6):645-646 1977 FRE A 42-yr-old man developed acroosteolysis and an angiosarcoma of the liver after a relatively brief exposure to vinyl chlorine. He had developed edema of arms and hands after only 2 yr occupational exposure to >'inyl chloride. Ten years later, he again took a Job involved with the carcinogen and the acroosteolysls occurred. Symptoms of the angiosarcoma aceeared 17 yr after initial exposure, and the patient died within Z yr. (no Refs ) W 00 to o o c Edmonds L Birth Defects Branch, Center Disease Control, Atlanta, GA BIRTH DEFECTS AND VINYL CHLORIDE. CARC/78/02425 Proceedings Conference on Women and the Workplace, June 17-19, 1976, Washington, 0. C. Society for Occupational and Environmental Health Washington, D.C., 364 pp., 1977. ENG A review of CNS birth defects in two cities that have vinyl chloride (VC )-producing plants revealed that the defect rates were higher Than expected but they were not significantly different from the US rates at that time. There was no statistically significant excess of defects in offspring of men who worked at the plant, or of families residing near the plant, (no Refs) Wagoner JK J Infante PF ; Brown DP Industrywide Studies Branch, Div. Surveillance, Hazard Evaluation and Field Studies, Natl. Inst. Occupational Safety and Health, Cincinna ti , 0M GENETIC EFFECTS ASSOCIATED WITH INDUSTRIAL CHEMICALS. CARC/7S/02373 Proceedings Conference on Women and the Workplace, June 17-19, 1976, Washington, 0,C. Society for Occupational and Eny i r enmen t al Health, Washington, DC, 364 pp., 1977. ENG The careinogen IcITy and mutagenicity of various chemicals found in the workplace are reviewed, with emphasis on their genetic effects. Women have been e>ciuded from workplaces where vinyl c c L L L 00005309 VINYL CHLORIDE PAGE 81 chloride (VC) may be inhaled, but studies have also shown an increased fetal death rate in the offspring of men exposed to VC. Two structural analogs of VC, vinylidene chloride and Trichloroethylene, which have wide industrial use, have been shown to be carcinogenic in rodents and mutagenic in microbial and plant assays. However, human data for both are lacking. Functional disruption of spermatogenesis occurred among men occupationally exposed to chloroprene (2-chlcrobutadlene ) for less than or equal to 10 yr, and morphological disruption of spermatogenesis occurred among men exposed for greater than 10 yr. Wives of workers exposed to chloroprene have a Threefold excess of miscarriage. (33 Refs) 150 AU - Guengericn FP ; Strickland TW AD - Dept. Biochemistry, Vanderbilt U'liv, Sch. Medicine, Nashville, TN 37232 TI - METABOLISM OF VINYL CHLOtRIDE: DESTRUCTION CF THE HEME OF HIGHLY PURIFIED LIVER MICROSOMAL CYTOCHROME P-450 BY A METABOLITE. SI - CARC/78/02333 SO - Mol Pharmacol; 13(61:993-1004 1977 LA - ENG AB - The NADPH-dependent , vinyl chloride (VC )-mediated destruction of cytochrome P-450 (Cy P-450) was demonstrated in rat liver microsomes and in highly purified reconstituted enzyme systems containing NADPH cytochrome P-450 reductase and cytochrome Cy P-450. This loss of Cy P-450 could be attributed to heme destruction, but not to lipid peroxidation or binding of electrophiles to free sulfhydryl groups. The system required all the components necessary for mixed-function oxidation, including molecular oxygen, and it was Inhibited by carbon monoxide, suggesting strongly that oxidative metabolism of VC by Cy P-450 is necessary for destruction. The NAOrM Cy P-450 reductase-catalyzed destruction of free and Cy P-450-bound heme was also observed in reconstituted systems in the absence of VC. Inhibition experiments with carbon monoxide and catalase suggested that the VC-mediated destruction of Cy P-450 heme differes from these processes. Two proposed VC metabolites, VC epoxide and 2-chlorcacetaldehvde, do not appear to be responsible for the heme destruction. Evidence for the involvement of free radicals could not be demonstrated when the reaction was examined by electron paramagnetic resonance spectroscony or when attempts were made to inhiblT Cy P-450 destruction with r-adi cal - trapp I ng agents. (56 Refs) 151 AU - Michelich VJ ; Buoen LC ; Brand KG AO - Dept. Microbiology, Medical Sch., l)niv. Minnesota, Minneapo1is, MN 55455 TI - IMMUNOSUPFPESSION STUDIES IN FOREIGN BODY TL'MCRIGENESIS: NO EVIDENCE FCR TUMOR-SPECIFIC ANTIGENICITY. SI - CARC/73/02154 SO - JNCI; 53(3):757-761 1977 LA - ENG AB - The effect of immunosuppression on The frequency and latency of 00005810 VINYL CHLORIDE PAGE 82 foreign bod'/ (FB)-induced sarcomas and The antigenicity of these tumors was investigated. Sarcomas Here induced in CBA/H strain mice by so implantation of polyvinyl chloride vinyl acetate copolymer films. The mice had been immunosuppressed by agaThioprine 14 mg/kg/das' beginning 1 wk before implantation and continuing throughout the experiment ), antilymphocyte globulin (0,25 ml of a 1:4 dilution ip on days 0, 1, 4, and 6 before tumor challenge and weekly thereafter), or thymectomy 48 hr after birth. Compared to nonlmmunosuppressed controls, all three treatments did not affect the appearance of F8-induced sarcomas. No tumor-specific transplantatiOn antigens could be demonstrated in the sarcomas of immunosuppressed mice. Oil the basis of these results, the concept of immune surveillance as a natural host defense mechanism against careinogenesis does not apply to this model of tumor development. (36 Refs) 152 AU - Laib PJ : Bolt HM AO - Inst. Toxicology, Tubingen, M, Germany TI - FORMATION OF IMIDAZOL DERIVATIVES CF NUCLEIC ACID BASES (DNA AND RtIA) BY METABOLITES OF VINYL CHLORIDE IN VIVO AND IN VITRO (MEETING ABSTRACT). SI - ICDB/70/04000 SO - Fourth Meeting of the European Association for Cancer Research Held at Universlte de Lyon, September 13-15, 1977. European Association for Cancer Research, Even, France 1977, LA - ENG AB - Rat liver microsomes were incubated with NADFH, Cl,2-C14] vinyl chloride and polvadenylic acid or polycytidyllc acid. The latter uere re-isolated from the incubations and hydrolyzed. The radioactivity originating from (C14) vinyl chloride, which was irreversibly bound to The polyadenylic or polycytidvlic acid, was confined to 1,N*6-ethenoadenosIne or 3,N#*4-ethenocytidIne. When rats were exposed to [1,2-014] vinyl chloride, part of the radioactivity was incorporated into liver PNA, Analysis of hydrolysates of liver RMA shewed that all natural nucleosides of RNA were labeled. Small amounts of radioactivity could be detected which were confined to 1 ,M*'"6-ethenoadonos me and 3iNx*4-ethenocyTidine. DMA of rat liver after exposure of the animals to Cl,2-C14) vinyl chloride also contained significant amounts of radioactivity. When DMA was incubated with rat liver microsomes, NADFH and (C14) vinyl chloride, radioactivity was also incorporated into the DMA. Re-isolation of the DNA, hyd-oi"sis and seoaratlcn of the nucleosides showed that radioactive 1,N**6-etheno 2'dcosyadencsine was formed. The e'-periments support the theory that vinyl chloride metabolites react with adenine or cytosine moieties of nucleic acids to form' otheno analogs. These alkylation mechanisms are consistent with The mutagenic properties of vinyl chloride, (no Refs) 00005811 VINYL CHLORIDE PAGE 83 153 AU - Fox AJ ; Colliar PF AO - Office Population Censuses and Surveys. St. Catherines House, 10 Kingswav, London HC2B 6Jp, England TI - MORTALITY EXPERIENCE OF WORKERS EXPOSED TO VINYL CHLORIDE MONOMER IN THE MANUFACTURE OF POLYVINYL CHLORIOE IN GREAT BRITAIN. SI - CARC/73/01959 50 - Br J Ind Med I 34(1),'1-10 1977 LA - ENG AB - The mortality incidence in 7.717 workers in the vinyl chloride industry in Great Britain was investigated. Approx 99/ of these workers Were traced! 12/ had been exposed to constant high levels, but only 39 men had been exposed to constant high levels for greater than 20 yr because of the newness of the industry. The standard mortality ratio was below that expected. Four cases of liver cancer were found, one primary cancer (vs 0,71 expected), and three other liver cancers (vs 0.93 expected). Two were angiosarcomas, and the other two were carcinomas. The two workers with angiosarcoma died 8 and 21 yr after initiation of exposure to high concentrations. Other cancers vs their expected Incidences were as follows-' stomach 14 vs 15,33! lung, 46 vs 51.23! brain, 2 vs 3.66! and lymphatic and hematopoietic tissues. 9 vs 9.01. The observed death rate from all cancers was 115 compared to an exoected 126.77! there is no evidence that cancer at sites other than the liver was associated with exposure to vinyl chloride. Conclusions drawn from this survey must be tempered by the reservation that the full impact of the prcblem may not yet be in evidence. (18 Refs) is*-* AU - Osterman-Golkar S ! Hultmark D ! Sogerback D ! Calleman CJ AU - Go the R ! Ehrenberg L ! Wachmester CA AD - Wallenberg Lab., Unlv. Stockholm, Lilia Frescati, S-1Q4 05 Stockholm 50, Sweden TI - ALKYLATION OF DNA AND PROTEINS IN MICE EXPOSED TO VINYL CHLORIDE, 51 - CARC/78/01072 SO - Biochem Olophys Res Commun! 76(2)1259-266 1977 LA - ENG AB - Male CBA, BALD, and ATL mice (2-3 mo old) were exposed to various doses (93-160 ppm/hr) of ** 14C-labeled vinyl chloride in glass inhalation chambers for 2-10 hr, and alkylation products recovered from their testes protein, and liver DMA were quantitatively measured. Chromaioqraphic results Indicated that vinyl chloride is metabollcally activated to form an alkylating agent that introduces the 2-oxoethv], group onto nucleophilic sites! alkylation by chloroethaool was noglible. The alkylation of c"steine and histidine in Mb and of guanine-N-7 in liver DNa varied with the strain of mice used. Considering the sensitivity of the alkylating agents to changes in nucleophilic strength, chloroethylene oxide appeared to be the main reactive metabolte. Male gonads were exposed to the alkylating intermediate, and a risk of heritable damage as well as cancer can be expected. (18 Fefs ) CY. a.' ` -"I- r c r c c ( s ( ( (. ( -j 33 CO co co (O o 4* 00005812 VINYL CHLORIDE ( PAGE 84 155 AU AO ri si so LA AB 156 AU AO TI 51 SO LA AB Styles JA Imperial Chemical Industries Limited, Central Toxicology Lab., Alderley Park, Macelesfield, Cheshire, England A METHOD FOR DETECTING CARCINOGENIC ORGANIC CHEMICALS USING MAMMALIAN CELLS IN CULTURE, CARC/78/01772 Br J Cancer; 36(5):553-563 1977 ENG A method for testing organic chemicals for their carcinogenic potential is described. Baby hamster kidney cells (BHK-21/C1 13) were exposed to different doses of a test compound (nitrcsofolic acid, diphenyInitrosamine ) in liquid tissue culture medium containing rat liver post-miTochondrial supernatant and cofactors (5-9 mix) to aid metabolism, but without serum. Survival of cells following exoosure to the compound was assessed by cloning in liquid growth medium, Transformation was assessed by colony growth in semi-sol id agar. The dose-response curve for survival was used to determine the LC50 (BOX lethal concentration) of the compound. A dose-response curve for transformation was constructed, and a five-fold increase in transformation frequency at the LC50 was regarded as a positive result. For application of the method to gases, cells qrcwn in monolayers and overlaid uith serum-free medium and S-9 mix were exposed to vinyl chloride gas mixed with air. After exposure, the treated cells were trypsinized, resuspended in growth medium, and survival and transformation assays performed. Increases in transformation frequency were seen uith nitrosofollc acid and vinyl chloride gas. In a study using 120 compounds, the methods described were greater than 90/ accurate in distinguishing between carcinogens and noncarclnogens. (19 Refs) Kline J I Stein 2 ! Strobino B ; Susser M ; Warburton 0 Columbia Univ. Coll. Physicians and Surgeons, New York, NY 10032 SURVEILLANCE OF SPONTANEOUS ABORTIONS. POWER IN ENVIRONMENTAL MONITORING. CARC/70/01770 Am J Epidemiol; 106(5 ) i365-350 1977 ENG The advantages of using spontaneous abortions rather than birth defects to monitor envirenmentally Induced carcinomas are discussed. Theoretically, a change in The incidence of spontaneous abortions or of anomalies in spontaneous abortions should be detectable 6 mo or mere before a change in The incidence of birth defects. Moreover, teratogens That cause many anomalies cannot be detected by studies of birth defects slr.se The majority of anomalous conceptions lead to spontaneous abortions. Abortion specimens can also be preserved for future studies. The spontaneous abortion approach is illustrated by the potential teratogenic effects of paternal exposure To vinyl chloride (VC). VC may affect male germ cells by causing chromosome breaks, dominant or recessive lethal mutations, and/or chromosome abnormalities. Morphologic and karyotype analyses of a c c ( ( V, L c c L L L L 00005813 VINYL CHLORIDE PAGE 65 sample series of spontaneous abortions are discussed. (14 Ref3 ) AU - Smith PM ; Williams DM ; Oalderup LM AD - Welsh Natl. Sch. Nadicine> Psnarthi Glamorgan. Wales TI - ANGIOSARCOMA OF THE LIVER IN GREAT BRITAIN'(LETTER TO EDITOR). SI - CARC/78/01605 50 - Br Ned J! 2(60 95 )" 1149-1150 1977 LA - ENG AB - Only two cases of angiosarcoma of the liver following vinyl chloride eyposure have been noted in Great Britain. In comparison i noncirrnotic portal fibrosis is commoner and therefore of greater importance. In the Netherlands. 27 case3 diagnosed as angiosarcoma were reviewed, and only 9 were found To be definite. None of The nine patients had any contact with vinyl chloride, but one had been on long-term arsenic medication. (6 Refs ) AU - Popper H AD - Mount Sinai Sch. Medicine, Stratton Lab. Study Liver Disease, Fifth Ave. and 100th St., New York, NY 10029 TI - LIVER TUMORS DUE TO ENVIRONMENTAL FACTORS. 51 - CARC/76/01560 50 - Internist (Berlin); 18(4):102-137 1977 LA - GER AB - The histoloqy and morphology of liver fibrosis and angiosarcoma due to long-term occupational exposure to vinyl chloride, inorganic arsenic, and thorium dioxide are reviewed along with The effect of anabolic steroids and oral contraceptives on hepatocellular adenomas and carcinomas. Reference is made to experiments with mice and rats. (56 Refs) AU - Tomatis L A0 - Unit Diemical Care 1 nogenes Is, International Aqencv Res. Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 2, Fr TI - VALI0ITY AND LIMITATIONS OF LONG-TERM EXPERIMENTATION IN CANCER RESEARCH. 51 - CAPC/78/01563 SO - IARC Sci Publ; (16)1299-307 1977 LA - ENG AB - The contribution of long-term experlmentation to the detection of carcinogenic agents is considered. There Is evidence in experimental carcinogenesis that, following chronic exposure, tumor incidence and induction time are dose-related. An acceptable exposure le"el would be a dose that one could assume would net produce cancer within the life soan of The exposed individuals. One example of the contributlon of animal experimentation to the prevention of hu'.'.n cancer is the case of acetylaminoflucrene , which was ready to be marketed on a wide scale as an insecticide when it was wiThdrawn because one experiment had shown it to be carcinogenic. A large number of food additives, pesticides, and herbicides have been reviewed with regard to their toxicity durino the past 15 yr, and to- a number of them the experimental evidence of caretnogenlcity was 00005814 VINYL CHLORIDE PAGE 86 160 AU AO TI SI SO LA AB 161 AU AD TI 51 SO LA A3 sufficient to recommend a zero tolerance in food. This extrapoiaTion from expertmental data to man has no! been widely applied occupationallyi as evidenced by the aromatic amines and Urinary bladder cancer, b i s ( cnlorome tns'l lether and lung cancer, vinyl chloride and liver cancer, and vlnylidine chloride, 2-chlorcbutadiene, and neoprene. (31 Refs) Biran D Rutgers Univ., The State University of New Jersey, New Brunswick, NJ SORPTION OF VINYL CHLORIDE BY SELECTED FOOD CONSTITUENTS. ICDB/78/03229 0 i 3S Abstr Int CBJ ; 39(5):2105-B 1977 EN3 The association of vinyl chloride (VC) with carcinogenic effects has caused a proposal by the FDA to restrict the use of rigid Unolasticized polyvinyl chloride for food packaging. A major area of concern involves the possible interaction between the VC and food. This study deals with parameters affectinq the sorption of VC in the gaseous state by selected food constituents and particularly the mechanism of VC sorption by dry casein particles. Partition coefficients for VC distribution between head space and oil, water, ot1/water emulsions and casein were determined. It was found that at concerntration levels studied the partition coefficients are fairly constant for all cases. Chemical nature of the substrate, starting head space concentrations and temperature were found to be Important factors affecting the extent of VC sorption. Oioole moment of the sorbate gas as well as the chemical nature and moisture content of the protein were found to be important parameters determining the sorption of VC bv casein. Particle size affects the sorption to a lesser degree. Transient state sorption measurements as well as the inverse gas chromatographic technique showed an active site binding as the major component in the binding interaction between casein particles and VC. An empirical kinetic model for the sorption VC by dry casein particles is proposed- The model suggests a possible clustering effect at the low temperature and most likely a monolayer sorption at the higher temperatures tested. An active site adsorption model is suggested. A correlation between the two models is shown, (no Refs) Laib RJ ! Bolt MM Inst. Toxicology, Un*'. Tubingen, D-7400 Tubingen-l, W. Germany ALKYLATION OF RNA BY VINYL CHLORIDE NETACOLITC5 IN VITRO AMO IN VIVO: FORMATION OF 1-N"*6-ETMtNO-A0EN05INE. ICD3/73/02914 Toxicology; 8(21:185-195 1977 ENG The lnccrporation of 14C radioactivity from vrnvl chloride into RNA of liver is described, and the possibility of formation of etneno-adenos1ne moieties in liver RNA on exposure of rats to 14C vinyl chloride is examined. Pat liver mlcrosomes were incubated with NADPM, I,2-14C vinyl chloride and poly-adenos1ne. 00005315 VINYL CHLORIDE PAGE 87 162 AU AO TI 51 50 LA AB 163 AU AU AO TI SI SO LA AB Poly-adenos i ne was reisolated from The incubations and hydrolyzed. 1AC vinyl chloride radioactivity uas confined to l-N*#6-etheno-adenosine. When rats wars exposed to 1>2-1AC vinyl chlorida. part of The radi oac t i v i ty was incorporated into RNA of liver and exhibited a first maximum, 1A hr, and a second maximum, 72 hr after ending the exposure. Analysis of hydrolysate of liver RNA showed that all natural nucleosides of RNA were labeled, and that small amounts of radioactivity were confined to l-N#*6-etheno-adenosine. Thus, the experiments Support the theory That vinyl chloride metabolites react with adenosine moieties of nucleic acid under formation of i-N'T*6~etheno-adenosine. The results show that measurement of incor-porat ion of radioactivity into nucleic acids after exposure of animals to radioactive vinyl chloride is not applicable as a means of determining the alkylating potency of vinyl chloride metabolites towards nucleic acids in vivo. (29 Refs) Kurliandskii BA ; Nevzorova HI Municipal Sanitary-Epidemiological Center, Moscow, USSR METHOD 0= CALCULATION OF THE EFFECTIVE DOSE AND CONCENTRATION OF CHEMICAL BLASTOMOGENIC AGENTS. CARC/78/01A09 Vopr Onkol! 23(9)159-62 1977 RUS Probit analysis according to Litchfield and HiIcoxon i3 `recommended for the calculation of the effective blastomogenic doses and concentrations (BD16, BD50, BD3A ) of various chemical carcinogens. Examples and values are presented for N,N1-dinitrosodime thyle thylene diamlne, benzot a )pyrene, 1,2,5,6-dibencoanthracene , 2-amino-5-azoToluene and vinyl chloride . (17 Refs ) Brady J ", Liberatore F Harper P i Greenwald P ', Burnett U Davies JN ', Bishop M i Pol an A ; Vi anna N Bureau Occupational Health and Chronic Disease Res., New York State D:pt. Health, Empire State Plaza, Tower Building, Albany, NY 12237 ANGIOSARCOMA OF THE LIVER: AN EPIDEMIOLOGIC SURVET. CARC/73/01001 JIICI; 59(5)11303-1305 1977 EMG An epidemiology survey of angiosarcoma of The liver (ASL) revealed that the annual incidence rate (cases diagnosed 1970 through 1975) amonq residents of New York State (excluding New York City) was 0.25 per million. A case-control study of 26 patients indicated that direct exposure to arsenic, vinyl chloride (VC), and thorium dioxide was a significantly important factor In the etiology of ASL (p less than 0.02). Seven patients had documented exposure to these chemicals, but 19 did not. The fact That 5/19 lh'ed nearer To VC fabricafion or polymerization plants than did Their matched controls indicated that indirect modes of exposure, not specifically related to occupation, might be an important factor In the etiology of ASL. The possibility 3J 2< </> CO GO (O O CO 00005816 VINYL CHLORIDE V PAGE 88 c that other toxic substances (chlorinated hydrocarbons ) may cause ASL was also mentioned. (17 Refs) c c164 AU AD Lu PY Metcalf RL ! Plummer ft Mandel D Oept. Entomology and Inst. Enwi ronmental Studies* Urbana, IL 61801 TI THE ENVIRONMENTAL FATE OF THREE CARCINOGENS: BENZOf ALFHA 1PYRENE, BENZIDINE, AND VINYL CHLORIDE EVALUATED IN LABORATORY MODEL c(' ECOSYSTEMS. SI CARC/78/00966 SO Arch Environ Contam Toxicol! 6(2-3):129-142 1977 LA ENG AB The degradation, environmental fate, bioaccumulation, and food chain transfer of radiolabeled benzotalphaIpyrene (BP), benzidine c (ED), and vinyl chloride (VC) were evaluated in two laboratory model ecosvsferns, In a closed aquatic system, 0.002 ppm BP and c<...- O.OOB ppm DO were applied directly to the water and allowed to pass through an aquatic food chain. Their transfer and degradation were observed over a 3-day period. In a c. (terrestrial-aquatic ecosystem, 0.2 mg of BP and 60, either alone or with 1.0 mg pipronyl butoxide, were topically applied in acetone solution to Sorghum vulgare seedlings, representing chemical fallout. They were then allowed to pass through a food chain. The resulting food chain by-products were then allowed to interact in the ecosystem over a 33-day period. It was shown that ( BP is highly lipophilic and it can bioaccumulate to potentially hazardous levels. This problem was intensified in snails and other organisms deficient in microsomal oxidase, or when there was a presence of mixed function oxidase inhibitors. BD was not bioaccumulafed or Transferred through food chains To high levels. c BD levels were not affected appreciably by the presence of mixed function oxidase inhibitors. Vinyl chloride did not bioaccumulate c( or transfer appreciably through the food chains, at least at the ordinary temperatures studied due to its high volatility. There was an excellent correlation between bioaccumuiatlon and octanol/water partition, illustrating That this property and c.( water solubility can be of predictive "alue in environmental toxicological studies. (19 Refs) 165 AU Baxter PJ ! Anthony PP ! MacSween RN ! Scheuer pj \ AD Health and Safety Executive, Employment Medical Advisory Service, London W2 4TF, England TI ANGIOSARCOMA OF THE LIVER IN GREAT BRITAIN, 1963-73. SI CARC/78/00902 SO Br tied J! 2(60921:919-921 1977 LA ENG AB Deaths attributed to primary angiosarcoma of the liver (ASL) in Great Britain between 1963 and 1973 were reviewed by submitting available histological material to a panel of hisTopathologists and by obtaining full occupational and residential histories for the cases considered as ASL by the panel. An av of four cases of ASL occurred annually, but in only one-third of the cases did the panel agree with the original diagnosis. OnLy one of the cases was definitely linked with exposure to vinyl chloride, (17 Refs) y,jf*mV-- * n c 00005817 VINTL CHLORIDE 33 e 03 co 03 <o o CO PAGE 89 166 AU - Reynolds ES c AO - Dept. Pathology Peter Bent Brigham Hasp., Boston, HA 02115 c TI - LIVER ENDOPLASMIC RETICULL'M: TARGET SITE OF HALOCARBON METABOLITES. SI - CARC/78/00S73 c SO - Adv Exp Med Biol! 89:117-137 1977 c cLA - ENG AB - The hepatotoxic effects of carbon tetrachlorlde, vinyl chloride, trichloroethylene, and Iqalothane are reviewed. Initial injury produced by exposure to these chemicals involves the endoolasmic reticulum. There is dispersion of the ergastoplasm, then vacuolization and degranulation of the rough endoplasmic reticulum with concomitant retraction of the smooth endoplasmic c reticulum into tightly clumped tubular aggregates. Membranes in these tubular aggregates seem to undergo supramolecular c(. disassembly. This structural disorganisation is accompanied by a diminished functional caoacity in the organelle. Activation of these halocarbons to toxic species by the endoplasmic reticulum ( is indicated (1) by the enhancement of their tcxicify upon pretreatment with chemicals, such as phenobarbital, or Arcelor f 1254 that induce components of the mixed function oxidase system and (2) by the formation of certain metabolites and/or covalently bound products. IT is not clear whether The halocarbons cause r liver injury by the covalent binding of free-radical metabolites to tissue macromolecules or by initiating lipid perodixidation. (51 Refs ) 167 AU AD TI SI SO LA AB Boyland E TUC Centenary Inst. Occupational Health, London Sch. Hygiene and Tropical Medicine, Keppel St., London UC1E 7HT, England BIOCHEMISTRY OF OCCUPATIONAL CANCER. CARC/78/00S72 J Soc Occup Med; 27(3 ):97-101 1977 ENG Environmental , particularly occupational, causes of cancer are reviewed briefly in terms of chemical reactions and intermediates. Chemical carcinogens can be divided into Two groups on biochemical grounds. The first group, which includes alkvlatinq agents such as mustard gas, nitrogen mustard, Mvleran, and the ethyleneimlnes plus related compounds, acts directly without metabolic transformation. The second group, including aromatic amines, nltrosamines , poiveyclic hydrocarbons , aflatoxin, satrole, and carbon tetrachloride, requires metabolic activation, usually through the formation of epoxides or ar;ne oxides, to carcinogenic torn,3. Pecent studies have indicated that vinyl chloride, chlorobutadiene , and trichlorccthylene are carcinogenic and are metabolized through epoxide intermediates. Gome ethylene derivatives or unsaturated compounds, therefore, can be carcinogenic because thev are metabolized to epoxides. Saturated compounds such as Trichloroetnane and *etrachio-ceTbane may be less hazardous than the unsaturated trichloroethy1e-e and tetrachloroethylene as solvents, (no Refs) t c c L L ' V ___ , . -- ' ' -,i " '*.*'! 5' '':~"*yrf-**i JO c/i GO oo CO C c c c 00005818 VINYL CHLORIDE PAGE 90 168 AU - Aryanpur J AD - Public Health and Occupational Medical Services, Natl. Iranian Oil Company, P. 0. Box 1853. Tehran, Iran TI - VINYL CHLORIDE: ITS INPACT ON OCCUPATIONAL HEOICINE PRACTICE IN IRAN. SI - CARC/78/00775 50 - J Occup Ned; 19(101:689-692 1977 LA - ENG AB - Measures taken to protect The workers at the Abadan Petrochemical Companv in Iran from the carcinogenic effects of vinyl chloride monomer CVCM1 and polyvinyl chloride (PVC1 are outlined. Since 1971, all workers have been required to undergo periodic medical examinations with an emphasis on liver function. Factors related to liver disease, such as endemic viral hepatitis, low alcohol and cigarette consumption, and dietary habits, are considered. To date, among 93 workers in The VCM and PVC production units, none have evidence of liver dysfunction or angiosarcoma. The threshold limit value for VCM has been set at 25 ppm Time weighted av for 8 hr with revisions expected in the future. No leakage to the community has been detected except for some chlorine release. (11 Refs ) 169 AU - Brown ER ; Sinclair T ; Keith L J Beamer P ; Hazdra JJ ; Nair V AU - Callaghan O AD - Dept. Microbiology, The Chicago Medical Sch., 2020 West Ogden Ave., Chicago, IL 60612 TI - CHEMICAL POLLUTANTS IN RELATION TO DISEASES IN FISH. 51 - ICD3/7S/OOS87 SO - Ann NY Acad Sci; 298:535-556 1977 LA - ENG AB - The relationship between water pollution and health hazards in fish in two water systems (pollutlon-free Canadian 'Lake of the Woods' and the polluted Fox River) was investigated. Fish were caught from both rivers and examined for tumors and nononcogenic diseases. The nononcogenic diseases encountered included columnaris disease, hemorrhagic septicemia, Dee disease, black spot disease, saproiegnia, channel catfish virus disease, and lymphocystis . Lymphoreticulan neoplasms were the most frequent neoplastic diseases observed. As these tumors mature, a large number of the malignant cells are intimately associated with fibers of the reticulum and appear to adhere to the walls of the capillaries in the mass being formed. Hepatomas appeared as larqa nodules of abnormal cells which developed within the 11ver, or ultimately the entire liver became a mass of these cells. Fathead minnows were grown in effluent taken from secondary treatment plants and effluent Treated with disinfectants. The presence of polio virus in monkey kidnev cultures plated with intestinal tract homogenates of these fish was used as an indicator of sewage contamination and the effectlvene33 of The disinfectants. Polio 'Mruses were found in the Intestinal tracts of fish raised in untreated effluent and effluent treated with bromochlcrtde and ozone. The viruses were not present in fish raised in effluent c c c c c e c L 00005319 VINYL CHLORIDE PAGE 91 Treated with chlorine. These results indicate that health hazards are associated with fish grown in sewage effluents. The Toxicity of vinyl chloride was investigated in northern pike. The development of skin lesions in these fish is discussed. (7 Refs I 170 AU - Carter SA AO - Environmental Science and Public Health, Cornell Univ., Ithaca, NY TI - THE POTENTIAL HEALTH HAZARD OF SUBSTANCES LEACHED FROM PLASTIC PACKAGING. SI - ICD0/7S/OO88O SO - J Environ Health! 60(2)173-76 1977 LA - ENG AO - The health issues surrounding the leaching of four different groups of chemical compounds from plastic products are presented. These groups include-' lead and ink from the printed material on plastic wrapping, stabilisers from soft plastic wraps, vinyl chloride from polyvinyl chloride (PVC) products, and plasticisers from various PVC products. Analysis of PVC peanut oil containers revealed vinyl chloride levels of 0.3-3.3 ppm. Traces of vinyl chloride have been detected in vinegars and alcoholic beverages packaged in PVC bottles. Plasticigers such as di-2-ethylhexyl phthalate and dimethosyethyl phthalate were found in human and rat blood which had been circulated in PVC tubing, and in Tissue samples taken from human patients who had received transfusions of blood stored in PVC bags. These findings and others are discussed in light of pertinent animal and human studies. (28 Refs ) 171 AU - Henschler 0 AD - Toxikoloqisches Institut der Univorsitat, Koellikerstr. 2, 8700 Wurgburg, W. Germany TI - ACTIVATION MECHANISMS IN CHLORINATED ALIPHATIC COMPOUNDS. EXPERIMENTAL POSSIBILITIES AND CLINICAL SIGNIFICANCE. SI - CARC/78/00236 SO - Argneim Forsch! Z7( 9b )'1827-1032 1977 LA - GER AB - Asymmetric chlorinated ethylene (Tri-1,1-dichloroethylene and vinyl chloride) are mutagenic in a modified Ames test system whereas symmetrically substituted molecules are inactive. These differences are attributed to the elecTron withdrawl effect of chlorine in the asymmetric molecules. The in vivo and in vitro rearrangement mechanisms in the biotransformatlon of These compounds are outlined. (20 Refs) 172 AU - Heath CW ! Dumont CR I Gamble J ; Wayweilcr RJ AD - Cancer and Birth Defects Div., Bureau EpibemIoloqv> Center Olsease Control, Public Health Service, U.5. Deot. Health, Education and Welfare, 1600 Clifton Road, N, E., Atlanta, GA 30333 TI - CHROMOSOMAL DAMAGE IN MEN OCCUPATIONALLY EXPOSED TO VINYL CHLORIDE MONOMER AM'O OTHER CHEMICALS. SI - CARC/78/00170 SO - Environ Res! 16(1) 160-72 1977 LA - ENG 00005320 VINYL CHLORIDE PAGE 92 AB - Cytogenetic analyses were conducted on men employed at a rubber* and plastics plant who were exposed to vinyl chloride monomer (VCM). Frequencies of chromosomal damage were measured in the peripheral blood lymphocytes of 35 men employed for greater than Or equal to 10 yr 14 in polyvinyl chloride (PVCI polymerisation (hi gh-e.vposure group)) 4 in PVC processing (low exposure group)> and 17 in rubber tire manufacture (negligible exposure group). In addition) four nonindustrial employees who had not been exposed to laboratory chemicals were included (controls). Breakage levels were significantly higher in all three test groups than in the controls. Chromatid gaps comprised the majority (367.) of aberrations seen. However) overall breakage levels were similar in the three industry grouos, which indicates that VCM was not the sole cause of the damage. (9 Refs) 173 AU - Brinton-Darnell M > Brand I AD * Wistar Inst., 36th and Spruce Sts., Philadelphia, PA 19104 TI - DELAYED FOREIGN-BODY TUMCRIGENESIS IN MICE INFECTED WITH LACTATE DEHYDROGENASE-ELEVATING VIRUS: BRIEF CCMMUNICATICN. SI - CARC/77/03526 SO - JNCi; 59( 3 ) 1027-1029 1977 LA - ENG AB - Delayed foreign-body (FO) tumorigenesls was studied in mice infected with lactate dehydrogenase-elevatinq virus (LDV). Eight-week-old CBA/H mice of both sexes were infected ip with LDV (10**3 1050's). Two weeks later, these mice and noninfected controls received double sc implants of unplasticiged vinyl chloride-vinyl acetate copolymer films (0.2 x 15 x 22 mm), FB tumorigenesis was delayed by 2 mo in infected animals of both sexes. Since cellular immunity is not known to influence the Course of FB tumor 1qenesis, these results could not be explained by an LDV effect on cellular immunity. (35 Refs) 174 AU - Green T ; Hathway DE AD - Imperial Chemical Industries Ltd., Central Toxicology Lab., Alcerley Park, Cheshire 5K10 4TJ, England TI - THE CHEMISTRY AND BIOGENESIS OF THE S-CONTAINING METABOLITES OF VIMYL CHLORIDE IN RATS. SI CAPC/77/0C421 SO Chem Biol Interact", 17(2)1137-150 1977 LA ENG AB The biogenesis of the various urinary 5-containinq metabolites of vinyl chloride (VC) was investigated in adult male rats. Groups of rats were administered the following chemicals Intragastricallv: (1) **14C-VC (100 mq/kg! 10 muCi), (2) chloroacetaIdehyde (50 mg/kq ), (3) S-(2-hydroxyethy1 )-L-cysteIne (500 mg/kq), or (4) 5-(car bo -:yne t hy 1 ) - L-cy s t e I ne (CMC: 250 mg/kq), and a 24-nr urine sa,..ole was Taken. Two rats were given repeated daily ip injections of L-(U-**14C) cysteine hydrochloride for 5 da"s and, 30 min after the final injection, a single dose of VC (100 mg/kg/); a 24-hr urine sample was then Taken. Two rats were given a single intragastric dose of **14C-VC (450 mg/kg) and sacrificed after 45 min; they were dissected and 00005821 VINYL CHLORIDE PAGE 93 their livers removal. N-Acetyl-5-t2-hydroxyethylJeysteine (AHC) was o major VC metabolite, but. according to the method of protective esterification used, either N-acetyl-S-(2-cnloroethyl leysTeine or AHC can be isolated from the body fluids. N-AceTy1-S-vinylcysteine was a second related metabolite. These 5-containing VC metabolites were not mutagenic in S. typhimurium. Administration of the VC metabolites and related compounds to rats indicated that chloroacetaldehyde and CMC. but not chloroacetic acid, are on a pathway connecting VC with thiodiglycollic acid. The fact that chloroacetaldehyde produced both thiodiglycol1ic acid and AHC in the animal and that CMC was identified among the hydrolytic products from a hepatic extract of VC-treated animals is consistent (1) with the formation of chioroacetaldehyde and (2) with the reaction of chioroethylena oxide or chloroacetaldehyde with glutathione in the presence of a glutathione S-epoxide transferase to give the identified S-containing metabolites. (22 Refs) 175 AU - Rowley JD AO - Dept, Medicine. Univ. Chicago. Chicago. IL 60637 TI - ARE NONRANDOM KARYOTYPIC CHANGES RELATED TO ETIOLCGIC AGENTS? SI - CARC/77/03350 SO - Prog Cancer Res Ther; 3:125-136 1977 LA - ENG' AG - It is hypothesised that specific chromosomal abnormalities in human tumors may be related to particular etiologic agents. Chromosome banding techniques hqvo shown nonrandom chromosomal abnormalities in chronic myelogenous leukemia and in acute leukemia. It appears that only certain chromosomes are abnormal in a particular tumor and that these same chromosomes may be aneuplold in a variety of tumors. Nonrandom chromosomal abnormalities occur in some animals exposed to chemical and viral mutagenic agents. When leukemia, sarcomas, and epithelial Tumors were induced by 7,12-dI methylbencta Janthracone (0M3A ) and 6,8,12-and 7,8.12-Tr1 methyibeno(a )anthraceno in rats, trisomy for the largest telocentric chromosome was observed. A different but very consistent karyotypic pattern was seen in sarcomas induced in the rat by Rous sarcoma virus. These observations suggest that the specific chromosomal abnormalities are associated with particular etiologic agents. In the rat, the order of carcinogenic potency is DM3A, mothylcholanthrene, and bengo(aJpyrene , in decreasing order; the frequency of nonrandom changes shows the same erder. It has been suggested that, if a given mutaqen is more potent as a carcinogen, it may attack certain genes more selectively in The induction of malignancy. Several human tumors are associated with known environmental carcinogens, but none of These otherwise rare tumors have been studied cytogenetically. Tumors suggested for such investigation are Thyroid carcinoma, In those who received therapeutic x-rays in The neck region, lung and gastric cancer In asbestos workers, oat cell cancers of the lung in workers exposed To halo ethers, hepatic angiosarcoma in 'Mnyl chloride workers , clear cell adenocarcinoma in women exposed to aiethyIs11Ibestro 1 In utero. 00005822 VINYL CHLORIDE PAGE 94 c and urinary bladder carcinoma in workers exposed To polycyclic aromatic compounds. (45 Refs) c 176 AU - Zielhuis RL AD - Ho affiliation given TI - VASCULAR CHANGES IN VINYL CHLORIDE UORKERS. 51 - CARC/77/00173 SO - Ned Tijdscnr Geneeskd) 121(29):1183-1184 1977 LA - DUT A3 - A possible method for the early detection of vinyl chloride CVC) -- induced abnormalities is discussed. There were changes in the capillaries of the fingers of 55/152 workers who had been exposed to VC for 5-28 yr. but similar charges occurred in only 3/50 controls , The vascular changes consisted of dilated or tortuous vessels and many avascular sites. (8 Refs) (. 177 AU - Kurokawa S ) Inagaki T ) Okuyama S AD ~ Nakatsugawa Municipal Hosp., Nakatsugawa-City, Gifu-Prefecture, Japan TI - ELECTRON MICROSCOPIC OBSERVATION OF THE LIVER IN PORTAL HYPERTENSION FOLLOWING CilRO-lIC EXPOSURE TO VINYL CHLORIDE MONOMER. SI - CARC/77/0 7996 SO - Gas troenterol Jpn I 12(2)164-69 1977 LA - ENG AB - Two men with portal hypertension and splenomegaly following chronic exposure to vinyl chloride monomer (VCM) were studied histologically and ultrastrueturally. The results suggest that VCM and its metabolites are not retained permanently in liver, because one patient who had been exposed for 12 yr, but not for the last 10 yr, had nearly normal appearing sinusoidal lining cells and Disse's spaces. (13 Refs) 178 AU - Border EA I Webster L AO Natl. Res, Inst. Occuoational Diseases, S. African Medical Res. Council, P 0 Dox 4783, Johannesburg, 2000 S. Africa V. TI THE EFFECT OF VIMTL CHLORIDE MONOMER, CHLOROETHYLENE OXIDE AND CHL0RACETALDEHY0E ON DMA SYNTHESIS IN REGENERATING RAT LIVER. SI CARC/77/07834 SO Cnern Biol Interact; 17(2)1239-247 1977 LA ENG AB A study was made of the effects of vinyl chloride monomer (VCM) and two of its presumed metabolites, chloracetaldehvde (CAI and chi oroethyiene oxide (CEO), on DMA synthesis m the regene"atinq c livers of 100-q Mi star rats subjected to partial hepatectoiv. VCM (0.5 ml of a 0.19/ solution) inject'd iv 30 min after partial hepatectamy reduced the first ensuing wa>'3 of DMA synthesis (at 21 hr) by about 50/) no effect on 'ice second wave of DMA synthesis (at 30 hr) was evident. Similar treatment with CEO and CA also depressed The first ua"e of DMA synthesis by about 50/. However, these substances had different effects on the second wave: CEO raised the rate of DMA synthesis by about 50/, but CA tended to desynchromoe the normally well-defined second wa'e. It is concluded that VCM, CEO, and CA na-e similar effects as 00005823 VINYL CHLORIDE PAGE 95 unrelated carcinogens in retarding DMA replication. (37 Refs) 179 AU - Li FP AD - 35 Blnney St., Boston, (1A 02215 TI - CLINICAL STUDIES OF CANCER ETIOLOGY. SI - CARC/77/07619 SO - Cancer; 90(1 .Suppl ) =995-997 1977 LA - ENG A3 - Careful clinical observation can lead to clues relating to cancer etioloqy, Among the more recent examples are the relationships between vinyl chloride and angiosarcoma of the liver, diethylstiibestroi and vaginal adenocarcinoma, and ataxia telangiectasia and the risk of lymphoretlcular neoplasia. Interactions among physicians are encouraged. (22 Refs) 180 AU - Bolt HM ", Laib RJ ', Kappus H Buchter A AO - Inst. Toxicology, Unlv. Tubingen, Tubingen, W. Germany TI - PHARMACOKINETICS OF VINYL CHLORIDE IN THE RAT. 51 - CARC/77/07531 SO - Toxicology; 7(2)1179-183 1977 LA - ENG AS - Ithen rats were exposed to **19C-vinvl chloride (VC) in a closed system, the VC in the atmosphere equilibrated with that in the animals tissues within 15 min. This course of equilibration uas determined in male Wistar rats treated ip with 6-nitro-1,2,3,-bancothiadiazole at a dose (50 mq/kg ) sufficient to block the metabolism of 200-1,200 ppm VC for 9 hr. Saturation of the VC-metabolizinq enzymes occurred at an atmospheric VC concentration of 250 ppm. Pharmacokinetic analysis showed no significant accumulation of VC or its major metabolites following repeated administration of the compound. The results support the theory that a reactive, short-lived metabolite, which occurs only in low conccntrat1cns, may be responsible for the toxic effects of VC. (25 Refs) 181 AU - Hatanabe PG ', Gehring PJ AD - Toxicology Res. Lab., Health and En"1ronmental Res., Dow Chemical Co., Midland, MI 98690 TI - DOGE-DEPENDENT FATE OF VINYL CHLORIDE AND ITS POSSIBLE RELATIONSHIP TO ONCOGENICITY If! RATS. SI - CARC/77/0 799 6 SO - Em-iron Health Perspect; 17:195-152 1977 LA - ENG AB - Studies were made of The disposition of radioactivity from different doses of po admints!ered or* inhaled "*19C-vlnyl chloride (VC) in excreta, expired air, and body Tissues of treated rats and of ronprotein sulfhydrvl !ewels in The livers of Treated rats. The disposition of VC was found To be a function of dose, particularly after admimstra11 on po. The percentages cf administered VC radioactivity in rats treated po with 0.05 mg/kg VC were 1.9/, 9.0/, 68.3/, 2.9/, and 10.1/ in'exhaled VC, exhaled carbon dioxide, urine, feces, and carcass, respectively; following 100 mg/kg VC, the corresponding values were 66.6/, 00005624 VINYL CHLORIDE PAGE 96 2.5k, 10.8k, 0.5k, 2nd 1,8k; following inhalation of 10 pom VC> the corresponding values were 1.6k, 12.1k, 68k, 4.5k, and 13.9k; following inhalation of 1,000 ppm VC, the corresponding values were 12.3k, 12.3k, 56.3k, 4.2k, and 14.5*. Exposure to 150, 250, 1,000 or 2,000 ppm VC caused a progressive depression of the hepatic nonprotein sulhydryl content; exposure to 50 ppm VC for 7 hr produced a small, inconsistent depression; no depression was observed in rats exposed to 10 ppm. These results indicate that statistical projections of data from rats exposed to high do3es of VC are not valid for predicting effects of low-level exposure, because the metabolism of VC at different dose levels is not the same. (13 R e t s ) 182 AU - Hill HZ ; Lin HS AD - Dept. Biochemistry, Marshall Univ. Sch. Medicine, Huntington, WV TI - CARCINOGENESIS AND TUMOR GROWTH. SI - CARC/77/07432 SO - Clinical Oncology. Horton J, Hill GJ, ed. Philadelphia, W. B. Saunders Co., 1977. LA - ENG A3 - This review article begins with tabulated data on the relative percentage of incidence of (1955-1964) and mortality from (1974) cancer by site and sev, in the US and on estimated new cases and deaths by site and sex for 1976. This is followed by a lengthy discussion of the causes of cancer, KNA animal viruses can be transmitted horizontally by infection and vertically by congenital infection or by genetic processes. Reverse transcriptase (RT) has been discovered in a number of cancer cells of several animals and man. The presence of RT in a tumor is often taken as clear-cut evidence of a viral etiology. RNA C-type viruses have been found in human cells after long-term culture, and, recent 1 v, C-type viral antigens were found in L'3C of five patients with acute leuke.nl a. These antigens cross-reacted with those from C-type viruses from a woolly monkey and a gibbon ape. B-type RNA viruses, or mouse mammary tumor viruses, are present In the milk of certain strains of mice. Several facts are given that suggest that RNA viruses are also involved in the induction of human breast cancer. Oncogenic DMA viruses (papillomaviruses, polyomaviruses, simian virus 40, and herpesviruses) are also discussed. Herpes"iruses are the most likely of the DNA viruses to produce cancer in humans. Recent findings are given concerning envircnmental carcinogens, such as benzol aIpvrene, asbestos, and "invl chloride, and ohysical carcinogens, such as irritation, trauma, radiation, and radionuc11des , and Their proposed mechanisms of action. Cellular Trans format ion, cancer genetics (mutation theory, inheritance factor, chromosomal aberrations, gene action), tumor progression (immune surveillance, influence of sex hormones and chalcnes, dlfferentiation , stem line evolution, biochemical factors), and tumor cell population kinetics are also surveyed. (164 Refs) 00005825 VINYL CHLORIDE PAGE 97 c 183 AU Blum B c AD Criteria and Standards Div., Office of Water Supply, c cEnvironmental Protection Agency, Washington, DC 20460 TI DRINKING WATER AND HEALTH: RECOMMENDATIONS OF THE NATIONAL ACADEMY OF SCIENCES. SI CARC/77/0 7185 c SO Fed Regist; 42(1321:35764-35779 1977 LA ENG ( AB Recommendations of The National Academy of Sciences concerning the contamination of water supplies with harmful substances are summarised. Four principles relevant to the assessment of risk from long-term exposure To carcinogenic substances at low doses are outlined: (1) effects in animals, properly qualified, are c applicable to man! (2) methods to establish a threshold for long-term effects of toxic agents are not in existence; (3) the c(. exposure of experimental animals to high doses of toxic agents is a necessary and valid method of discovering possible carcinogenic hazards in man; (4) materials should be assessed in terms of human risk, rather than as safe or unsafe. Risk estimates have c(. been made for some known water suopiy contaminants for which data were available. Estimates of lifetime cancer risks (with a 95X upper confidence limit) are 5.1 X 10-**7> 2.6 X 10-##4, 4.4 X 10-**4, 1.2 X 10--"*6, 3.1 X 10-*#6, and 3.7 X 10-*#7 (expressed as risk/uq/1iter ) for vinyl chloride, dieldrin, kepone , DDT, polychlcrinated biphenyls (with data for arochior 1260), and carbon tetrachlorido , respectively. The highest observed concentrations in drinking water of These substances are 10, 8, unknown, unknown, 3, and 366 uq/iiter, respectively. The max observed levels of a larqe number of organic pesticides and other e organic contaminants in drinking water are listed, together with recommended acceptable daily intake levels, (no Refs) 184 AU AD TI SI SO LA AB Stokinger HE Natl. Inst. Occupational Safety and Health, Robert A. Taft Labs., Center Disease Control, U.S. Public Health Service, Cincinnati, OH TOXICOLOGY AND DRINKING WATER CONTAMINANTS. CARC/77/07154 J Am Water Work Assoc; 69(71:399-402 1977 ENG The concept of a threshold le''el of exposure to carcinogens and the extrapolation of careinoqenesls data from animal studies to man are discussed. IT is contended that The threshold le^el (below which no biological response is observed) is a valid concept in careinogenesis and that genetic inborn errors of metabolism may cause a shift in carcinogen thresholds. This genetic basis may underlie the susceptibility of certain exoosed workers to the induction of liver hemangiomas bv vinyl chloride (ie, 50 cases of hemangioma were reported among 25,000 heavily excosed workers). It is also stated that fallacies are involved in the extrapolation of data from hiqh-dose animal experiments to normal low-dose human situations. This point is illustrated by a discussion of chloroform carcinogenesis. Chloroform levels c. c L L 00005826 VINYL CHLORIDE PAGE 98 (' currently -found in drinking water are not believed To constitute a danger to health, (27 Refs) c 185 AU - Mukerji A AO - Catalytic, Inc., 1500 Market st,> Philadelphia, PA, 19102 TI - UNLOADING AND STORAGE TECHNIQUE FOR VINYL CHLORIDE MONOMER. SI - ICDB/77/30075 SO - Cham Eng News; 89(191:155-160 1977 LA - ENG AB - An unloading and storage Technique for vinyl chloride monomer (VCM) is described. The method is based on a vapor-1iquid-exchange process. With This process a compressor draws vapor from a plant's storage tanks and feeds the compressed vapor into a tank car, forcing VCM from the Tank car up through a dip tube and into the transfer piping system. Monitoring systems i for this carcinogen are described also. (10 Refs) rxh-A/CV'^ 1 ^ 1 186 AU - Murdoch IA ; Hammond AR AD - Standard Telecommunication Lab. Limited, Harlow, Essex, England TI - A PRACTICAL METHOD FOR THE MEASUREMENT OF VINYL CHLORIDE MONOMER (VCM) IN AIR. SI - ICD5/77/29155 SO - Ann Occup Hyq; 20(1):55-61 1977 LA - ENG AB - A new method for The determination of vinyl chloride monomer in air is described which uses gas chromatography and a sealable Trap sampling svsTem. For practical purposes the detection limit is 0.1 vol/i-.i l 11 i on, since below this level there is a possibility of peaks from minor impurities. (3 Refs) 187 AU - Picciano 0J ; Flake RE ; Gay PC ; Kilian OJ AD - Occupational Health and Medical Res., Dow Chemical, Freeport, TX 77541 TI - VINYL CHLORIDE CYTOGENETICS. SI - ICDB/77/2G642 SO - J Occup Med! 19(81:527-530 1977 LA - ENG AB - This report presents cytogenetic findings from a qroup of 209 worker's employed for up to 28 yr in the manufacture of vinvi chloride monomer at The Texas Division of Dow Chemical USA. Cytogenetic evaluation results from this group were compared to results found in examination of individuals being considered for employment. Statistical analyses were performed on a group basis for chromatid aberrations, chromosome aberrations and proportion of abnormal cells; no statistical difference of significance was found between the Two groups . Cctvparison of these results with reported studies suggests that the level of cytogenetic aberrations in vinyl chloride workers is probably related to the length and level of exposure, and that risk of adverse genetic effect can be avoided in controlled, m i n i i.ia 1 -exposure environments. (Author abstract) (31 Pefs) 00005827 VINYL, CHLORIDE PAGE 99 183 AU - Strickland TW t Guengerich FP AQ - Vanderbilt Univ, Nashville, IN 37232 TI - VINYL CHLORIDE-MEDIATED CYTOCHROME P-950 DESTRUCTION (MEETING ABSTRACT) . SI - IC03/77/23311 SO - Fed Proc! 36( 3):991 1977 LA - ENG AB - The vinyl chloride (VC)-mediated destruction of cytochrome P-950 (P-950) and loss of mixed-function oxidase activity uere demonstrated in rat liver microsomes. This P-950 destruction was also demonstrated in highly-purified reconstituted systems consisting of P-950, NADFH-P-950 reductase (FpI. phosphatidylcholine, deoxycholate, VC, 02, and NAOPH; all components were required and destruction was inhibited SOX by the addition of 20X CO, suggesting that oxidative metabolism of VC by P-950 To a reactive metabolite is responsible for the destruction. Loss of heme paralleled P-950 destruction while the free sulfhydryl content was not lowered during incubation! several experiments indicate that lipid peroxidation does not play a role in the process. The destruction is not due to VC-epoxide or chloroaceTaldehyde, Fp (in the presence of NAOPH and 02) also destroys both free heme (ferriprotcporphyrin IX) and P-950 heme in the absence of P-950 substrates. The latter two processes appear to be similar, but distinct from VC-mediated P-950 destruction, as judged by their sensitivity to catalase and insensitivity to CO. (Author Abstract) 189 AU - Schattenberq PJ ; Totovic V I Gedigk P ; Marsteller HJ AD - Pathologlsches Institut der UniversitaT Bonn, Postfach 2120, D-5300 Bonn, Bundesrepublik Deutschland TI - ULTRASTRUCTURE CF LIVER DAMAGE IN CHRONIC VINYL CHLORIDE INTOXICATION. SI - ICD3/77/21639 SO - Virchow Arch Pathol Anat Histol; 373(3)1233-297 1977 LA - GER AB - Liver biopsies taken from 15 workers at a PVC-producing factory were examined by electron microscopy. The hepatocytes showed focal hydropic swelling, disseminated toxic steatosis, peculiar para-crystaliine inclusions in enlarged mitochondria, focal cytoplasmic degradations, and occasional single cell necroses. These regressive changes were more prominent in cases with a shorter interval of non-exposure prior to the biopsy. Further, a focal compensatory hyperplasia of the smooth endcplasmatiC reticulum was found. With increase of the non-exposure time interval, a regression of The degree of steatosis as well as an age-1 independent excessive lipofuscln deposition was seen in the hepatccvtes. Apparently, these are secuelae of increased autophagia of lipids and increased lipid oxidation by the vinylchioride. In the sinusoids, activation, enlargement and proliferation of Kupffer cells was noted. The tendency of These cells to proliferate is apparently caused by The cancerosenic Stimulation by vInylchioride. The prominent hyperplasia of c c ( c c c c c L L c 00005628 VINYL CHLORIDE PAGE 100 lipocytes is probably connected with the deposition of collagen end the peculiar peri sinusoidal fibrosis. (28 Refs) (Author Abstract ) 190 AU - Dahl GA J Miller EC J Miller JA AD - McArdle Lab.> Univ. Hi, Madison, Wi. 53706 TI - VINYL CARBAMATE, A POTENT CARCINOGEN AND A POSSIBLE URETHAN METABOLITE IN THE MOUSE (MEETING ABSTRACT). SI - ICD3/77/16265 SO - Proc Am Assoc Cancer Res; 18:6 1977 LA - ENG AB - The ethyl group of urethan (U), CH3CH2-0-C0-NH2, a multipotential carcinogen (Tannenbaum, Natl. Cancer Inst. Monogr. 14, 341, 1964), is essential for carcinogenicity (Mirvish, Adv. Cancer Res. 11, 1, 1968). Covalent binding of the ethyl group or a derivative thereof to cellular macromolecules occurs in vivo (Pound et al. Chem.-Biol. Interact. 14, 149, 1976). These facts and the induction of hepatic mesenchymal tumors by U and vinyl chloride suggested that vinyl carbamate (VC), CH2=CH-0-C0-NH2, might be a proximate carcinogenic metabolite of U. VC was prepared from NH3 and vinyl chlorofcrmate; the latter uas obtained in low yield from the pyrolysis of ethylene glycol bis-chloroformate (Schaefqen, J, Polymer Sci. Part C, No. 24, 75, 1968). VC proved to be much more toxic than U in the mouse with the lung as a primary target. Likewise, in this species VC uas much more carcinogenic than U in the lungs and skin. VC uas not mutagenic towards S. typhimurium TA1535, but became mutagenic upon incubation with rat or mouse liver microsomes plus NADPH and 02. U uas not mutagenic in TA1535 with or without microsomal activation. Studies so far in the mouse and in vitro with mouse tissues have failed to detect the metabolic conversion of U to VC. However, the high carelnoqeniclty of VC relative to that of U and the mutagenicity of metabolically oxidized VC suggests that VC and its epoxide may be proximate and ultimate carcinogenic metabolites, respectively, of U. (Author Abstract) 191 AU AU AU AD TI SI SO LA AB - Loprieno N ! Barale R ; Baroncelli S ; BarTsch H ; Bronzettl G - Cammellini A ; Corel C ; Frezza 0 ", Nieri R ; Leporini C - Resell ini D ; Rossi am Laboratorio di Nutaqsnesi a DifferenziAmento C.N.R. Via Cisanello 147/B, 56100 Pisa, Italy INDUCTION OF GENE NUTATIONS AND GENE CONVERSIONS BY VINYL CHLORIDE METABOLITES IN YEAST. ICDB/77/05901 Cancer Res! 37(11:253-257 1977 ENG Chloroethyieoe oxide and 2-chloroacetaldehyde, tuo metabolites of vinyl chloride, and 2-chloroethanol , a putative metabolic intermediate, were assayed for their genetic activity in the yeasts Schizosacchcromycas pombe and Saccharomyce3 cere'Msiae. Chloroethylene oxide uas found to be the most effective in inducing forward mutations in Sch pombe and gene conversions in S Cerevlslae, increasing the mutation and conversion frequencies 00005329 VINYL CHLORIDE PAGE 101 192 AU AD TI 51 SO LA A3 193 AU AD TI SI SO LA A3 340 end 50 times, respectively. over* Those of the controls. In either the presence or the absence of mouse liver microssmesi 2-chloroacetaldehyde showed only feeble genetic activity! and 2-chIcroethanol was completely inactive in both yeast strains. In contrast to vinyl chloridet 2-chloroacetaldehyde did not induce forward mutations in Sch pombe in the host-mediated assay in mice. The results strongly support the hypothesis that chloroethy1^ne oxide is one of the principal mutagenic agents formed from vinyl chloride in the presence of mouse liver enzymes. (Author Abstract) Veitman G ; Lange CE ; Stein G Bonni W. Germany NEW DISCOVERIES AND OBSERVATIONS ON THE PROGRESS OF VINYL CHLORIDE DISE (MEETING ABSTRACT)ASE. ICDB/77/27330 Z Hautkr; 52(6)1196 1977 GER The symptomatology of vinyl-cnloride (VC) disease with special attention to newer discoveries and the danger To the worker in VC-related industries are discussed. Variousperiodic checks on skin and bone changesi thrombocytes and liver functions are available. The preventive measures that have arisen from this knowledge have generally removed the immediate threat at The factory, (no Refs) Vicary FR Unlv. Coll. Hosp.i London. Enqland PROGRESS REPORT. ULTRASOUND AND GASTROENTEROLOGY: TECHNICAL CONSIDERATIONS. ICOS/77/26 998 Gut; 13(5)1336-397 1977 ENG Advances in the use of ultrasound in gasTroenterology are reviewed. The underlying principle of ultrasonic Tissue examination is that, at certain frequencies, sound is reflected when passed between two tissues of unequal acoustic density. An interface, such as that between liver and diaphragm, reflects much sound, while fluid reflects virtually no sound. Recent advances have made it possible to record different levels of sound in varying shades of grey, between black and white, with the loudest sounds beii'.q the most white. This means that tissues of relatively similar, but different, acoustic Textures can be portrayed as different shades of cyey. Thus it is possible to differentiate such Tissues as a solid hepatic metastasis from normal 1lver tissue. The uses of ultrasound in liver imaging; biliary system examination in cases of Jaundice! The diagnosis of liver tutors, hepatic and abdominal abscesses, hepatic cysts, and vinyl chloride liver disease; the determination of liver volumes I pancreatic investigation; and examination of abdominal masses are discussed. (63 Pefs ) c ;.;... ,;v.,. ( c 3) (/> co oo ID N> ro 00005330 VINYL CHL0RI0E PAGE 102 194 AU - Veltman G 1 Lange CE AO - Univ, Hautklinik, Bonn-Venusberq, 5300 Bonn i W. Germany TI - INDUSTRIAL MEDICINE AND VINYL CHLORIDE. SI - ICD3/77/Z6059 50 - Berufsdermatosen; 25(Z):67-77 1977 LA - GER AS - After a shorT review of the history of some other occupational diseases, the institutions and government agencies in West Germany concerned with regulating industrial medicine and occupational hazards are listed. The vinyl chloride (vc) syndrome is recognized as an occupational hazard, and patients are eligible for workmen's compensation. Directions for dealing with vc are described: teaching the employees the hazards of vc, criteria for selecting new employees, regular medical examinations, and recommendations and rules governing hazard-free working conditions. Nsw products of economic importance should be examined carefully before being commercialized. (4 Refs) 195 AU - Anonymous AD - No affiliation given TI - ACRYLONITRILE LINKED TO CANCER IN WORKERS. 51 - OARC/77/05586 50 - Chem Eng News! 55(22):6 1977 LA - ENG AB - Due to acrylonitr1 la's (AN) structural similarity to vinyl chloride, a study was conducted on 470 AN workers at a textile fibers plant in Camden, Thera were 16 cases of cancer reported, all occurring in workers initially exposed to AN during the startup of the plant in 1950-52. This preliminary study does not provide definitive evidence of the carcinogenicity of AN in man. Follow-up studies and investigations at other plants are planned, (no Refs ) 196 AU - Lee FI ; Harry DS Adams WG ! Litchfield M A0 - Dept. Nediclne, Victoria Hosp., Blackpool, England TI - SCREENING FOR LIVER DISEASE IN VINYL CHLORIDE WORKERS. 51 - CARC/77/05484 SO - Dr J Ind Med! 34(2)1142-147 1977 LA - ENG AB - The results of screening for liver disease in workers exposed to vinyl chloride are presented. There was no significant difference in liver function tests of workers exposed to vinyl chloride as compared to men in trie same factory who were not exposed. However, four exposed workers had splenomegaly. (21 Refs) c c c c c c L L L L ( . .>Tirw. it sU&rwtfA c 00005331 VINYL CHLORIDE PAGE 103 c 197 AU Leonard A ; Decat G J Leonard ED ; Leisure MJ ; Oecuyper LJ AU Nicaise C c AO Lab. Genetics, Dept. Radiology, C.E.N,-S.C.K. B 2900 Mol, Belgium 30 II CYTOGENETIC INVESTIGATIONS ON LYMFH0CYTE5 FROM WORKERS EXP05ED TO fi VINYL CHLORIDE. C/J SI CARC/77/05213 SO J Toxicol Environ Health; 2(51:1135-1191 1977 w c LA ENG 03 A3 Eleven male workers from the polymerisation department of a VC (O factory, seven people emploved in the laboratory of another VC plan! , and ten controls from Outside the factory environment were examined for the presence of chromosome aberrations in blood lymphocytes and these cvtoiogicai findings were viewed in light of the occupational and medical histories of the subjects. Most of The workers from the polymerisation department had chromosome anomalies such as fragments, rings, Translocations, and dicentrics. However, since these workers received frequent radiographs of the hands, feet, vertebral column and digestive tract, it is impossible to determine whether these chromosome V anomalies result from vinyl chloride exposure or from diagnostic exposure To loniping radiations. It is concluded that the risk of significant increase in chromosome aberrations due to occupational exposure to VC seems Small and That present working conditions in VC plants are within acceptable safety limits. (17 Refs ) c 193 AU AO Reimsr RR ; Fraumeni JF ; Ogols PF ; Bender R Environmental Epidemiology and Medicine Branches, NCI, Bethesda, M0 20019 TI PANCREATIC CANCER IN FATHER AND SON (LETTER TO EDITOR). SI CARC/77/C9930 SO Lancet; 1(6017):911 1977 LA ENG t AB The occurrence of a pancreatic tumor in successive generations is reported. A 03-yr-old chemical worker and his 36-yr-old son both developed pancreatic cancer. Several years before he died. The son worked briefly with his father, and both were exposed to c vinyl chloride and other chemicals. Neither patient smoked or had any condition that predisposes to pancreatic cancer. The patients Consumed larqe quantities of pistachio nuts, and they may have ingested some that were contaminated with mvco toy. i ns . The L occurrence of this tumor in successive generations may be due to clv.r.ce or genetic trapismi ss l on . Seme char ac t er i s T i c s of the case Suggest an environmental influence. (8 Refs) L L ."V'ci'-v 'i'VrVi 'X:' . n:`i 5. ff 00005832 VINYL CHLORIDE PAGE m 199 AU - John JA Smith FA ; Leonq DK Sehwetq BA AO - Toxicology Res. Lab. Health Environmental Res. > Oou Chemical U.S.A., Hidland> Hi 9S69Q TI - THE EFFECT5 OF MATERNALLY INHALED VINYL CHLORIDE ON EMBRYONAL AND FETAL DEVELOPMENT IN MICE, RATS, AND RABBITS. SI - CARC/77/09793 SO - Toxicol Appl Pharmacol; 39(3)1997-513 1977 LA - ENG AB - Groups of pregnanT CF-1 mice, Spraque-Oawley rats and New Zealand white rabbits were exposed to an atmosphere of gaseous vinyl chloride (VC: mice. SO or 500 ppm; rats and rabbits, 500 or 2500 ppm) for 7 hr/dav during the period of major organogenesis. Some animals were given 15/ ethanol in Their drinking water. Maternal toxicity was observed in all three species. Among the effects were: a decrease in maternal gain and in absolute liver wt and an increase in maternal deaths for mice exposed to 500 ppn VC! a decrease in maternal wt gain and an increase in liver wt for rats exposed to 500 and 2500 ppm VC, respectively', and a decrease in food consumption for all three species (p < 0.05 for all differences). VC alone did not cause consistent significant embryonal or fetal toxicity. Some decrease in fetal body wt and cretin-rump length was observed in fetal mice and rots but not in rabbits. Inhalation of VC was rot teratogenic in any of the species at the concentrations tested. Except for dilated ureters in litters of rats exposed To 2500 ppm VC, no external or soft Tissue anomalies were observed at a significantiy higher incidence than observed in the control animals. Examination of The fetal skeletons showed minor but no major skeletal variations in the VC groups. Ethanol treatment enhanced maternal toxicity more than embryo toxicity, (11 Refs) 200 AU - Newell GR ; Golumbic N AO - Natl. Cancer Program, NCI, Bethesda, HD 20019 TI - CHAT YOU CAN DO TO PROTECT YOURSELF AGAINST CANCER. SI - IC03/77/20235 SO - AORM JJ 25( 5 )' 909-910,912,919,916,918,922,929 1977 LA - ENG AB - The prevention and early detection and diagnosis of cancer are discussed. Individuals can make a significant contributicn to cancer prevention through their decisions about life style and their concern for the environment. Individuals who smoke, are frequently overexposed to direct sunlight, or are exposed To occupational carcinogens such as vinyl chloride or x-rays run an increased risk of developing cancer. Scientists estimate that per'haos 70/ to 90/ of ail cancers are associated with cancer-causing elements in the environment and that most could be avoided. Individuals can increase their chances of detecting earl" cancer and obtaining effective Treatment bv becoming aware of the early signs of cancer and by having regular physical examinations, (2 refs) 00005833 VINYL CHLORIDE PAGE 105 201 AU - Bonneton G J Champetier J ; Fournet J ; Guidicelli H ; Legrand J AU - Dupre A ; Hostein M I Marty F I Palin M AD - Service o'e Chirurgie Vasculaire, C.H.U, da Grenoble, F 33700 La Troncha, Franca TI - ANGIOSARCOMA OF THE LIVER A,`JO PORTAL SCLEROSIS IN VINYL CHLORIDE WORKERS. REFORT OF TWO CASES. SI - CARC/77/0A613 SO - Mpuv Prasse Mad; 6(91:735-742 1977 LA - FRE A3 - A 63-yr-old man davaloped an angiosarcoma of The livar aftar 12 yr occupational exposure to polyvinyl chloride. Ha entered The hospital with acuta abdominal pain and hypochromic anamia. Hepaiospleno.negaly and ascites wore evident clinically and confirmed by endoscopic and artariographic studies. Hapatlc scintigraphy showed a multilacunar araa near tha margin of tha right lobe. Laparotomy re''aaled abdominal hemorrhage and a large, hemorrhagic cyst on the liver. Hepatectomy and Splenectomy ware performed with immediate satisfactory results; however, rupture of tha esophageal varices as a result of portal hypertension led to fatal hemorrhage on The 16*h postcoerative dav. In addition to angiosarccma of the night lobe of The liver, areas of infarct and intrahepatocytic biliary retention were observed in tha left lobe at autopsy. In the second case, the worker developed portal fibrosis and collagenous sclerosis of the liven after more than 20 yr exposure to polyvinyl chloride. A splenectomy was performed in 19oS for splenomeqaly; the spleen proved to be inflamed and fibrous without evidence of malignancy. Five years later, the patient was hospitalised for melena and found To have hypochromic anemia, moderate hepatomegaly, and significant esophageal varices. At surgery, the liver appeared to have disseminated micronodules , but no Tumor was detected. The portal vein was fibrosed and a mesenterico-vena cava anastomosis was performed with excellent postoperative results. (13 Refs) 202 AU - Kay K AO - Mount Sinai Sch. Medicine, City U.iiv. New York, New York, NY 10029 TI - CHLOROFORM TOXICITY (LETTER TO EDITOR). SI - CARC/77/04301 SO - Am Ind Hvq Assoc JJ 33(2 ):A-24-A-25 1977 LA - ENG AB - The author criticises a previous paper that covered tests of chloroform toxicity over 6 mo. During that time, as might be expected from what is known about chemical carcinogenesis, cancers did not develop. The report is misleading, because The question as To whether cancers might F.va developed over the longer exposure period used in the NCI chloroform tests was not answered. The noncarctnooon1city of chloroform in a 6-mo test may indeed be inconsequential In comoarlson with its careinogenic1Ty, as was the case with vinyl chloride. (0 Refs) 00005834 VINYL CHLORIDE PAGE 106 c 203 AU - Ivanetich KM ; Aronson I I KaTp ID c AD - Oept. Physiology Medical Biochemistry, Univ. Cope Town Medical Sch.i Cope Town, South Africa c 33TI - THE INTERACTION OF VINYL CHLORIDE WITH RAT HEPATIC MICROSOMAL CYTOCHROME P-450 IN VITRO. SI - CARC/77/04085 SO - Biocheni Biophys Res Common; 74(4)11411-1418 1977 fiR 05 LA - ENG A3 - The interaction of vinyl chloride (VC) in vitro with the cytochrome P-450 enpyme system of the hepatic endoplasmic reticulum of Long Evans male rats was investigated. The binding of VC to cytochrome P-450 in vitro was studied spectrally in microsomes from uninduced, 3-methylcholanthrene (3-MC )-induced, co 03 (D ro at and phenobarbital (PB)-induced rats. VC bound to hepatic microsomal cytochrome P-450 in all types of microsomes, ulTh I production of a type I difference spectrum. Hanes plots of the spectral binding of VC to cytochrome P-450 were linear for all types of microsomes. VC increased CO- inhibitable NADPH consumption by hepatic microsomes from induced rats. Induction by 3-MC did not increase the apparent max velocity much above that obtained for uninduced microsomes. However, for PB-induced ( microsomes, max velocity was approx fivefold greater than the apparent max velocity obtained with uninduced microsomes. The effects of inhibitors on the interaction of VC with cytochrome P-450 were determined. $KF 525A fully inhibited the binding of VC to cytochrome P-450, but it did not decrease the enhancement of CO- sensitive NADPH consumption bv VC, However, metyrapone did not significantly inhibit the binding of VC to cytochrome P-450 but did inhibit the enhancement of CO- sensitive NA0FH c consumption by VC. The influence of incubation of hepatic microsomes from induced rats with VC on microsomal enpyme levels was assessed. The levels of cytochrome P-450, cytochrome b5, and NAOPH-cytochrome c reductase wer-e not altered after incubation of c hepatic microsomes with either VC, NADPH, or NADH. Cytochrome b5 and ftAOPH-cy toehrome C reductase were not affected after incubation of hepatic microsomes with VC plus NADPH, but cytochrome P-450 was decreased. The VC-mediated decrease in c cytochrome P-450 was slight in control (8/) and 3-MC (7Z) microsomes, but was significant in PB microsomes (31Z). In PB-induced microsomes, microsomal heme was decreased bv approx 30/ of the decrease in cytochrome P-450. Reduced glutathione and c CO inhibited the VC-mediated decrease in cytochrome P-450 in P3-induced microsomes by approx 30/ and 80Z> respectively, NAOH I. supported the VC-mediated decrease in cytochrome P-450 by aoprox L 30/ in comparison to NADPH. The results may provide an explanation for the observation that prior exposure of laboratory animals to VC protects Them against The toxic effects of VC, (17 Refs ) L 00005S35 VINYL CHLORIDE PAGE 107 20 A AU - Hoffmann D ; Uynder E AD ~ Naylor Dana Inst, for Disease prevention., American Health Foundation, Valhalla, NY, 10595 TI - ENVIRONMENTAL RESPIRATORY CARCINOGENESIS. SI - IC08/79/1616? SO - Am Chem SoC Moncr Ser; (173 ):3ZA-365 1976 LA - ENG AB - Three factors are implicated in the overall increase of lung cancer: tobacco (especially cigarette smoking), urban pollution, and the emergence of new industrial environments. A review is presented of the relationship of lung and other cancer to tobacco, urban air pollution, and exposure to industrial carcinogens. Topics discussed include carcinogenic stimuli in occupational respiratory environments, such as radioactive aerosols in mining of radioactive ores, arsenicals, chromium in chromate workers, nickel and its relationship to lung and nasal cancer, coke oven effluent and its relationship to skin as uell as lung cancer, chloromethyl ethers and lung cancer, vinyl chloride and liver angiosarcoma, the possible careinoqenicity of nitrosamines, and other less common respiratory carcinccens. The possible role of air pollution on The induction of respiratory cancer is reviewed. Polynuclear aromatic hydrocarbons in urban atmosphere are listed, and their sources identified. Indoor pollution is discussed briefly. Air pollution is probably one factor which increases the risk of urban populations, especially cigarette smokers, of developing lunq cancers. Cigarette smoke, which is by far the most important single factor contributing to increased risk of developing respiratory tract, especially lung cancer is discussed. Epidemiological observations are reviewed. The characterlsTics of tobacco smoke are reviewed, including major smoke components, particle sizes in smoke, temperature reached in the burning cone, and pH of the smoke. Studies dealing with experimental tobacco carcinogenesis are briefly reviewed, and the identification of carcinogens in the gas and particulate phases of smoke are outlined. Some experimental approaches for the reduction of tumorigeniciTy of cigarette Smoke are discussed. (IAS Refs 1 205 AU - Eartsch H AD - Unit of Chemical Careinogenesis, International Agency for Research on Cancer, 150 cours Albert Thomas, 69003 Lyon France. TI - MUTAGENICITY TESTS IN CHEMICAL CARCINOGENESIS. SI - CARC/70/01571 SO - Environmental Pollution and Carcinogenic Risks. Lyon, International Agency for Research on Cancer, IARC Scientific Publications No 13, INSERM Symposia Series, vol. 52, 1976. LA - ENG AB - The use of mutagenicity tests in the assessment of chemical carcinogenicity is assessed. The validity of this application is demonstrated with the vmvl chloride experiments in rats, mice, human liver, and Salmonella typhimur1um and the N-n1trosamine activities In rats, human liver, and S. typhlmurium. The R&S 138927 c ( L L c e L 00005836 VINYL CHLORIDE PAGE 108 R&S 138928 use-fulness of mutagenicity tests in predicting possible carcinogenic effects of chemicals in man is valid only if the short-term bioassay is corroborated by data from long-term tests in experimental animals and is then taken together ui Th epidemiologic studies. Mutagenicity tests, therefore, although effective in predicting The carcinogenic potential of chemicals, are not able to indicate organ and species specificity of the carcinogenic activity of the chemical or correlate mutagenic potency with carcinogenic potency. (50 Refs) 206 AU - Henscnler D I Bonse G Greim H TI - CARCINOGENIC POTENTIAL OF CHLORINATED ETHYLENES. TENTATIVE MOLECULAR RULES. SI - CAP.C/77/07537 SO - Environmental Pollution and Carcinogenic Risks. Lyon. International Agency for Research on Cancer. IARC Scientific Publications No 13. INSERM Symposia Series. Vol. 52, 1976. LA - ENG AO - The mechanisms of bioactivation and the mutagenic activity of the chlorinated ethylenes were studied with a short-term in vitro system using metabolic activating liver microsomal enzymes. Chlorinated ethylenes were activated in mammalian metabolism to oxiranes. Asymmetric chlorine substitution of the ethylenes and oxiranes rendered the molecules unstable and mutagenic. Vinvl chloride was The most active; trichlcroethylene and vlnylidene chloride were far less active but still significantly so. Chlorinated ethylenes metabolized via symmetric oxiranes Itetraohloroethylene, els- and trans-1,2-dichloroethylene ) were relatively stable, and were not mutagenic. IT was concluded that mutagenic activity and possible carcinogenic potential were related directly to oxirane stability. (13 Refs) 207 AU TI SI SO LA AB - Lawther PJ t Waller RE - COAL FIRES, INDUSTRIAL EMISSIONS ANO MOTOR VEHICLES AS SOURCES OF ENVIRONMENTAL CARCINOGENS. - CARC/77/07533 Environmental Pollution and Carcinogenic Risks. Lyon, International Agency for Research on Cancer, IARC Scientific Publications No 13. INSERM Symposia Series, Vol. 52. 1976. ENG The rural/urban difference in the concentrations of benzol aIpyrena was for many years Thought to be a notable factor in the occurrence of lung cancer! but now that industrial emissions and domestic smoke have; been controlled considerably in Great Britain, the concentration of benzol a Ipyrene in the urban environment has been reduced by a factor of ten. In addition, Traffic contribution To the benzol a Ipyrene level, although variable, is small in c-reat Britain. Correlations with a reduction in lung cancer are not yet possible, partly because recent cancers could have been induced bv The former high levels and because The effect of cigareTte smoking is now known To be an important etiological factor in lung cancer. Of other possible carcinogenic materials dispersed into the environment, asbestos 00005837 VINYL CHLORIDE PAGE 109 c has undergone the most investigation. The established association between asbestos and lung cancer and pleural mesothelioma is c predominantly occupational; thus the general public is at very low risk. Similarly) many metals in trace amounts) eg> nickel) chromium) beryllium and vinyl chloride monomer) are suspected o-f being occuoationai carcinogens. Careful monitoring of urban air c is advisable when investigating possible etiologies of lung cancers. (37 Refs) 208 AU - Antweiler H AD - Uni versitat Dus3eldorf) Dusseldorf) W. Germany TI - STUDIES ON THE METABOLISM OF VINYL CHLORIDE. SI - CARC/77/07435 SO - Environ Health Perspect; 17:217-219 1976 LA - ENG AD - Current ideas concerning the metabolism of vinyl chloride (VC) in mice and in humans are discussed. It 13 believed that VC is first metabolized by oxidases to chloroathylene oxide, a strong c mutagen, Socntaneous conversion to chloroacstaldehyde (CA) follows) CA may be mutagenic and carcinoqenlc. Dehydrogenation of CA leads to cnloroacetic acid (CAA), a substance of known toxicity but unknown mutagenicity. Conjugation of CAA with glutathione leads to the formation of the principal urinary c. metabolites of VC I namely S-carboxymsthylcysteine and thiodiacetic acid. CAA may also be converted, via glycolic acid, to oxalic acid. (13 Refs) 209 AU - Wolff MS AD Environmental Sciences Lab., Dept Community Medicine, Mount Sinai Sch. Medicine, City Univ. New York, New York, NY 10029 TI EVIDENCE FOR EXISTENCE IN HUMAN TISSUES OF MONOMERS FOR PLASTICS AND RUDDER MANUFACTURE. SI CARC/77/0 7281 SO Environ Health Perspect; 17:183-167 1976 LA ENG AB Oiscussion is made of the storage in fat of lipophilic substances such as DDT, polychlorinated biphenyls, tetrachloroethylene, and trichloroethylene , which are chemically similar to many industrially-used monomers, plus styrene, acrylamide, and vinyl chloride. Data on the uptake, metabolism, storage, and excretion of these substances in humans are provided when available. The storage and removal of lipophilic substances from fat tissues depend on fat solubility, volatility, and metabolism. Styrene is very soluble in blood and fat: foilowinq exposure at 100 ppm, blood levels of 0-2-15 ppm styrene ha,-e been determined. The urinary and breath half-lives of styrene metabolites and styrene, respectively, are about 8 hr and 1-3 Hr, respectively. Detectable levels of styrene were cresent in the fat of styrene workers greater than 2 days following exposure, a much longer period than that over which styrene could be detected in the breath of people experI men tally exposed to 100 ppm styrene for sustained periods. (28 Refs ) c c ( ^' , (. .'St v_ '-^ V/ .^T ' y' *, ( i.. C. 00005833 VINYL CHLORIDE ( PAGE 110 r!'.J. 210 AU TI SI SO LA AB 211 AU AD TI SI SO LA A3 Maltoni C OCCUPATIONAL CHEMICAL CARCINOGENESIS: NEW FACTS, PRIORITIES AND PERSPECTIVES. CA.RC/7 7/06880 Environmental Pollution and Carcinogenic Risks. Lvon, International Agency for Research on Cancer, IARC Scientific Publications No 13, INSERM Symposia Series, vol. 52, 1976. ENG The results of experiments on the carcinogenicity of vinyl chloride (VC) are presented in 18 tables a3 part of a paper calling for a more active approach to the problem of environmental oncogenesis. VC uas inhaled at doses from 30,000 ppm to 1 ppm for A hr/day, 5 davs/uk for 52 uik by rats (Sprague-Dauley, Webster), mice (Swiss), and hamsters (Chinese); 50 ppm was the dividing dose in carcinogenic potential, and a variety of cancers resulted frcm the higher dosages. VC uas also administered by inhalation at 10,000 ppm and 6,000 ppm, A hr/day for 1 wk. The resulting cancers uere monitored in the animals and their offsprings. In addition, VC was inqested at 50.00, 16.65, and 3.33 mg/g body weight, once daily, A-5 days/uk for 52 uk; liver angiosarcomas uere the predominant resulting neoplasms. Lower dosages of 1, 0.3, and 0.03 mg/g body weight produced no tumors. Subcutaneous administration into rats of 30 mg of compound in 1 cc of water of chromite, neochromium, chromium allumen, lead chromate, molybdenum orange, cadmium sulphide, iron oxide, pine chromate, and titanium oxide resulted in rhabdomyosarcomas and fibrosarcomas in all cases but chromite, iron oxide (red), titanium oxide, and pine chromate. Adriamycine was tested in rats by sc injection of 2 mq in 1 cc olive oil. Tumors resulted in 35/ of females and 30/ of males after an average latency of 31-32 wk. Plans of experiments to test the oncological effectiveness of styrine, vinylidene chloride, and acrylonitrile are also given in tabular form. (1A Refs) Winell M i Holmberg B i Kronevi T Section Occupational Toxicology, Dept. Occupational Medicine, Natl. Board Occupational Safety and Health, S-100 26 Stockholm, Sweden BIOLOGICAL EFFECTS OF VINYL CHLORIDE: AN EXPERIMENTAL STUDY. CARC/77/06811 Environ Health Perspect, 17:211-216 1976 ENG Liver damage caused by the exposure of albino NMRI mice to atmospheric vinyl chloride (VC) was assessed by estimating the plasma activities of alkaline phosphatase (API, the transaminases> and lactate dehydrogenase (LDH ). Three groups of 2A mice each were exposed by inhalation for 6 hr/day, 5 days/uk, to 50 ppm (52 uk ) or 500 ppm VC (26 wk), or to air only (controls). The animals were also autocsied, and the tissue pathology was studied. Liver damage was indicated by a significant increase in Total LDH levels after about A0 uk. After A6 wk, total LDH levels were Increased about 2.5-fold following R&S 138930 c c ( c c c c e c 00005839 c VINYL CHLORIDE c PAGE 111 cc exposure to 500 ppm, A significant shift in the LOH isoenzyme profile to the M form also occurred. There was no corresponding c celevation in transaminase activities) which might have served as an alternative Indication of-liver injury. AP activities also increased after about 90 wk: at this time levels were elevated 30X-90X and 50'/.-60'/. following exposure to 50 and 500 ppm VC, c crespectively. This elevation could indicate lesions In the hepatobiliary tract. Upon autopsy 12 mo after the start of exposure) no control mice had any lung adenomas or hemangiosarcomas) and 29 mice exposed to 9 ppm VC had lung adenomas and 8 had hemangiosarcomas. (30 Refs) 33 12 AU - Bartsch H ; Malaveille C I Barbin A ; Bresil H ; Tomatis L AU - Nontesano R P <D AD - International Agency Res. Cancer> Unit Chemical Carcinogenesis) 69008) Lyon> France TI - MUTAGENICITY AND METABOLISM OF VINYL CHLORIDE AND RELATED COMPOUNDS. SI - CARC/77/06SQ9 co 00 (> CO SO - Environ Health Perspect; 17:193-198 1976 LA - ENG AS - Experimental data concerning the metabolism and mutagenicity of vinyl chloride (VC) and related compounds are reviewed. The data ( suggest that the biological effects of VC are related to its conversion by microsomal enzymes into chemically reactive alkylating agents that can bind covalently to various cellular macromolecules. The mutagenicity of VC to Salmonella typhimuriurn strain TA1530> which is reverted to his+ by single base-pair substitutions) was increased 28-fold after exposure to an atmosphere of 20/ VC (volume/volume I in air. Hepatic microsomal c cmixed function oxidases from rats, mice, and humans were equally effective in transforming VC into alkylating agents in vitro. Two of the products of reaction with the microsomal enzyme system, chloroethylene oxide and 2-chloroacetaldehyde> demonstrated potent mutagenicity in microorganisms and Chinese hamster V79 cells. (31 Refs ) c 213 AU AD TI SI SO LA AB Byren D I Engholm G \ Enqlund A ; Westerholm P Kema Nord i 85013 Sundsvall, Sweden MORTALITY AND CANCER MORBIDITY IN A GROUP OF SWEDISH VCM AND PCV PRODUCTION WORKERS, CARC/77/06792 Environ Health Perspect; 17:167-170 1976 ENG Mortality and cancer morbidity data are presented from studies of 750 workers employed in a Swedish vinyl chloride (VC )/polv(vinyl chloride) plant since 1990, Cbserved/e-'pec ted deaths from various causes were: 2/0.33 (brain cancer), 3/1.73 (lung cancer), 9/0.97 (cancer of 1iver/pancreas , Including 2 angiosarcomas of the liver), 28/18.26 (Total circulatory disease), 6/3,02 (cerebrovascular disease), 15/9.15 (myocardial Infarction), and 5/1.93 (cerebral hemorrnzge ), Observed/expected morbidities were: 3/1.30 (lung cancer) and 2/0.98 (cancer of 11ver/pancreas ). The c. L c. c K' C c (' c-"' c 'anuvc.'-7 - v g m u--: ryd ~ -- . -- > k" '-.- -. 30 W 03 co to 03 TO 000053*40 VINYL CHLORIDE PAGE 112 /SI V excess of cancers of the liver/pancreas increased with latency time (time between first employment and end of follow-up). The possible etiology of the cardiovascuiar deaths is discussed. (7 Refs ) 214 AU - Gokel JM I Liebezeit E ; Eder H AD - Patholog i sches Institut der Uni v/ers i tat . Thalkirchner Str. 36 i D-8000 tlunchen 2, Federal Republic of Germany TI - HEMAN3I03ARC0MA AND HEPATOCELLULAR CARCINOMA OF THE LIVER FOLLOWING VINYL CHLORIDE EXPOSURE A REPORT OF TWO CASES. SI - IC03/77/10635 SO - Virchow Arch Pathol Anat Histol; 372(31:195-203 1976 LA - ENG AB - A report is given of the clinical f.nd autopsy findings of two men who died from malignant liver neoplasm following occupational exposure to vinyl chloride. The first patient was a 44-vear-old man with an hemangiosarcoma of the liver, the second patient a 67-year-old man with an hepatocellular carcinoma. So far an hepatocellular carcinoma due to vinyl chloride has not yet been observed in man. Its occurrence, however, has been suggested from the results of animal experiments. The connection of hepatocellular carcinoma with exposure to vinyl chloride is discussed. (Author Abstract) 215 AU - Loprieno N ; Abbondandolo A ; Barale R Baroncelli S j Bonatti S AU - Bronzetti G; Cammellini A ; Corsl C I Corti G j Frezza D AU - Leporini C ; Mazzaccaro A i Nierl R ', Rosellini 0 ; Rossi AM AD - Laboratorio di Mutagenesi e Differenziamento, CNR e Istituto di Genetica dslla Universita, Pisa, Italy TI - MUTAGENICITY OF INDUSTRIAL COMPOUND: VINYL CHLORIDE, STYRENE AND THEIR POSSIBLE METABOLITES (MEETING ABSTRACT). SI - ICDD/77/10294 SO - Third International Symposium On Detection And Prevention Of Cancer. 1976. LA - ENG A3 - It has been proposed that mutagenicity tests are at the present the most appropriate for the prescreening of substances for possible carcinogenic activity. It is therefore interesting to develop bioloqical analyses to assess the mutagenic activity of toxic industrial compounds already known as human carcinogens or these compounds under suspicion. In out' analyses we have applied mutagenicity methodoLcqies in the study of vinyl chloride (human carcinogen) and to styrene (under carcinogenic analysis at the present): the same analyses have been applied also to their possible metabolites (2-chloreethvlene oxide, 2-chloroethanol, E-chloroacetaldehyde> and styrene oxide) in order to correlate the mammalian metabolic fate of the compounds with their biological activity- The compounds hav-e been studied by means of liver microsomal assay and host mediated assay (mice), employing as a test organism the yeast S combe and 5. cere'Msiae on which tile induction of gene-mutations and of gene-conversions has been analyzed. Preliminary evperiments have been done also with somatic mammalian cells (V79 Chinese hamster), on which the ( c ( c c ( c t 1. L L L 00005341 VINYL CHLORIDE PAGE 113 216 AU AD TI SI SO LA AS 217 AU AD TI SI SO LA AB induction of S-azaguanine resistant clones has been assessed. From our analyses it has been found that vinyl chloride is mutagenic in the presence of liver microsomal preparations (in vitro) or in the host mediated assay (in vivo). (Author Abstract) Banerjee S > Van Duuren BL Laboratory of Qrqanic Chemistry & Careinogenesis, Institute of Environmental Medicine, New York University Medical Center, New York, N.Y. U.S.A. INTERACTION BETWEEN TRICHLOROETHYLENE AND HEPATIC ENDOPLASMIC RETICULUM (MEETING ABSTRACT). ICD3/77/10279 Third Internalicnal Symposium On Detection And Prevention Of Cancer, 1976. ENG Trichloroethylene (TCE) is a structural analog of vinyl chloride, which is known To induce angiosarcoma of the liver in rodents and is also a human carcinogen. TCE is a widely used organic solvent in industry and has also been used for many years as an anesthetic. We predicted recently that TCE is likely to be carcinogenic and That its epoxide prcbablv is The activated carcinogenic intermediate. Subsequently, the National Cancer Institute reported that TCE induces heoatocellular carcinoma and other tumors in B6C3F1 hybrid mice. TCE epoxide is expected to be highly reactive toward cellular nucleophiles, eg proteins and nucleic acids. Hence, The microsomal metabolism of TCE and its covalent binding to microsomal protein was examined. Rat liver microsomes were incubated in vitro with *#14C-TCE. The results showed that TCE binds covalently to microsomal protein since extensive organic extractions and pronase diqestion do not dissociate The TCE-protein complex. The binding was decreased by 7,8-benzoflavone , blocked by SKF-525A and enhanced by intraperitoneal administration of phenebarbital. The possibility that TCE epoxide, once formed, could be contorted to water-soluble products through enzymatic hvdrolvsis by epoxide hydrase was also invesTigated. Addition of 3>3,3-trichloro propane oxide, a potent inhibitor of epoxide hydrase to the incubation system markedly enhanced the binding of TCE. These observations support the view That TCE is metabolized to its epoxide, which is most likely involved in TCE carcinogenesis and toxicity. (Author Abstract) Aranha GV Gold J I Gi'aqe TB University of Minnesota Hospitals, Department of Surgery, P.0. Cox 90, Minneapolis M.M 55455. HEMANGIOSARCOMA OF THE SPLEEN: REPORT OF A CASE AND REVIEW OF PREVIOUSLY REPORTED CASES. IC03/77/04781 J Surg Oncol; 8(6) =481-487 1976 ENG Solenic hemangiosarcomas are rare tumors, usually discovered at autopsy. In a few instances the diagnosis was made premortem, at the Time of splenectomy for spontaneous rupture. The Tumors JJ <n CO 00 CO C/3 4* c 00005842 VINYL CHLORIDE ( PAGE 114 cc usually present uith abdominal pain, left upper quadrant mass and tenderness , and occasionally uith a microangiopathic type of c canemia. The histogenesis of the tumor is in dispute. Some authors feel that they are degenerations of hemangiomas. Others feel that they arise de novo in the spleen. There is no proven association of thorotrast administration or vinyl chloride ( cexposure to the development of hemangiosarcomas in the spleen. The prognosis of the tumor is uniformly poor and most of the patients surviving laparotomy have followed a uniformly fatal clinical course. In a feu cases treated with chemotherapy there has been no evidence of clinical benefit. The case report in this article presented uith essentially all the features enumerated above. (Author Abstract) c 218 AU A0 - Whelan JG ! Creech J i Tamburro CH - Digest Dis and Nutri Sect and Cancer Ctr, Med, Louisville, KT 40201 Univ Louisville, Sch c TI - FRIMARY LIVER CANCER DETECTION IN VINYL CHLORIDE WORKERS (MEETING ABSTRACT). SI - ICDD/77/04524 \ SO - Third International Symposium On Detection And Prevention Of Cancer. 1976. LA - ENG ( A3 - The recent discovery of hepatic angiosarcoma in vinyl chloride V. , polymeriration uorKers led to a medical screening program which utilired radioisotopic scanning as a primary screening procedure among asymptomatic uorKers. Nine hundred employees underwent el medical examination, biochemical blood studies and ##99mTc hepatic scanning. Sixty-six of these employees had hepatic angiographic studies and hepatic biopsy. Thirty five were studied because of pathological abnormalities on liver scan and 30 because of biochemical abnormalities with normal scans. Thirty one percent of those with abnormal li>'er scans had angiographic c lesions. Five had angiosarcoma, 2 of whom had no biochemical abnormaliTies at the time their scan indicated a lesion present. Four had cirrhosis and 2 pelios is hepatis. Of the 31 employees with normal scan, only 72 (2) had angiographic lesions! both had peliosis hepatis. Within one year, one developed a positive liver scan associated uith the progression of his peliosis hepatis and the development of hepatic arterialporTal venous shunts. The majority of those uith positive liver scans without L angiographic lesions did have significant histological disease including portal fibrosis, granulomatosi3 and fatty matamorphos1s . In contrast, only minor nonspecific histological abnormal 1ties were found in Those with normal scans and negative L angiographic studies. These data illustrated the effectiveness of The 1iver scan as a primary screening procedure boTh by iTs early cetecTion of hepaTic Tumors and its low incidence of false positivity (less than 32) in this cohort of asymptomatic vinyl L chloride polymeripation workers . In addition, vascular abnormalities such as pellcsls hepatis, possibly a pre-malignant lesion, may also be detected in the absence of biochemical ,`x abnormalities. (Author Abstract) 00005843 VINYL CHLORIDE PAGE 115 219 AU - Laumbach AD \ Wong JL Streips UN AD - Dept Microbiol and Immunol , Sch Med, Dept Chem, Univ Louisville, Louisville, KY 40201 TI - STUDIES ON THE MUTAGENICITY OF VINYL CHLORIDE METABOLITES AND RELATED COMPOUNDS (MEETING A5STRACT). SI - ICDE3/77/03900 SO - Third Intarnational Symposium On Detection And Prevention Of Cancer. 1976. LA - ENG AB - The mutagenic potential of several purified metabolites of vinyl chloride monomer (VCM) was determined by utilicing bacterial assay methods. First, a preliminary screen, the repair C25t using DNA repair deficient mutants of Bacillus subtilis uas performed, then the compounds were tested quantitatively for mutagenicity with Salmonella Typhimurium LT-2 strains obtained from D N Ames. From all the tested compounds the following were found to be mutagenic in the bacterial assays: chlorooxlrane (cnlorcethyleneoxide ), chloroacetaldehyde, chloroacetaldehyde hydrate, chloroacetaldehyde dimer hydrate, and chloroacetaldehyde trimer. In additional epichlcrohydrin (l-chloro-2,3 epoxypropane ), a related compound to chlorooxirane, uas weakly mutagenic in our assays. All of the above compounds specifically reverted the Salmonella tester strain TA 100, indicating base pair substitution type of mutations. A recombination repair deficient strain of B subtilis, NC-I, was specifically inhibited in growth by The VCM metabolites. However, several excision repair deficient strains and the wild type (repair-positive) strain were relatively unaffected. These experiments suggest that VCM metabolites elicit recombination repair, an error prone process, for correction of damage, epichlorohvdrin uas not reactive in these experiments, indicating that either eplchlorohydrin-induced lesions or the repair of these lesions differ from those caused by VCM metabolites. (Author Abstract) 220 AU AD TI SI SO LA AB Garro AJ ; Guttenplan JB I Mi Ivy P Mt. Sinai Sch Med, NY, NY 10029 VINYL CHLORIDE DEPENDENT MUTAGENESIS: EFFECTS OF LIVER EXTRACTS AND A FRCE RADICAL GENERATING SYSTEM (MEETING ABSTRACT). ICDB/77/03379 Third International Symposium On Detection And Prevention Of Cancer, 1976. ENG The relationship between vinyl chloride (VC) dependent mutagenesis and metabolic activation of VC by hepatic extracts uas examined. VC itself was observed to be mutagenic for Salmonella typhimurium and mutagenesis was enhanced by the presence of mouse or rat li^er extracts. The extracts prepared from mice pretreated .either with VC or the microsomal enzyme inducer, Aroclor 1254, did not produce any qre-ater stimulation of VC dependent mutagenesis Than extracts from untreated animals. These same extracts, however, differed markedly In their capacity to stimulate the mutagenic activity of d1 me ThyInitrosamine> a R&S 138936 14 00005844 VINYL CHLORIDE PAGE 116 compound which is converted To a mutagen by an NADPH-dependent microsomal mixed function oxidase. In contrast to what was seen with dimethyIniTrosamlne> the stimulatory effect of the liver extracts on VC mediated mutagenesis did not require NAOPH and was still evident in liver extracts in which the microsomal mixed function oxidase had been heat inactivated. Since VC polymerises by a free radical reaction mechanism and since free radicals are known to be mutagenic, the possibility That a free radical generating system would stimulate VC dependent mutagenesis was examined. Free radicals were generated by photo-excitation of riboflavin and it was observed that this system did stimulate the mutagenic activity of VC. We have concluded that the mutagenic effect of VC may involve a free radical process and that the stimulatory effect of liver extracts may not be due to engymatic activation of VC by a microsomal mixed function oxidase. (Author Abstract ) 221 AU - Anderson HA I Snyder J ; Lilis R . Selikoff IJ AD -MI. Sinai Sch Med. NY, NY 10029 TI - LEVELS OF CEA AMONG VINYL CHLORIDE AtJO POLYVINYL CHLORIDE EXPOSED WORKERS (NEETING A3STRACT). SI - 1003/77/03873 SO - Third Internetional Symposium On Detection And Prevention Of Cancer. 1976. LA - ENG AB - In 1965. the term careinoembryonic antigen (CEA) was first used to describe an antigen found in extracts of fetal gut and carcinoma of the digestive tract. The refinement of a rapid, highly sensitive radioimmunoassay for the detection of this antigen has made The test available for use on a larger scale. CEA was initially felt to be specific for entodarmally derived tumors. However. further studies have described significant CEA elevations in other malignancies and in some non-malignant inflammatory disorders. Cigarette smoking has also been demonstrated to have an effect on the CEA titer. Rather Than tumor specificity. CEA titers less than 20 ng/ml are now felt to reflect active disease processes, both malignant and nonmaiignant . Titers above 20 ng/ml are more indicative of an occult malignancy. Whether individuals with CEA Titers less than 20 ng/ml are at higher risk of developing a malignant disease has not been adequately evaluated. We are evaluating the use of the CEA titer as a possible method of identifying specific individuals at high rioX in occupational groups already known To ha>'e an increased risk of developing malignancies. One such group has been vinyl chloride and polyvlnwl chloride exposed workers. its ha>'e examined 1.177 workers from three VC/PVC polymerisation plants and 254 workers from a PVC extrusion plant manufaoturing PVC textile leather, obtaining respectively 1140 and 253 CEA titers. After removing the confounding effects of past medical illnesses, cigarette and alcohol use. the distribution of CEA Titers among the polymer 1 catlon workers was significantly different from the extrusion grouo and an unexposad comparison group. The extrusion group was not significantly different from c 00005845 VINYL CHLORIDE r PAGE 117 cc the unexposed group, CEA titers also correlated well with other VC/PVC related changes such os liver chemistry abnormaliTies and c chepato-spienomegally. Our investigation demonstrates that occupational exposures in VC/PVC polymerisation plants can cause elevations in the CEA titers of otherwise healthy individuals. The exposures experienced by the extrusion workers did not appear c to have a similar effect on the CEA titer distribution. Prospective follow-up is necessary before conclusions con be drawn concerning the relative health risks of these two 33 occupational groups and the usefulness of the CEA titer as an indication of possible increased risk. (Author Abstract) CO 222 AU AD TI SI Espinosa E Univ Louisville. Sch Med. Louisville. KY 40202 IMMUNOPATHOLOGIC OBSERVATIONS IN LIVER ANGIOSARCOMA ABSTRACT ). ICDE5/77/03S72 (MEETING GJ OO <> GO SO Third International Symposium Oil Detection And Prevention Of c Cancer. 1976. LA ENG AB Two patients with liver angiosarcoma and ten with liver dysfunction with fibrosis, all with histories of industrial vinyl chloride exposure, were tested for anti-tissue serum antibodies and for circulating tissue antigens associated with liver damage. Tumor-associated antigens and bound immunoglobulins were searched for in the anqiosarcomatous tissue. No significant levels of serum autoantibodies to nuclei, mitochondria, smooth 1 muscle, other normal human and rat tissue components, and liver tissue from rats intoxicated with vinyl chloride could be demonstrated by indirect immunofluorescence. Liver-damage-related circulating tissue antigens, with or without liver specificity, were not detected. Immunoqlcbulin G was found bound to c. angiosarcomatous tissue but not to adjacent liver tissue or to liver tissue from normal controls. Antigenic analysis of angiosarcomatous tissue by immunodiffusion using anti-angiosarcoma rabbit serum revealed an antigen in angiosarcoma not detected in normal liver but found to be present in normal spleen and lung. This antigen was susceotible to Pronase and trypsin, relatively thermolabile. affected by acid pH, and precipitated at 20 to 30/ saturated ammonium sulfate and at 50 to 70/ ethanol concentration. In conclusion neither anti-tissue antibodies nor circularinq tissue antigens associated with liver damage were detected in patients with liver Lc. angiosarcoma or other liver abnormal i 11 es ('elated to vinyl chloride exposure. In angiosarcomatous tissue, bound immunoalobulin G and an antigen not detected in normal liver were demonstrated, (Author Abstract) L 00005S46 VINYL CHLORIDE PAGE ne 223 AU - Kupe'nella CE I Tamburro CH AD - Univ Louisville, Louisville, KY 40203 TI - URINARY AMO TISSUE GLYCOSAMINOGLYCAN PATTERNS IN ANGIOSARCOMA AND OTHER VINYL-CHLORIDE-EXPOSURE-ASSOCIATED LIVER INJURY (MEETING ABSTRACT). SI - ICD3/77/03S71 SO - Third International Symposium On Detection And Prevention Of Cancer. 1976. LA - ENG AB - Both the presence of certain cancers and disorders of connective tissue metabolism are accompanied by alterations in urinary glycosaminoglycan patterns. Because both fibrosis and angiosarcoma of the liver have been connected to vinyl chloride exposure, ue evaluated glycosaminoglycan patterns associated with vinyl chloride injury to assess the usefulness of The patterns in early detection. Urines from fifty paTients were analyzed for glycosamlnoglycans. These included Two angiosarcomas, ten cases of viny1-cnloride , work-related, liver injury other than angiosarcoma, and cases of hepatitis, cirrhosis, other cancers, metabolic disorders of the liver, and normal controls. Examined both hi sTochemically and biochemically for glycosaminoglycans were liver tissue samples including two liver angiosarcomas--both tumor tissue and non-tu:nor tissue--five normal livers, and two cirrhotic livers. The urine of patients with vinvl chloride-associated liver injury other than angiosarcoma exhibited a characteristic shift toward the chondroitin sulfates. Tissue analysis revealed up to four-fold greater concentrations of hyaluronic acid and heparin in tumor tissue than in adjacent non-Tumor tissue, Angi osarccmiatous livers exhibited greater concentratione of glycosaminoglycans than were found in normal livers. Biochemical results confirmed histochemical studies. One patient whose urinary glycosaminoglycan excretion patterns were followed for a two-week period prior to death from liver failure exhibited a pulse of glycosaminoglycan excretion peaking ten days prior to death. Several of These observations appear to have diagnostic significance. (Author Abstract) 224 AU AD TI SI SO LA AS Tamburro CH I Kupchelia CE ; Greenberg R - Cancer Ctr, Univ Louisville, Sch Med, Loisvllla, KY 40202 PROSPECTIVE MEDICAL SURVEILLANCE PROGRAM FOR DETECTION AND PREVENTION OF INDUSTRIALLY RELATED CANCER (MEETING ABSTRACT). ICOO/77/O 3870 Third Internationa1 Symposium On Detection And Prevention Of Cancer. 1976. ENG Most industry related cancers have been recognized re trospec T l vely as illustrated by vin^l chloride (VC) induced hepatic anqlosarcoma. The discovery of This rare liver cancer among VC polymerizafton workers led to The development of a prospective industrial medical sur'-ei 1 lance cancer control program. This program is designed To identify, at The earliest possible tine, potentially harmful cne,heals and to reduce c c c ( ( I, v '\ V. -r, (. , (. V. 0QQ05897 VINYL CHLORIDE PAGE 119 2.75 AU AQ TI SI SO LA AB 226 AU AO TI SI SO LA AB exposure related injuries. This is being accomplished by an early evaluation system relating exposure to screening studies. Screening and detection methods include biochemical, radiological, radioisotopic and immunological studies. These are applied to all members of the high risk population in. as far as possible, an economical, safe and effective method and without significant interference with industrial function or employment of workers. This prototype program includes a data bank for ongoing systematic collection and evaluation of all data obtained; it is appliable to any industrial complex utilizing potentially carcinogenic chemicals. The data bank includes an early warning system, an exposure index system and an epidemiological program. Also included is a concomitant educational program for both industry and labor concerning the new concept of preventive medical surveillance requiring voluntary participation by individuals who, for all intense purposes. are medically and physically well. Finally, this program is designed with diagnostic, therapeutic and rehabilitative components for individuals discovered to have industrial related precancerous lesions or cancer and for The adaptation to either small (250-350) or larger (1,200-2,000) industrial complexes dealing with potential carcinogenic chemicals. (Author Abstract) Hoffmann D 5 Schmeitz I Meet SS Brunneman KD Wynder EL Amer Health Found, Valhalla, NY 10575 VOLATILE CARCINOGENS OCCURRENCE, FORMATION AND ANALYSIS (MEETING ABSTRACT). ICDB/77/03700 Third Internetional Symposium On Detection And Prevention Of Cancer. 1976. ENG In certain occupational as well as general respiratory environments , we can detect known human and/or animal carcinogens. The occurrence and formation of such respiratory carcinogens will be discussed for nickel carbonyl, arsine, nltrcoleflns , nitrosamlnes, vinyl chloride and hydrazines. Special conslderation is given to the detection of minute amounts of these agents in man's respiratory environment, (Author Abs trac t ) Bartsch H International Agency for Research on Cancer, Unit of Chemical Careinoqenesis , 150 cours Albert Thomas. 69003 Lyon, France. TISSUE MEDIATED MUTAGENICITY AND CARCINOGENESIS (MEETING ABSTRACT ). ICDB/77/03775 Third International Symposium On Detection And Prevention Of Cancer. 1976. ENG Studies on the mechanism of the organotropic action of chemical carcinogens prowide better criteria for an extrapolation from animal data to t ui.ior l gen t c processes in man if human tissues or R&S 1 3 8 9 3 8 c c c t c v. L L L 00005348 VINYL CHLORIDE PAGE 120 fluids are included in the experimentation. For many chemical carcinogens i the generation of specific ultimate reactive metabolites by one or multi-step activation processes and their subsequent covalent binding to information controlling cellular macromolecules is thought to induce mutagenesis and carcinogenesis. Mutagenicity assays permit a quantitative comparison of the engymic capacity for carcinogen activation in animal and human target and non-target tissues. Tissue mediated mutagenicity of vinyl chloride and certain N-nitroso compounds uas measured using S typnimurium strains in agar-plate assays containing 9.000 x g liver or lung fractions from untreated rats or from humans, either by exposing the Petri dishes to gaseous mixtures of the test compound with air (vinyl chloride. 20X by volume for 6 hours) or by incorporation of the substrate into the soft agar (0.5-10 microMol of N-nitrosamines per plate). The relative capacity of tissues from human individuals (represented by A. 0. C. D. X. Y and Z) to convert various substrates into mutagens uas as follows (rat = 100); vinyl chloride! A. B. C. 0(275. 101, 93. 80); N-nitroscmorpholine: A, B, C. D (90. 50. 40, 30); N-nitrcsopyrrolidine: Z, X, Y (115. 90, 50); N-nitrosopiperidine; Z, Y. X (215, 135. 85); .'1-ni troso-N `-me tnylpi perac ine: Z, Y, X (3,200, 1800, 400 ). Liver fractions from untreated rats and human specimens Z and Y were Unable to convert N-nitrosodl-n-propylamine and N-nitroso-di-n-buty1-amine into mutagens. With the latter two compounds a tissue mediated mutagenicity was detected with liver fractions from phencbarbitone pretreated rats. With the hepato-carcinogen N-nitrosomorpholine as substrate, no mutagenic action uas detected after incubation with rat and human lung fractions. The data indicate That human liver specimens can convert some N-nitroso compounds and vinyl chloride into electrophi1ic mutagenic metabolites as efficiently as rat tissues. Engymic capacity of different human specimens varied 2 to 8-fold. Analysis of a larger number of human individuals by this Technique may eventually allow a correlation between genetic background or induced state of carcinogen activating enqymes and the individual susceptibility towards certain careinogens. Organ specific activation of chemical carcinogens appears To be a prerequisite but not a finally determining factor for The induction of Tumours in experimental animals and probably man: examples will be presented from the in vitro studies which support the concept that, for certain carcinogens, the formation of short-lived ultimate metabolites in situ can be correlated with the site of tumour formation. (Author Abstract) 227 AU " Elmore JD ; Wong JL ; Laumbach AD Strelps UN AO - Department of Chemistry, University of Louisville and Department of Microbiology, University of Louisville, Louisville, Ky. 40203 (U.S.A.) TI - VINYL CHLORIDE MUTAGENICITY VIA THE METABOLITES CHLOROOXIRANE At JO CHLCROACETALDEHYDE MONOMER HYDRATE. SI - ICDB/77/02416 SO - Biochirn Biophys Acta; 442(31:405-419 1976 r-V-V- c c ( ^-55* Vi-^A'f-J.L/*'. *' - I ^.-i-CaO jf-lv.;;, ,-f> 00005349 VINYL CHLORIDE PAGE 121 LA - ENG AB - Mutagenicity tester- strains of Bacillus and Salmonella were used to assay vinyl chloride in nutrient broth at a practical concentration level. Also screened without exogenous activation were seven potential metabolites of vinyl chloride in their pure forms as well as the related epichlorchydrin. Chlorooxirane> chloroacetaldehyde> chloroacetaldehvde monomer hydrate, chloroacetaldehyde dimer hydrate, chloroacetaldehyde trimer, and epichlorohydrin produced significant mutagenic activity in Salmonella typhimurturn strains sensitive to base-pair mutation. A recombination repair deficient strain of Bacillus subtilis was inhibited in growth by these compounds. whereas excision repair deficient and wild type strains of Bacillus subtills were relatively unaffected. Cn the basis of these assays a working hypothesis for the vinyl chloride carcinogenesis mechanism is proposed which involves chlcrcoxirane and chloroacetaldehyde monomer hydrate as the ultimate carcinogenic metabolites of vinyl chloride. (Author Abstract) 223 AU - Grand KG ; Bucen LC ; Brand I AB - Department of Micrcbio1ogy> Medical School. University of Minnesota, Minneapolis, Minnesota 55455 TI - MULTIFHASIC INCIDENCE OF FOREIGN BODY-INDUCED SARCOMAS. SI - ICDB/77/02332 50 - Cancer Res ; 36(10):3531-3633 1976 LA - ENG AB - Single or multiple plastic films (unplasticired vinyl chloride vinyl acetate copolymer) of different sices and shapes were implanted so in female CBA/H and C3A/H-T6 mice. Tumor incidence increased and accelerated with increased total surface area of multiple implants cr with increased sice of single implants. Tumor distribution curves ower time were generally multiphasic. The profiles changed in proportionate relation To implant sice. These findings indicate class differences between tumors according to latency. Since latency is known to be a predetermined characteristic of foreign body-induced tumors, class differences seem to exist at the originator cell level, reflecting diversity of intrinsic carcinogenic factors. (Author Abs trnct ) 229 AU - Bartsch H ", Malaveille C ", Barbin A I Blanche G ; Montesano R AD - Internalional Agency for Research on Cancer, 69003 Lyon, France TI - ALKYLATING AMO MUTAGENIC METABOLITES CF HALOGENATEO OLEFINS PRODUCED BY HUMAN AND ANIMAL TISSUES. 51 - ICD3/77/Q3B74 SQ - Pros Am Assoc Cancer Res; 17:17 1976 LA - ENG AB - S typhimurium TA100 In the presence of a 9,000 x g sup of PB-pretreated mice was exposed to gaseous mixtures of I-IX/air. Nutation rates (his**+ rev co I cn i e s/u.nol/ hr/plale) Taken 'rom linear regions of dose and time dependent assays either with or without (figures bracketed! NAQP>**+, were as follows: I: Vinyl acetate 0(0)`, Ii: 1.1-d i f luor e thy iene 0(0); III: R&S 138940 00005850 VINYL CHLORIDE PAGE 122 230 AU AD TI 51 SO LA AB 231 AU AD TI SI SO LA AD trichloroethylene 0(0); IV: vinyl chloride 6(2); V: 1.l~dichlorceThylene 15(1); VI: vinyl bromide 26(9); VII: 2-chlcro-l>3-butadiene 51(9); VIII: 1-chloro-l>3-butadinj 157(31); IX`- 3,4-dichlorobutene-1 490(345). Liver fractions from 3 human biopsies converted compounds IVi VI. VII into mutagens with an activity comparable to those of untreated mouse liver. 1>4-Dichloro-butane-2 was mutagenic for TA100 and liver microsomal fractions from mouse or humans enhanced the mutagenic effect. Epoxide formation from vinyl chloride and vinyl bromide by mouse liver microsomes was demonstrated by traoping with 4-nitro (4-bengyl) pyridine. Using the same systemi compound VII yielded an alkylating intermediate while compounds II. Ill and V did not. Thus, the conversion of these compounds to potential carcinogenic metabolites by human and animal tissues has been demonstrated. (Author Abstract) Whelan JG ; Creech JL ; Tamburro CH Department of Radiology. St. Anthony Hospital. 1313 St. Anthony Place. Louisville. Ky. 40204 ANGIOGRAPHIC AND RADIONUCLIDE CHARACTERISTICS OF HEPATIC ANGIOSARCOMA FOUND IN VINYL CHLORIDE CORNERS. ICDB/76/155S3 Radiology; 113(31:549-557 1976 ENG Hepatic anqiosarcoma. recently discovered in a large series of vinyl chloride workers. demonstrates characteristic angle-graphic and radionuclide changes. Tumors exhibiting central hypovascularity with puddling are usually surrounded by a peripheral stain. A negative peripheral defect is demonstrated on hepatic scan. Healing hepatic infarction secondary to wedged hepatic venography creates a false-positive lesion on angiography similar to angiosarcoma. Splenomegaly and systemic venous hypertension develop in a number of these patients. Colvin Ft ; Brundrett RB I Cowens M ; Jardlne I Ludlum DB Johns Hopkins Oncology Center, B2-South, Baltimore City Hasps.. 4940 Eastern Ave. . Baltimore. t'.D 21224) A CHEMICAL BASIS FOR THE ANTITUMOR ACTIVITY OF CHLOROETHYLNITROSOUREAS. ICCB/77/22923 Elcchem Pharmacol; 25(61:695-699 1976 ENG Studies are reported that are consistent with the hypothesis that chloroothyl carbonium ion generation is responsible for The cytotoxicity of chlcrcethyln1trosoureas against murine L1210 leukemia cells. The decomposition products of 1-chloroathvi-l-nitrosourea (CNU ) . 1.3- bis-chioroothy1-1-n1trosourea (BCNU ). 1-ch1orce thy 1-3.3-dime thy 1 -1-n1trosourea (dMCNU). 1.3- bIs-fluoroethy1-1-nitrosourea (BFMU). and 1-chlcrcethy1-3-cycionexy1 -1-ni tresourea (CCNU) were analyzed. CCNU. ECNU. and CNU all yielded vinyl chloride, acetaldehyde. chloroethanoL and dtcnioroethane . BFNU yielded the Corresponding 00005851 VINYL CHLORIDE PAGE 123 232 AU TI SI SO LA A3 233 AU AD TI SI SO LA A5 fluoro compounds fluoroethanol and vinyl fluoride, as well as acetaldehyde. Evidence is presented that These products are derived -from an intermediate haioathyl carbonium ton. Decomposition of dMCNU did not yield vinyl chloride, chloroethanol, or dichloroethane, but it did produce acetaldehyde along with smaller quantities of two other uni dentifiable volatiles. The decompos i t i on rate of CN'J in aqueous soln proceeds rapidlyj that of CCNU less so. and that of diTCNU very slowly. Both BCNU and CNU were very cytotoxic to L1Z10 cells in vitro at 25 nanomoles (nmol )/.nl . but cUCN'J had no effect on the viability of these cells at concentratioos to ICO nmol/ml. (20 Refs) Selikoff IJ CARCINOGENS IN THE HUNAN ENVIRONMENT. CARC/77/049A9 Advances in Cancer Surgery. Na]arian JS. Delaney JP, ed. New York. Stratton Intercontinental Medical Book Corp, 1976. ENG Estimates indicate that 60X-95/C of human cancer is due to environmental causes. Associations have been demonstrated between bladder cancer and aromatic amines, scrotal cancer and chimney ash, lung cancer and cigarette smokinq, and bladder cancer and aniline dyes. In most cases, There is a long latent period between onset of exposure to an environmental carcinogen and first, clinical evidence of disease. Prospective cohort studies in asbestos workers have repeatedly shown an excess of deaths due to cancer (bronchogenic cancer, mesothelioma, gastrointestinal cancer). Less than 3 mo exposure to asbestos can result in an important increase in cancer risk. However, excess deaths due to bronchogenic cancer among asbestos uorkers occur only amonq cigarette smokers, the result of multiple factor interaction. Cigarette smoking is also associated with increased lung cancer amcnq uranium miners, and occupational exposure to bencene with increased risk of leukemia among survivors of the Hiroshima bombing. Dissemination of asbestos from industrial sources is also associated with a significant cancer risk; pleural plaoues and mesothelioma are increased in persons living with asbestos workers or near asbestos mills, and asbestos bodies are routinely found in lunq smears from routine autopsies. Potential causes of cancer include the contamination of Lake Superlor by Tactonita tailings and the dissemination of vinyl chloride into the general environment, (No references) Lassiter 07 Occupational Safety and Health Admin., US Dept. Labor, Washington, DC 20210 CAGE STUDY 3= VINYL CM LOR IDE--BEST AVAILABLE TECHNOLOGY. ICDD/77/21773 Ann MY Acad Sc i ; 271H76-173 1976 ENG Several tumors nave been directly linked with occuoational e>posure To various carcinogens. Guidelines that determine policy for the regulation of occupational carcinogens, as set forth by 00005852 VINYL CHLORIDE PAGE 124 The Occupational Safety and Health AdminisTration, are quoted and commented upon. Any regulations should ideally assure minimum risK of cancer To the employee while allowing The manufacturer To remain competitive in a situation in which costly controls must be instituted to restrict exposure. (0 Refs) 234 AU - Lloyd J'd AD " Natl. Inst. Occupational Safety and Kealthi Public Health Service Center Occupational Safety and Health, Rockville, MO 20352 TI - CANCER RISK AMONG WORKERS EXPOSED TO CHLCROPREHE. SI - ICDB/77/21763 SO - Ann NY Acad Sci! 271=91"93 1976 LA - ENG A3 ~ The limited information on the potential carcinogenicity of chioroprene is discussed, along with some recently initiated assessments of this carcinogenicity. Chioroprene is used primarily as a monomer for The manufacture of neoprene synthetic rubber (introduced by duPont in 1931), No excess of any disease related to vinyl chloride, including angiosarcoma of the liver, has been observed at duPont upon investigation of employees' records. Although a recent increase in deaths from lung cancer in this population was observed, further investigation revealed no relationship to work assignment. Two studies of approx 45,000 chioroprene workers in Russia are also discussed with respect to the development of lung and skin cancer in these individuals. (2 Refs ) 235 AU - IARC Working Group TI - BENZYL CHLORIDE. SI - ICDO/77/21735 SO - IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Cadmium, Nickel, Some Epoxides, Miscellaneous Industrial Chemicals and General Considerations on Volatile Anaesthetics. International Agency for Research on Cancer, Lyon France, Vol 11, 1976. LA - ENG AD - The chemical and physical data', production, use, occurrence, and analysis! and biological data relevant To the evaluation of carcinogenic risk to man of benzyl chloride are described. Approx 65X-70X of the total U5 production of benzyl chloride Is used as an intermediate in The manufacture of butyl benzyl phthalate, a vinyl resin plasticiser. Of 14 14-wk-old BO rats qiven weekly sc injections of 40 mg/kg body wl benzyl chloride in arachis oil for 51 wk (total dose, 2.1 q/kg), 3 developed local sarcomas uitnln 500 davs. Of eight rats gi'-on 30 mg/kq weekly for 51 wk (Total dose, 3.9 g/kq), six developed local sarcomas by 500 days. Lung metastases were observed in most animals. The injection of arachis oil alone did not produce local tumors in control rats. I 13 Refs ) ii ( 00005053 VINYL CHLORIDE PAGE 125 ( 236 AU - Smith FH ; Crossley IR ; Will isms DM AD - Dept. Msdicine> Llandough Hosp., Penarth, South Glamorgan. Kales C II - FCRTAL HYPERTENSION IN VINYL-CHLORIDE PRODUCTION WORKERS. SI - ICOB/77/21715 SO - Lancet; 2t7936) :602-609 1976 LA - ENG AB - Portal hypertension was observed in seven patients who had been c involved in the production of vinyl-chloride monomer (VCM) for 9-15 yr. The patients were 36-57 yr old at the time of presentation, and they had been exposed to VCM gas for 9-15 yr. Four had hematemesis from esophageal varices, and tuo of these had had prior Splenomegaly and thrombocytopenia. At laparotomy, the liver appeared finely nodular and cirrhotic, but biopsy revealed a noncirrhotic fibrosis in four patients and slight fibrosis in tuo. Of the four patients uho bled from the (. esophageal varices, one died 2 mo after an esophageal transection from hepatic failure and Escherichia coli septicemia. The other three have done extremely well after end-to-side portacaval shunts. They have survived so far for 3, 6, and 0 yr, c. respectively. Kith improvements In technology, workers should no longer be exposed to VCM gas levels > 5 ppm. (15 Refs) 237 AU - Uatanabe PG j Hefner RE ; Gehring PJ AO - Toxicoloqy Res. Lab., Health and Environmental Res. 1603 Building, Dou Chemical Company, Midland, MI 90690 TI - VINYL CHLORIDE-INDUCED DEPRESSION OF HEPATIC NON-PROTEIN SULFHYDRYL CONTENT AND EFFECTS ON BROMOSULFHALEIN (BSP) CLEARANCE IN RATS. SI - ICD3/77/21633 SO - Toxicology", 6(1) '-1-0 1976 LA - ENG AB - The effects of acute inhalation exposure to vinyl chloride on the non-protein sulfhydryl content in male Sprague-Dauley rat liver were studied. The rats were exposed to 2,000, 1,000, 250, 150, 50, or 10 ppm. Exposure to 2,000 ppm resulted in a progressive depression of hepatic non-protein sulfhydryl content reaching 33X within 2 hr, 97X after 9 hr, and 62K after 7 hr. An apparent max depression was observed after 9 to 5 hr of exposure to vinyl chloride at 1,000, 250 or 50 ppm. Depression after- 7 hr exposure to 50 ppm was inconsistent. Exposure to 1,000 ppm vinyl chlo-lde did not alter the serum clearance of bromosulphalein. (25 Refs) 233 AU AD TI SI SO LA AB - Potter HR - No affiliation given - VINYL CHLORIDE--PART I. - ICD3/77/20590 - Food Cosmet Toxicol; 19(9)1397-399 1976 - ENG - Workers involved in the production of polyvinyl chloride (PVC) are exposed to alf-erinq levels of ''ln''l chloride monomer, the greatest exposure being to Those involved in cleaning the polymerioation autoclaves. These exposures can lead to c c c " fiT'S'-Tvi-y- A- --jw* * cf f,;'d ,-.,i*- a 00005354 VINYL CHLORIDE PAGE 126 239 AU AD TI SI SO LA AS 240 AU AD TI SI SO LA AD acro-osteolysis end to angi osarcoma . Less severe exposure can occur during The subsequent processing or PVC> and alThougn clinical changes wav not be manifesti patholoqicol Tests detect effects characterisTic of clinically advanced cases. An association of PVC manufacture wt th hemangiosarecm.a was first suspected as a result of several deaths in the industry from this otherwise rare type of liver Tumor. Swstematie tests carried out in an attempt To relate liver abnormality to VC exposure levels revealed two cases of angiosarcoma and nine cases of portal fibrosis in 274 PVC production workers, and two cases of porTal fibrosis in 909 workers not associated with PVC production in a Louisville plant, (no refs) Andrews AW ; Zawistowski ES ; Valentine CR Frederick Cancer Res. Center, Frederick, MO 21701 A COMPARISON OF THE MUTAGENIC PROPERTIES OF VINYL CHLORIDE AND METHYL CHLORIDE. ICD3/77/20359 MuTaf Res! 40(3)1273-276 1976 ENG The mutagenic properties of vinyl chloride and methyl chloride were compared in Salmonella Typhimunum tester strain TA 1535. A level of 23k methyl chloride was toxic to the bacteria! an inhibitory level of vinyl chloride was not reached. With the exception of 0.5k methvl chloride, all concentrations of both chemicals (0.4-15.4k vinyl chloride and 0.5-23k methyl chloride) caused a significant number of revertants. Decause of the similar properties of these gases and because vinyl chloride is a mutagen/cai'cinogen, methyl chloride should be considered and investigated as a possible carcinogen. (9 refs) Fishbein L Natl. Center Toxicological Res., Jefferson, AR 72079 INDUSTRIAL MUTAGENS AND POTENTIAL MUTAGENS. I, HALOGENATED ALIFHATIC DERIVATIVES, ICCB/77/20357 MuTat Res; 32(3/4 ):267-307 1976 ENG Many Industrially and environmentally significant haloqenated aliphatic derivatives are discussed in terms of their use patterns, residue levels and distribution patterns, chemical and physical properties, and metabolism. Haloqenated hydrocarbons are discussed in general, while mutagenic and potential mutagenic haloqenated aliphatic derivatives are specifically discussed. These derivatives include vinyl chloride, vinyljdene chloridei Tr i chlor oe thy lene , te trachloroeth'-lsne , ethylene dichlcrlde and dibromide, ch lor opr'One , chloroform, carbon Te Tr ach lor I de , fluorocarbons, epichlorohyjrin, 2-chloroethanol . and haloethers. (242 re fs 1 ' '""'........................ {' it c 0Q005855 VINYL CHLORIDE PAGE 127 R&S 138946 c c W> / K. 'Ai .'vr* 74 291 AU - Haltoni C AD - Inst. Oncology and Tumour Centre, Bologna> Italy TI - FRECURSOR LESIONS IN EXPOSED POPULATIONS AS INDICATORS OF OCCUPATIONAL CANCER RISK. SI - ICDS/77/20229 SO - Ann NY Acad Sci ; 271'.999-997 1976 LA - ENG AB - Occupational cancer risk was monitored on two separate occasions by cytological examinations. The first involved three groups of workers who were known or suspected of being at risk for developing pulmonary cancer-- chromium industry workers, vinyl chloride-polyvinyl chloride (VC-PVC) industry workers, and workers at different chemical factories not directly involved in the production or use of known carcinogens. The results of sputum cvtology shewed that the incidence of abnormal cases was higher than expected among chromium and VC-PVC workers, even when compared to populations of heavy smokers. The second occasion was the cytologic investigation of urinary sediments m a group of Italian dve stuff factory workers exposed to aromatic amines and, therefore, at risk for urinary Tract tumors. A high incidence of 1V. for Class III cytology and over was obtained. These results indicate both the value and need for cytologic examinations as preventive measures that can be taken to overcome occupational risks of carcinogenesis, (no Refs) 292 AU - Kappus H ', Bolt HM ; Buchter A ; Bolt U AO - Inst. Toxicology, Univ. Tubingen, W, Germany TI - LIVER MICROSOMAL UPTAKE OF [**19C] VINYL CHLORIDE AND TRANSFORMATION TO PROTEIN ALKYLATING METABOLITES IN VITRO. SI - IC0B/77/201G9 SO " Toxicol Appl Pharmacol; 37(3)1961-971 1976 LA - ENG A3 - Microsomal uptake and irreversible binding of vinyl chloride (VC) radioactivity were determined in l-llstar rat liver microsomes incubated with tl 2-**19C) vinyl chloride, gas in an all-glass vacuum system. Both the uptake of VC by microsomes and the alkylation of proteins by VC were dependent on incubation time, enzymatically active microsomes, NAOPH, oxygen, and the partial pressure of VC in the atmosphere, and couid be inhibited by carbon monoxide. Incubation in the presence of NADPH resulted in a 10-x increase in The amount of VC Taken up by microsomes. Uptake of VC by albumin solutions and liposomal suspensions was one-third to one-fourth of The microsomal uptake in the absence of NADPH. Addition of glutathione and cytoplasmic fractions to microsomal Incubations with NACPM resulted in an Increase in VC, uptake and a decrease in protein alkvlaticn by VC metabolites. Trichloropropene oxide had no effect on microsomal VC uotnke but caused a 2-fcld increase in the amount of protein bound by VC me t a.bo 1 i t es . The results are consistent with The involvement of chlcroethylene oxide as the primary microsomal metabolite of VC capable of reacting with proteins. (31 Refs) c c c c. L 00005856 VINYL CHLORIDE PAGE 128 243 AU - Duck. BW ', CarTer JT AD - Occupational Health Unit> B.P. Res. Centre, Sunbury-on-T'names > Middlesex, England TI - VINYL CHLORIDE AND MORTALITY? (LETTER TO EDITOR). SI - IC0B/77/20159 SO - Lancet; 2(7978 ) s195 1976 LA - ENG AB - Dr. Joan Davis has pointed out the value of additional tabulation of deaths more than 15 yr after first exposure of vinyl chloride in those exposed for at least 15 yr. The observed vs expected deaths were 25:29.15 for all causes 1 8:6.51 for all cancer, 9:1.98 for digestive system cancer, and 3:2.96 for lung cancer. An age-standardiced death rate can be calculated only if the age structure of the population is known. (2 Refs) 299 AU - Kappus H ", Kaufmann R *, Appel KE ) Bolt HM AD - Inst. Toxicology, LViiv. Tubingen, Wllhelmstr. 56, Tubingen, W. Germany TI - COVALENT BINDING OF #*19C-VINYL CHLORIDE TO FROTEINS AND NUCLEIC ACIDS IN VITRO AND IN VIVO (MEETING A35TRACT). 51 - ICDB/77/20020 SO - Arch Pharmacol! 293(5uppl): R 69 1976 LA - ENG A3 - When rat liver microsomes were incubated in atmospheric air containing C19-vinyl chloride (VC) gas, a max of 0.5 nanomoles of VC metabolites was covalently bound to microsomal protein. RNA and sulfhydryl-containing proteins bound VC metabolites when added to the incubation medium. All these microsome binding reactions could be inhibited by 1-naphthyl~9(5 )-imidacole and CO. The addition of glutathione plus cytoplasmic fractions decreased the covalent binding of VC metabolites to microsomal proteins while the total metabolism of VC during incubation was enhanced. There was a two-fold increase in the covalent binding of VC metabolites to microsomal proteins when tr 1 chiorcpropene ox-ide was in the medium. The results support the concept that chloroethylene oxide formed by microsomal enoymes via an epoxidation step is involved in covalent binding of VC to proteins. After exposure of rats to C19-VC gas, VC-derlved radioactivity incorporated into proteins was mostly detected in the liver, lung, kidney, and spleen. VC radioactivity was also incorporated into DMA and RMA isolated from rat liver. These results support the view that VC-lnduced care 1 nogen 1city is caused by the alkylation of nucleic acids and/or' proteins by a reactive metabolite of VC. (0 Refs) 00005857 VINYL CHLORIDE PAGE 129 c 295 AU - Wagoner JK ; InfanTe PF ; Saracci R AD - Div. Surveillancei Hazard Evaluations and Field Studies. Natl. c Inst. Occupational Safety and Health. Cincinnati. OH 95202 TI - VINYL CHLORIDE AND MORTALITY? (LETTER TO EDITOR). SI - IC0B/77/19929 SO - Lancet; 2(7978):199-195 1976 LA - ENG AB - The article by Duck on a decreased risk of death with increasing exposure to vinyl chloride is discussed. If. in this study, one selects a subgroup of workers by the fact that they have achieved 15 yr experience exposure, then none of these workers could have died before the 15th anniversary. Information on risk of dying can only come from the number of man years at risk and the number of deaths after 15 yr. When this factor is corrected, the death rate tends to increase with increasing duration of exposure. This (. example of misallocation of person years at risk, the resultant erroneous conclusions, and subsequent reference to these conclusions demonstrate the need for standardization of data handling techniques for cohort mortality studies. (13 Refs) c ?96 AU - Fishbein L TI - ATMOSPHERIC MUTAGENS. SI - CARC/77/09263 f SO - Chemical Mutagens. Principles and Methods for Their Detection. Hollaender A, ed. New York. Plenum Press, vol. 9, 1976. LA - ENG AB - The source and effect of atmospheric mutagens on man are discussed. Various pollutants are the products of man's own waste: sulfur oxides, nitrogen oxides, polynuclear aromatic hydrocarbons, peroxyacyl nitrates and miscellaneous oxygenated derivatives. Many of these compounds, such as banco (a)pyrene and dlbenzanthracene. are mutagenic. Drastic disturbances in respiratory function have been attributed to ozone, and a variety of studies have indicated that it is a general mutagenic agent. Various halogenated hydrocarbons with mutagenic properties have now been located throughout the world. These hydrocarbons include fluorccarbons , vinyl chloride, trichloroethylene, tetrachloroethylene, carbon tetrachloride, miscellaneous halogenated hydrocarbons> and bromoalkanes. Fluorine, another mutagen that is worldwide in distribution . is prevalent in urban settings. Studies have shown the mutagenic potential of sodium fluoride in a variety of female mammalian qerm cells. Other mutagenic compounds that are discussed are pesticides and related V compounds (DDT and its metabolites, dichlorvos, formaldehyde and ethylene oxide) and polychlorinated biphenyls and aerosols (lead, mercury). Information is sparse or lacking on many of these mutagens and on aspects of their transport, residence times, and stability, The fate and mutagenic hazard to man of many of these compounds, particularly halogenated hydrocarbons . is speculative. (606 Refs) OOOOS858 VINYL CHLORIDE PAGE 130 247 AU TI SI SO LA AS Hoffman D Uynder EL ENVIRONMENTAL RESPIRATORY CARCINOGENESIS. IC03/77/19233 Chemical Carcinogens. Searle CEi ed. Washington DC, American Chemical Society, American Chemical Society Monograph 173, 1976, ENG 1 Environmental respiratory carcinogenesis is discussed. The topics include industrial carcinogjns, radioactive aerosols, arsenicals, chrcml urn, nickel, ccke oven efrluonts, chloromethvl ethers, vinyl chloride, and nitrosaminas. Air pollution is discussed in terms of epidemiological considerations, laboratory studies, sources for atmospheric carcinogens, indoor pollution, and reduction of atmospheric carcinogens. Tobacco smoke is discussed in terms of some epidcmiologlcal observations, characteristics of tobacco smoke, experimental tobacco careinogenesis, and reduction of tumor 1genlcity . (148 refs) 248 AU AO TI SI SO LA A3 Shahin MM Dept. Genetics, Univ, Alberta, Edmonton, Alberta T6G 2E9, Canada THE NCM-NUTAGENICITY AND -RECCN3IN0GENICITY OF VINYL CHLORIDE IN THE ABSENCE OF METABOLIC ACTIVATION. ICD3/77/1S392 Mutat Rest 40(3)1269-272 1976 ENG The ability of vinyl chloride to induce reversion and mitotic recombination in the yeast Saccharomyces cerevisiae was investigated. Strain 05 was chosen for study of the induction of recombinational events and XV105-19C was chosen for reversion induction in mutants. Negative results were obtained for mutagenicity and recombinocenicitv of vinyl chloride. Vinyl chloride had no effect on viability, even at a conccntration as high as 0.55k and treatment up to 43 hr. The results demonstrate that vinyl chloride is not mutagenic or recombinogenic in yeast under those experimental conditions. (7 refs) 249 AU AD TI SI SO LA AB Davis W ; Mai torn C International Agency for Research on Cancer, 150 ccurs Albert-Thomas , 6 9008 Hvon , France BIOLOGICAL CHARACTERIZATION OF HUMAN TUMORS. ICDB/77/10325 Ad Tumor Pi-ev Detect Charact", 3:1-424 1976 ENG Lectures and papers presented at the Sixth International Svupos i uni on the Biological Char ac ter l rat I on of Human Tumors, Copenhagen, May 13-16, 1975, are grouped into chapters covering the biochemical Guidelines in cancer chemotherapy (17 papers ) , cC'noarl sons of classical and modern techniques for the charactor Iration of turners (5), the careinogen IcIty of vinyl chloride (4), malignant melanoma (6), hormones and cancer (4), and clinical and experimental studies (10). Epidemiolog 1c studies indicate that The Incidence of malignant melanoma Is related to the amount of skin exposed To sunlight. Histologic classification 00005S59 VINYL CHLORIDE PAGE 131 is discussed, particularly in relation to prognosis, and the possibilities for immunotherapy of this tumor are considered. The problems of surgery and application of hyperthermic treatment are also discussed. The role of hormones 13 considered in relation to cancer of the breast> cervix, and endometrium, (refs) 250 AU - Schaffner F Popper H ; Selikoff IJ AD - Mount Sinai Sch. Medicine, City Univ, New York, Heu York, MY 10029 TI - INITIAL FEATURES OF VINYL CHLORIDE (VC) HEPATIC INJURY (MEETING A3STRACT ). SI - IC03/77/1S775 SO - Gastroenterology! 71(5):A35/923 1976 LA - ENG AB - An attempt was made to define the vinyl chloride (VC)-indueed lesions in the livers of mica after exposure to gaseous VC 5 hr/day 1 5 days/wk for 1, 3 and 6 mo at 2,500 and 6,000 ppm. Animals were also studied 1 mo after exposure ceased. Hepatocellular changes seen as early as 1 mo included hypertrophy of the <3mooth endoplasmic reticulum, reflecting metabolism of VC and plasma membrane loss of microvilli and invagination. These findings reflected a movement of a possible injurious metabolite across the membrane. The sinusoidal reaction was multicellular. The sice and number of lipocytes was increased with little fibrosis. These cells appeared normal except during recovery, when their fat content decreased in a patchy fashion. Macrophages were large and filled with phagosomes, some containing long needle-like crystals. Lymphocytes were numerous, but no plasma c cells were seen. The main abnormality involved the endothelial lining cells. Early changes resembled swollen cells', later, the bulky, and, in places, multilayered cells contained more Organelles, especially mitochondria and endoplasmic reticulum (. (ER) but no phagosomes. Discontinuities developed in the sinusoidal walls so that RGC were not only in but also around sinusoids dilated by beginning poliosis hepatis. Platelet thrombi were also seen in and around sinusoids. The lining cells, probably the precursors of angiosarcoma, resembled fibroblasts but nowhere did their ER contain fluffy collagen components. These observations suggest that VC is metabolised in hepatocytes, and that metabolites leave these cells through the plasma membrane To injurs sinusoidal lining cells, eventually producing anqiosarcomas. Attempts at screening for VC hepatic injury should be directed at endothelial Cells and altered ml crocirculation rather than at hepatocytes, macrophages or fibroblasts, (no refs) 251 AU AO TI SI SO LA AB Infante PF J Wagoner JV. ; Waxueller RJ Division Surve1 1 lance, Natl. Inst. Oocvcational Safety and Health, Main Post Office Building, Cincinnati, OH 95202 CARCINOGENIC. MUTAGENIC AND TERATOGENIC RISKS ASSOCIATED WITH ' VINYL CHLORIDE. ICCB/77/17C93 MuTat Res; 91( 1 )'-131-192 1976 ENG Results of an epidemiological survey of cancer, birth defects and 00005860 VINYL CHLORIOE PAGE 132 fetal mortality in groups of people with some kind of exposure to vinyl chloride (VC) are presented. In a cohort of uorkers occupationally-exposed to VC for at least 5 yr and for whom at least 15 yr had elapsed since the time of initial exposure, observed/expected deaths from all cancers , brain and Cf.'S cancers, respiratory system cancers, biliary and liver cancers, lymphatic and hematopoietic system cancers were 31/16.9. 3/0.6, communities uith VC polymerication facilities, observed/expected deaths for CHS cancer, leukemia and aleukemia, and lymphomas were 33/26, 67/48.1 and 61/48.7 respectively, and observed/exoected rate of congenital malformation (per 1000 live births) uas 73/40.3. The fetal mortality rate among wives of uorkers exposed to VC uas assessed by questionnaire and interview surveys to have been 10.IX prior to their husband's exposure to VC; after such exposure, the rate uas increased to 16.5X, with the excess in fetal mortality being associated with younger-aged husbands. (30 refs ) 252 AU - Scentesi I ; Hornyak E ; Ungvary G ; Cceirel A ; Bognar 2 AU - Tlmar M AD - Lab. Human Genetics, Natl. Inst. Hygiene, H-1966 Budapest, Gyali ut 2-6. Hungary TI - HIGH RATE OF CHROMOSOMAL ABERRATION IN PVC WORKERS. SI - IC08/77/16454 SO - Mutat Rest 37<2-3):313-316 1976 LA - ENG AB - Chromosome examinations uere performed on 45 polyvinyl chloride (PVC) workers exposed to vinyl chloride for 0.5 to 12 yr. Two control groups were used. The first was composed of 44 industrial uorkers uho uere not exposed to PVC and uere only indirectly exposed To other chemicals. The second control group uas composed of 49 individuals who had no occupational exposure to chemicals. The rate of numerical chromosome aberrations did not differ significantly between PVC uorkers and either control grouo. The frequency of chr oma 11 d-T'pe aberrations was higher in PVC uorkers than in either control group. Unstable chromosome-type aberrations were also significantly higher in PVC uorkers. The PVC uorkers uho showed a slqnificantly higher frequency of chromatid -Typ-e abberations or unstable chromoscme-1ype aberrations had been e>posed to the compound for longer periods than other PVC workers. They are To undergo a clinical check-up to determine whether they can continue in Thair present occupations. (17 refs) 253 AU AD TI SI SO LA AB Salmon AG Central Toxicology Lab., Imperial Chemical Industries Limited, Alder-ley Park, North Macclesfield, Cheshire 5K10 4TJ, UK CYTOCHROME P-650 AND THE METABOLISM OF VINYL CHLORIOE. ICQ3/77/15198 Cancer Lett (Amsterdam); 2(21:109-114 1976 ENG The involvement of cytochrome P-450 in vinyl chloride metabolism was studied. Rat liver mlcrosomes uere obtained from male Alderly 00005861 VINYL CHLORIDE PAGE 133 c Park, strain SPF albino rats (weighing 150-200 g)i and CU-C14]vinyl chloride (1 mCi /m 111imole) was utilized. Enzymic c oxidation of vinyl chloride was assayed by the formation of nonvolatile products. There was a time-dependent increase in the amount of label incorporated into nonvolatile water-soluble material. The reaction rale remained constant for 15 min but decreased later, possibly due to exhaustion of substrates and ( further metabolism of products. Label was not incorporated into either the soluble or solid fractions in the absence of microsomes or NAQPH or in the presence of microsomes previously heated to 100 C for 5 min. Addition of 1 mtl reduced glutathione to the reaction mixture increased the microsome-eatalyzed formation of nonvolatile uaTer-soluble products. In the absence of active enzymes, there was no reaction of vinyl chloride with glutathione. The concentration of cytochrome P-450 was found to V be 0.6 nanoM/mg protein. Addition of 100 microti phenobarb i t al to a mlcrosome suspension increased absorbance at 390 nanometers and decreased it at 420 nanometers (a typical type 1 difference Spectrum). A similar difference spectrum was demonstrated after saturation of a microsomal suspension with vinyl chloride. The 3D type 1 difference spectrum suggests an interaction with a cytochrome P-450 present in liver microsomes without induction. CD (12 refs ) 254 AU - Anderson D ; Hodge HC ; Purchase IF AD - Imperial Chemical Industries Ltd., Central Toxicology Lab., Alderley Park, North Macclesfield, Cheshire SK10 4TJ, England TI - VINYL CHLORIDE: DOMINANT LETHAL STUDIES IN MALE CD-I MICE. SI - IC0B/77/13363 SO - Mutat Res *, 40(4):3S9-370 1976 LA - ENG AB - The mutagenic activity of vinyl chloride (VC) was investigated in CO 00 CD Ol to CD-I mice by the dominant lethal test at inhalation exposure levels of 30,000, 10,000 and 3,000 ppm (6 hr/day for 5 davs ). The onlv significant mortality occurred in the groups exposed to the highest level of VC. Mice were also given ethyl methanesuifonate ( 200 mg/kg/day x 5, po) or cyclophosphamide (200 mg/kg on day 5, ip). Cyclophospnamida or methanesulfcnate Treatment increased the number of pregnancies with early deaths. The effect was significant in weeks 1 and 2 for the cyclophosphamide-treated group and week 2 for the methanesulfonate-treated group. No differences from controls were observed in the VC-treated group. As indicated by the total implants per pregnant female, VC caused V no preimplantat1 on egg losses. As demonstrated by the number of females with one or more early deaths, the number of early deaths/preqnancy, or The number of early deaths/Total 1mp1 ants/preqnancy, VC caused no significant increase in the number of postimplantational early fetal deaths. It is concluded That, although mutagenic effects of VC have been reporTed, no such effects, as determined in The present study, occur in the germ cells of CD-I mice. (14 refs) ' 3' ' c 00005862 VINYL CHLORIDE c PAGE 134 c 255 AU - Douglas DB ; Owen R TI - OCCUPATIONAL CANCER. 33 0) SI - CARC/77/03201 c SO - The Physiopathology of Cancer. Homburger F> Brennan MJ, KraKoff w 00 I, ed. Baseli S Karger, Diagnosis. Treatment. Prevention, vol 2. CD 1976. cn LA - ENG 03 ( AB - Occupational carcinogens, an agent or substance which induces cancer as a result of occupation, ore reviewed, as are the prevention and control of occupational cancer. Most occupational cancers develop m the skin, upper and lower respiratory tracts, and urinary bladder. A recent epidemic of cases of epithelioma of the scrotum has been seen among workers exposed to mineral oils. ( Gases emitted from various coal carbonisation processes may induce lung cancer. The relationship between 2-naphthylamine, benzidine, and human cancer is well-established but the association between human bladder cancer and other aromatic ( amines, such as 4-amincbiphenyl, 4-n1trcbiphenyl, auramine, and magenta, is equivocal. Occupational exposure to benzene has ( caused leukemia. Isopropyl oil had been responsible for an V increased risk of paranasal. laryngeal, and pulmonary cancer, but the hazard no longer exists because of changes in production. Exposure to leather dust in footwear manufacture and to wood dust in furniture manufacture has been linked to cancer of the nasal cavity and paranasal sinus. Workers engaged in mustard gas t, production ha>'e an increased risk of cancer of the paranasal sinus, larynx, and lung. The association between exposure to vinyl chloride monomer in the plastics industry and the development of a rare liver cancer has been recognized recently. c Arsenic exposure has been associated with skin cancer! its association with lung cancer is less well-established, though not disproved. Exposure to asbestos has been linked with cancer of the lunq, pleura, and peritoneum- In the chromate industry, c workers have a risk of lung cancer 15 times that of the general population! the insoluble chromium compounds, e.g., chromate dust and chromic oxides, are the active carcinogens. Exposure to nickel compounds during refining is associated with a higher risk c of cancer' of the nasal sinus and lung. Exposure to UV and ionlzinq radiation may cause skin cancer! in addition, ionizing V.. radiation has been linked to cancer of the hemopoietic tissues, L bone, and lung. Potential occupational carcinogens include alkylating agents, such as chlcromethyl methyl ether and bis (chlorome thy 1 ether ); 4,4 ' -me thy1enebis-or tho-chloroani1ine! N-n1trosamine ! and some compounds of nickel and beryllium. Recognized carcinogens should be replaced by less harmful agents, L but where this is not practicable, environmental and personal monitoring must be carried out. (97 refs) L 00005865 VINYL CHLORIDE PAGE 135 256 AU - Whelan JG ; Creech JL i Tamburro CH AO ~ ST. Anthony Hosp., 1313 ST. Anthony Place. Louisville. KY 40204 TI - AH3I0GRAFHIC AND RADIONUCLIDE CHARACTERISTICS OF HEPATIC AN3I0SARCCMA FOUND IN VINYL CHLORIDE WORKERS. SI - CARC/77/03042 SO - Olagn Radiol; USE 3 ) '.549-558 1976 LA - ENG AB - The angiographic and radionuclide changes associated uith hepatic angiosarcoma, recently discovered in a large series of vinyl chloride uorKers. were illustrated. All 1,180 workers at a Louisville. KY, vinyl chloride polymerigation plant were given liver scans; 50 were subsequently followed with hepatic and splenic angiography, trans]uguiar hepatic venography, venous pressure studies, and liver biopsies. Four cases of hepatic angiosarcoma were found, and there was one false-positive case. Of the screening procedures used, the liver scan was the most useful in detecting tumors- No single biochemical liver test was consistently abnormal in these patients. The characteristic anglcqraphic features of the angiosarcoma are peripheral Tumor stain, puddling of contrast agent extending from the mldarterlal phase up to 34 sec, and some degree of central hypovasculari ty within the tumor. Trans jugular hepatic pressures and biopsies are essential procedures, since svstemic venous hypertension seems to develop in some workers. Subcapsular fibrosis, portal fibrosis, sinusoidal dilatation, and endothelial lining cell hyperplasia are associated with the tumors. (32 refs) 257 AU AD TI SI SO LA AB - Maltoni C - Inst. Oncoloqy and Bologna Tumour Centre, Boloqna, Italy - CARCINOGENICITY OF VINYL CHLORIDE: CURRENT RESULTS. EXPERIMENTAL EVIDENCE. - CARC/77/02911 - Adv Tumor Prev Detect Charac*I 3:216-237 1976 - ENG - Partial results are presented from a series of experiments designed to study the effect of vinyl chloride (VC) administered Through different routes aT different concentrations , for varying periods of time, by continuous or intermittent Treatment, cn animals of different species (rats, mice, hamsters), strains (Spraqua-Dauley and Wistar rats), sex, and age (adults, newborns, embryos). A complete autopSS' was made on each animal, which was kept under observation until spontaneous death. Histoloqlcal examinations were performed cn Z'mibal glands, interscapular brown fat, salivary glands, tongue, lungs, liver, kidneys, spleen, stomach, different segments of the intestine, bladder, brain, bones of the legs and feet, and any other organ with pathological lesions. Animals exposed to the highest doses 130,000 and 10.000 ppm), with or without tumors , were examined rad Ioloqically. When given by inhalation, VC produced the following tumors: in rats, Zymbal qiand carcinomas, nephroblastomas, anq i os ar comas , mamn-sry carcinomas, and forestomach papillomas; in mice, lung adenomas, mammary carcinomas, ang103arcomas and angiomas of the liver and 00005364 VINYL CHLORIDE PAGE 136 other sites, skin epithelial tumors > and forestomach papillomasi and in hamsters, liver angi osorcoma: i skin trichoepiTheliomas, melanomas , foresTomach papiHomesi acanthomas, hapatomast and lymphomas. The response was affected by the length of exposure and by the strain. The onset of tumors in the offspring of breeders exposed during pregnancy for 7 days suggests a transplacental effect. When given by stomach tube at high doses> VC induced angiosarcomas of liver and other sites and Zymbal gland carcinomas in rats. The doses producing these Tumors, howeveri were extremely high when compared to possible human exposure. Thirty cases of liver angiosarcoma have been identified among workers of VC-FCV (polyvinyl chloride) industries in the US and several European countries. The majority of cases did not occur until 15 yr or more after the first exposure to VC, An excess mortality for cancers of the respiratory tract, blood-fcrming tissues, and brain has also been observed among workers of VC polymeripation plants in The US. IT is concluded that VC carcinogenesis has shown the value of experimental bioassays in predicting oncogenic risks. (7 refs) 253 AU - De Serres FJ AD - Hat 1, Inst. Environmental Health Sciences, Research Triangle Park, NC TI - PROSPECTS FOR A REVOLUTION IN THE METHODS OF TOXICOLOGICAL EVALUATION. SI - CAKC/77/02903 SO - Mutat Res; 33:165-176 1976 LA - ENG A3 - The impact of research programs to develop efficient assay systems for mutagenic activity to screen untested environmental chemicals and to develop better methods to determine their effect on man is considered. Food and feed additives in widespread use such as sodium nitrite, sodium bisulfite and other nitrofuran derivatives are mutagenic in experimental organisms, A nitrofuran derivative called AF-2, which was used widely as a food preservative in Japan for 10 yr, was found to be a poTeot mutagen and its use as a food preservative was banned. Most pesticides are also potent mutagens in experimental organisms, and ethylene dibromide, heptachlor, and chlordane are also carcinogenic in mice and rats. ATragine, a herbicide used widely on most commercially grown corn, is concerted to a potent mutagen. HvcanThone, a drug used to Treat schistosomiasis, is a supermutagen in exper1 mental organisms. Its long-term genetic effects on treated populations nave not been evaluated adequately. The majority of commercial hair dvas available in the United States, England, and Janan are potent mutagens in '-arlous short-term tests for mutaqenicity. Industrial chemicals that are mutagenic in experimental organisms and have been associated ulth occupational carcInogenes1s include b-proprio1actone, e thy lene i m 1 ne , 4-eminobi pheny 1 , 4-nI Tr obi pheov 1 , b1s(chloromethy 1 ) ether, beneidine, and vinyl chloride. Vinvl chloride has produced significant levels of chromosome damage in somatic cells of exposed workers. The primary concern over the 00005865 VINYL CHLORIDE PAGE 137 R&S 138956 259 AU TI SI SO LA A3 260 AU AD TI SI SO LA AB effects of environmental mutagens on men is that exposure may produce damage in germ cells that will be transmitted to future generations. Newly developed short-term tests for mutation induction include assays for both forward and reverse mutation at specific loci and tests for inhibition of ONA repair. In the assays for mutation induction! the best correlation between carcinogenic and mutagenic activity is with Salmonella', at least 7Q/.-75X of the carcinogens tested with this system show mutagenic activity. It is generally agreed that these short-term tests provide a mechanism for identifying potential mutagenic and carcinogenic agents and that they are most effectively used to establish priorities for testing in higher organisms. (39 refs) Hutt tlS ! Anthony PP EPIDEMIOLOGY OF SOME HUMAN CANCERS: (3) LIVER. CARC/77/02793 Scientific Foundations of Oncology. Symington T> Carter RLi ed. London, William Heinemann Medical Books Ltdi 1976. ENG A discussion is presented of the epidemiology and possible etiology of liver cancers, in particular, of hepatocellular carcinoma. Cirrhosis is a common precursor to hepatocellular carcinoma, but not to cholangiccarcinoma (bile duct carcinoma). Animal experiments indicate that the increased cell turnover associated with cirrhotic regeneration leads to a higher risk of malignant transformatlon. a-Fetoprotein production is seen in hepatocellular carcinoma but not in cholangiocarcinoma. The following possible etiological factors in hepatocellular carcinoma are briefly considered: parasitic infections, malnutrition , natural carcinogens, drugs, vinyl chloride, and mycotoxins (particularly, aflatoxin B1), A more detailed consideration is gi''cn to the frequent association of hepatitis B antiqsn (HBAg) with cirrhosis and hepatocellular carcinoma: in Uganda. 27X of patients with cirrhosis and 90X with hepatocellular carcinoma possessed IIBAg compared to 3Z of control subjects. It was also shown that younger persons and men were more commonly positive and that macronodular tvpes of cirrhosis, which predominate in Uganda, were particularly associated with the presence of HBAg. (95 refs) Watanabe PG McGowan GR ; Gehring PJ Toxicology Res. Lab., Dow Chemical Co., Midland, MI 98660 FATE OF (*#19 C)VINYL CHLORIDE AFTER SINGLE ORAL ADMINISTRATION IN RATS. CARC/77/02613 Toxicol Appl Pharmacol; 36(21:339-352 1976 ENG Male Spraque-Dawley rats were given single doses of 0.05, 1, and 100 mq/kq po of **19 C-vinyi chloride (VC), and the routes and rates of elimination of **19 C activity were followed for 72 hr. Following 0,05 and 1 mq/kq, excretion in the urine as nonvolatile metabolites and as ***19 C02 in expired air accounted for 59X-68X and 9X-13X, respectively, of the ad.nl nl s * ered dose. Only 1X-2'/. of VVs/I'SSt*, > ; c c c ( V 00005866 VINYL CHLORIDE PAGE 138 the dose Has expired by The lungs os VC. Conversely, after 100 mg/kg! 67X of the dose was eliminated by the lungs as VC, and urinary nonvolatile metabolites and #*14 C02 comprised 11/ and 3Z > respectively. Pulmonary elimination after 100 mg/kg showed an apparent biphasic clearance with half-times (tl /Z ) of 14,4 and 40.8 min for the respective fast and slow phases. Following 0.05 and 1 mg/kg i the pulmonary clearance of VC uas monophaslc, with tl /2 of 53.3 and 57.8 min. The percentage of The dose remaining in the carcass after 72 hr uas 10X, 11'/., and ZV. of the 0.05-, 1-, and 100-mg/kg doses, respectively, The urinary radioactivity uas separated by high-pressure liquid chromatography into three major metabolites. Tuo of the Three major urinary metabolites uere identified as N-aceTy1-S--(2-hydroxvethyl leysteine and thiodiglycolic acid by gas chromatography-mass spectrometry. The proportions of the urinary metabolites uere not influenced by dose. The fate of doses of 1-100 mg/kg VC uas clearly dose-dependent. The results suggest that the metabolism of VC is a saturable process. (20 refs) 261 AU - Couderc P I Panh MH ', Pasquier B ; Pasquier D ; N'Golet A AU - Faure H AD - Laboraforie d'Anatomie Pathologi que, C.H.U., 38043 Grenoble Cedex, France Tl - ANGIOSARCOMA OF THE BONE REVEALING A HEPATIC TUMOR IN A VINYL CHLORIDE U'ORKER. SI - CARC/77/02353 SO - Sem Hop Paris! 52(31/32):1721-1722 1976 LA - FRE A0 - A case history is presented of a vinvl chloride-induced angiosarcoma of the liver in a 33-yr-old man occupationallv exposed to the chemical for 10 vr. The liver neoplasm uas asymptomatic and was discovered when the patient uas hospitalised for dorsal and lumbar pain increasing in intensity after a fall 5 mo previously. X-ray studies revealed osteolysis and compression of the lumbar vertebrae and a portion of the 5th rib missing. Myeloma and thyroid, kidney, and prostate neoplasms uere ruled out by diagnostic studies. A costal tumor uas removed and diagnosed as an angiosarcoma, rare in bones, particularly costal and vertebral bones. Subsequently, the hepatic tumor was diagnosed by scintigraphy, arteriography , etc. A spontaneous rupture of the hepatic tumor required emergency 1nterven11on I however, the patient died. Multiple bone tumors as well as a subcapsular angiosarcoma occupying the right lobe of the liver were found at autopsy. It was not determined whether the multiple tumors were primary multifocal neoplasms on metastases of the hepatic tumor. (5 refs) R&S 138957 00005867 VINYL CHLORIDE PAGE 139 62 AU - Preussmann R c AO - Deutsches Krebsforschungszentrum Institut fur Toxikologie und Chemotherap 1 = > Im Neuenheimer Feld 280 > D-6900 Heidelberg, Uest Germany TI - CHEMICAL CARCINOGENS IN THE HUMAN ENVIRONMENT: PROBLEMS AND c QUANTITATIVE ASPECT5. SI - CARC/77/02335 SO - Oncology; 33(K51-57 1976 LA - ENG 33 AB - A review is given of The concept of environmental causation of human cancer. The problem of determining rick evaluations and 03 preventive measures involves determination of a chemical's carcinogenicity and the monitoring and quantification of environmental carcinogens. Although some chemicals are clearly carcinogenic! others such as cyclamntes are questionable. Currently envircnmental carcinogens are not being monitored reoulariy, partly because determination of Trace quantities is CO CO CD cn oo analytically difficult and standardized reference methods have not been adopted. Problems that enter into quantification of environmental carcinogens and risk evaluation are discussed. Envi rcnmental levels of poi-'cvdic arcmatic hvdrocarbons (PAH), aflatoxins, vinyl chloride (VC)i and N-nitroso compounds are compared to the doses necessary to experimantaliv induce tumors. Exposure to PAH, the best representative of uhich is benzta Ipyrene (BP ), is mainly via ingestion and inhalation. Among i aflatoxins, which grow well in food products under certain conditions, aflatoxin B is the most potent hepatocarcinogen known, Occuoational exposure to VC is causally connected with the induction of human angiosarcoma of the liver. Industrial discharae of VC and the use of PVC as a packaging material for food are sources of e>oosure of the general population. Several aspects of carcinogenic N-niTroso compounds are reviewed, Including their content in food products. With the exception of c afiatoxlns , quantities of sinqle carcinogens mav be subthreshold. In view of syncarcinogenlc and other enhancing and/or modifying effects, however , the probability of u-.ul t i fas tor i al cause of human cancer does not allow the definition of safe levels. (8 refs ) 63 AU - VomBruck CG ; Eckert WR ; Rudolph FB AD - Unilever Gesellschaft mbH, Hamburq, West Germany TI - MIGRATION OF VINYL CHLORIDE FROM PVC PACKAGINGS. SI - CARC/77/02106 SO - FetTe Siefen Anstrichml 78(8):330-337 1976 LA - GER AB - Gas chromaiograohic assav of vinyl chloride (VC) migration in polyvinyl chloride (PVC) or fat simulant HB 307 was made by Puschmann1 s method with a sensitivity of 0.00001/ ( 0.1 mg/kg 1 for PVC and 0.000001/ (0.01 mq/kq I for MB 307. VC migration from PVC was directly proportional to the initial VC concentration. In Two separate PVC samoles the VC level fell from 0.005/ to 0,002/ and from 0.0017/ To 0.0006/ after 35 days. At 0 C a linear relation c L L 00005868 VINYL CHLORIDE PAGE 1A0 was also obtained for the VC flow into HB 307 for 100 days. At AO C a max VC concentration was reached in HB 307 in 50-60 days> after which The level gradually fell. The appearance of a max suggests a reflux from HB 307 through PVC into the ambient atmosphere. On the average> an adult will consume about 1 kg of packaged food per day. Since only a small fraction of that Kilogram is in PVC packaging, the threat of VC contamination, even at a 0,006k concentration in PVC. is very small. (A refs) 26A AU - French JE I Andersen ME 1 Jenkins LJ AD - Experimental Pathology Dept,. AFRRI-NNMC, Bethesda. MS Z001A TI - VIHYLIDENE CHLORIDE-INDUCED ULTRASTRUCTURAL CHANGES IN RAT LIVER (MEETING ABSTRACT). SI - CARC/77/01991 SO - J Cell Biol! 70C Z/PantZ):361a 1976 LA - ENG A3 - Vinvi chloride and vinylidene chloride(1.1-dichloroethvlene. DCE ) are closely related chemicals and are known occupational and environmental contaminants. The pathobiological effects after oral adm1n1stration of DCE (in corn oil) to fasted male Holtcman rats was determined by correlating the ul ti'as true tural damage to the liver with chances in the serum levels of qlutamic-pyruvic transaminase (SGPT) and glutamic-oxaloacetic Transaminase (S30T ). In a completely randomised studv, fasted rats received a single oral dose of A0 to BO mq DCE/mg of bob'' wt . After 0. 1. Z, A. and 8 hr, SGPT and SG0T values were determined and liver tissue samples were immersion fixed in 3k cacodylate buffered glutaraldehyde, post-fixed in osmium Tetroxide and prepared by conventional EM methods. SGPT and SGOT values increased dramatically according to dosage and time of exposure in a linear manner, which indicated significant hepatic damage. The appearance of myelin-like bodies occurred at a similar frequency in both control and treated rats. Control rats were also characteriged by slightly dilated rough endoplasmic reticulumfRER ) and perinuclear clsternae. However, DCE-exposed rats showed significant dilation of the RER, loss of ribosomes, mltochondriai swelling, loss of cristae and chroma*inolysis in a dose and time related manner. Marqination of the chromatin along the nuclear envelope (chromatinorrhexis ) did not occur within this time period of exposure and dosage of DCE. DCE is a very hepatoxic xenobiotic and its pathcbiclogy may be different according to the route of administration. (No refs) 265 AU AD TI SI SO LA A3 - Watanabe PG ; McGowan GR ; Madrid EO I Gehring PJ - Toxicology Res. Lab.. Dow Chemical Co., Midland, MI - FATE CF 1 -"*XA CWIltfL CHLORIDE FOLLOWING INHALATION EXPOSURE IN RATS (MEETING ABSTRACT). CARC/77/01962 - Toxicol Appl Pharmacol) 37(l)`-93-9A 1976 - ENG The objective of the oresent study was to determine the rate of inhaled ('"lA C)vinyl chloride (**1A C-VC) at different exposure concentrations in rats. Male rats were exposed to 10 Or 1000 ,'.r .-.o-v-.-....- <|m.,.'* -.-- , A-*.7 { t'-`-..,>*, *k*-A*. %. c 00005669 VINYL CHLORIDE PAGE 141 c ppm(**14 C)VC for 6 hr and the routes and rates of elimination of *#14 C activity were followed for 72 hr after termination of exposure. Following exposure to 10 ppm VC, urinary **14 C c activity and expired VC comprised 66 and ZV. respectively, of the recovered radioactivity. After exposure to 1000 ppm VC, the proportion of the radioactivity in the urine decreased while that expired as VC increased, representing S6 and 12k respectively. The pattern of pulmonary elimination of VC per se was prescribed bv similar monoexponential processes following 10 or 1000 ppm with respective half-lives of 20.4 and 22,4 min. The elimination of **14 C in the urine was described by a biexponential process; the half-lives for the initial phase of excretion were 4,6 and 4.1 hr following 10 and 1000 ppm, respectively. T'ne percentage of the recovered *#14 C remaining in the carcass after 72 hr uas 14 and 15X at The respective low and high exposure levels. The **14 C remaining in the tissues uas comprised primarily of nonvolatile metabolites of VC rather than VC per se. The urinary **14 C was separated bv high-pressure liquid chromatography into three major metabolites corresponding to H-acetvl-S-(2-hydroxyethyl levsteine, (. thiodiglycolic acid, and a third unidentified metabolite. The proportions of the urinary metabolites were not markedly influenced by the exposure magnitude. The fate of inhaled 1**14 C)VC was shown to be dose-dependent and this is consistent with (' previous studies on the fate of VC following ingestion. 266 AU - Kravbill HF AO - NCI, NIK, Bethesda, NO 20014 TI - DISTRIBUTION OF CHEMICAL CARCINOGENS IN AqUATIC ENVIRONMENTS. SI - CARC/77/01664 SO - Prog Exp Tumor Res ; 20:3-34 1976 LA - ENG AB - Various contaminants in raw and finished water supplies that may have impact on the health of marine animals and man are reviewed, and specific categories of pollutants are considered. The orgsnochlorine insecticides appear to demonstrate the greatest potential for a tumor 1qenIc response. From bloassoy data, DDT and chlordane could be classified as suspect carcinogens. A polychlorinated biphenyl (Arocior 1260) has induced hyperplastic nodules with histological evidence for carcinomas in female rat livers. Polycyclic aromatic hydrocarbons are ubiquitous in the aquatic environment and may present the greatest carcinogenic insult. If these chemicals are discharged into waterways solublligod in solvents, there may be some miscibility or they may precipitate out of the solution. A few of the compounds are: aura.ii i no , benzidine, o-tolldine, 3,3 '-d I me thyibeng 1 d i ne , and 2-naphthy1 awine. The effect of benzene on marine animals should be observed especially since It is a leukemogenic agent. It may Occur at low concentrations as a contaminant In water from refinery wastes or intentional dumping. A systematic monitoring of aerial discharge and water effluents around plants producing vinyl chloride and polyvinyl chloride showed that values could range from 0.15-327 ppm. The fact that vinyl chloride has been detected and concentrations have been measured in waterways R&S 138960 00005870 VINYL CHLORIDE PAGE 142 suggests that marine animals could be adversely affected and That vinyl chloride might be included in marine foods Taken from contaminated waters. Soma correlations have been found between levels of carcinogenic metals in certain river basins in the US and cancer mortalities in The region. Nickel concentration seemed1 to correlate with mouth and intestinal cancer death rates and arsenic with eye and larynx cancers and myeloid leukemia. Beryllium was correlated with bona cancer and mortalities from breast and uterine cancer. Lead was associated with kidney canceri leukemias, lymphomas, and stomach, intestinal, and ovarian cancers. (70 refs) 267 All - Stafford J AO - Plastics Oiv., ici. PO Box 6, Bessemer Road, Uelwyn Garden City, Hertfordshire AL7 1HD, England TI - THE VINYL CHLORIDE MONOMER HEALTH PROBLEM. SI - CARC/77/01663 SO - Chem Ind ; 5(11) :466-470 1976 LA - ENG A3 - Proceedings of the British Plastics Federation conference on 'Vinyl Chloride and Safety at Hork1 of May 18, 1975 and the conference of the Occupational Health Section of the Royal Society of Medicine of September 12, 1975, were reviewed, as were recent developments on The vinyl chloride health problem in the UK, Europe, and the US. The health hazards associated with polyvinyl chloride manufacture seem to be entirely related to the vinyl chloride monomer (VCM). During 1969-71 the first fibrosarcoma due to VCM was produced in experimental animals. Soon after, another investigator found that VCM exposure produced a considerable yield of tumors of many Types in the glands and liver of rats exposed to varying dosages, with a linear relationship between the log concentrat1 on and The number of tumors. Numerous epidemiological surveys have turned up over 40 cases of angiosarcomas connected with VCM in the world. Nearly all of these cases were autoclave cleaners who experienced high exposures to VCM. Much more statistical data will be necessary to assess the threshold for plant exposure so that a proper perspective can be placed on those standards now being used by manufacturers . (No refs) 268 AU AU AO TI SI SO LA AO - Berk PD ; Martin JF ) Young R5 ; Creech J I Selikoff IJ i Falk H - Walanabe P ; Popper H ; Thomas L - Room 40-52, Building 10, Section on Diseases of the Liver, Digestive Diseases Branch, Natl. Inst. Arthritis, Metabolism, and Digestive Diseases, NIH, Cethesda, M0 20014 - VIMYL CHLORIDE-ASSOCIATED LIVER DISEASE. - CARC/77/01512 - Ann Intern Med! 84(61:717-731 1976 - ENG - The association of vinyl chloride exposure and liver diseases is reviewed. Polyvinyl chloride has been produced from vinyl chloride monomer for o"sr 40 yr, but recognition of Toxicity among vinyl chloride polymerira11 on workers is more recent. In 00005371 VINYL CHLORIDE PAGE 143 269 AU AD TI SI SO LA AB 270 AU AD TI SI SO LA AB the mid 1960's, aero-osteolysis was -found in workers involved in cleaning polymerigation tanks. In 1974, The same population of workers was found to be at risk for an unusual type of heoatic fibrosis and angiosarcoma of the liver. Two cas3 of vinyl chloride-associated liver injury, one of hepatic fibrosis and one of angiosarcoma, are presented. The histologic features of these lesions are similar to the hepatic fibrosis and angiosarcomas resulting from chronic exposure to inorganic orsenicals. Preliminary studies suggest that the toxicity of vinyl chloride mav result from formation, during high-dose exposure, of active metabolites by mixed function oxidases of the liver. Epidemiologic studies indicate an increased incidence not only of liver disease, but also of cancers of The brain, lung, and possibly other organs. (51 refs) Gamble J ; Liu S i McMichael AJ i Uaxueiler RJ NCN3 Plaza, Suite 32, Chapel Hill, NC 27514 EFFECT OF OCCUPATIONAL AND NOMOCCUPATIONAL FACTORS ON THE RESPIRATORY SYSTEM OF VINYL CHLORIDE AND OTHER WORKERS. ICDB/77/09719 J Cccup Med; ISt10 ):659-670 1976 ENG The respiratory function and symptoms in 174 vinyl chloride workers , 81 polyvinyl chloride workers, 72 former vinyl chloride workers , 136 rubber workers and 68 maintenance workers with exposure to vinyl chloride, polyvinyl chloride and rubber at the same plant were investigated. Respiratory questionnaires and lung function tests were administered to all workers. Except for small airway obstruction associated with rubber, increased respiratory symptoms and decreased pulmonary function were not associated with working in chemicals, plastics, or rubber. Some increases in baseline pulmonary function were associated with vinyl chloride exposure. Acute reductions in pulmonary function were observed in smokers working in chemicals, plastics, and rubber. Heavier ciqarette smokers over 40 yr of age had the most adverselv affected respiratory system. Work was not associated with chronic respiratory effects, but all exposure groups experienced some acute respiratory insult. The literature on this subject is reviewed. (34 refs) Anonymous No affiliation given PREDICTIVE ONCOLOGY: FOLLOWING PATIENTS AT HIGH CA RISK. ICQB/77/06647 Patient Care; 10(6 ):56 - 70 1976 ENG The factors that directly relate to tumor developments, and the management of high risk cancer patients is discussed. An estimated 65-05X of all cancers are envlronmental1y related. The patient's total environmental exposure to or ingestion of Implicated substances such as vinyl chloride, asbestos, aflatoxlns, and overuse of alcohol should be determined, Chloromycetin and other antibiotics with OKA inhibiting qualities 00005872 VINYL CHLORIDE PAGE 144 271 AU AD TI SI SO LA A3 272 AU AD TI SI SO LA should be avoided. Whan possible* immunosuppressants * hamatodepressants, and antihistamines> and the use of cyclophospham i da . methoTraxate> or tetracycline for* skin disorders or protection should be avoided. Benign skin lesions or bursitis should not be irradiated. The patient should chack any drug> even nonprescription, with his physician. High risk women should not be given estrogens* and if undergoing hy3tereetomy, the ovaries should be removed at the same time. Cancer risk factors are less decisive than heart disease factors, so enthusiastic recommendations are necessary. Patients must be educated before significant changes occur in morbidity and mortality. Community resources are available* and detecticn clinics can be organized to work in league with rehabi1itation facilities, (no refs) Hoffmann D Wynder EL Naylor Dana Inst. Disease Prevention, American Health Foundation* Valhalla, NY 10S95 SM3KING AND OCCUPATIONAL CANCERS. CARC/77/00959 Prev tied; 5t 2 ):245-251 1976 ENG Epidemiological evidence that tobacco use has an added effect to that of occupational carcinogens is reviewed. There is a lack of epidemiological data for the joint reaction of occuoational carcinogens and tobacco Smoke. This applies particularly to workers in nickel refineries* coke oven and gas workers, and for workers in the chemical industries related to halo ethers and vinyl chloride and certain urinary carcinoqens. Synergistic and/or additive effects of occupational carcinogens and tobacco smoke are epidemiologically established in the areas of exposure to radon daughters and to some types of asbestos. Experimental evidence of syncarcinogenic and/or cocarcinogenic effects of tobacco smoke and occupational carcinogens is needed in the areas of carcinogenesis of nickel, chromium, arsenicals, vinyl chloride, and halo ethers. The latter, however, are very potent respiratory carcinogens by themselves. Similarly, the aromatic amines as potent industrial bladder carcinogens may be studied for cocarcinogenlc mechanisms with tobacco smoke constituents. Epidemiological studios In occupational cancer must include the smoking histories in order to determine the relative contrlout 1 on of causative factors. Furthermore, it is the heavy cigarette smoker who is most likely to be the first affected by traces of carcinoqens. (105 refs) Watanabe PG t McGowan GR Madrid EO ', Gehrinq PJ Toxicology Res. Lab., Health and EnvIronmontal Res,, Midland, MI 48640 FATE OF C**14 Cl VINYL CHLORIDE FOLLOWING INHALATION EXPOSURE IN RATS. CARC/77/00949 Toxicol Appl Pharmacol; 57(11:49-59 1976 \ m* I 00005873 VINYL CHLORIDE PAGE 145 AO - The fate of inhaled **14 C-vinyl chloride tVC 1 at different exposure concentration3 was studied in rats. Male rots were exposed to 10 or 1.000 ppm **14 C-VC for 6 hr. and the routes and rates of elimination of **14 C activity were followed for 72 hr after termination of exposure. Following exposure to 10 ppm of VC. urinary **14 C activity and expired VC comprised 68'/. and Z/.i respectively 1 of the recovered radioactivity. After exposure to 1.000 ppm of VC) the proportion of the radioactivity in the urine decreased and that expired as VC increased, representing 56/. and 12k, respectively. The pattern of pulmonary elimination of VC per se was described by similar apparent first-order kinetics following 10, or 1,000 ppm with respective half-lives of 20.4 and 22.4 min, **14 C activity in the urine uas eliminated in accordance with a two-exponential equation; the half-lives for the initial phase of excretion were 4.6 and 4.1 hr following 10 and 1,000 ppm, respectively. Recovered **14 C activity remaining in the carcass after 72 hr uas 14X and 15k. VC per se was not found in tissues. The urinary **14 C activity uas separated by high-pressure liquid chromatography into three major metabolites corresponding to N-acety1-S-(2-hvdroxyethy1 Icysteine. thlodi glycolic acid, and a third unidentified metabolite. The proportions of the urinary metabolites were not markedly influenced by the exposure magnitude. The fate of inhaled **14 C-VC uas dose-dependent; This is consistent with previous studies on the fate of VC following ingestion as well as inhalation, (13 refs ) 373 AU - Maqnusson J Ramel C AD - Wallenbet-q lab., Univ. Stockholm, Stockholm, Sweden TI - MUTAGENIC EFFECTS OF VINYL CHLORIDE IN OROSOFHILA MELANOGASTER lMEETING ABSTRACT). SI - CARC/77/00S59 SO - Mutat Res; 33(2):115 1976 LA - ENG AB - Genetic investigations on Salmonella have shown that vinyl chloride is converted to a mutaqenio metabolite in liver microsomes . To studv the effect of vinyl chloride in the gonads and the transmission of mutations To the next generation, tests with sex-linked recessive lethais in Drosophila were performed by the Muller 5 method. Males were treated with doses of vinyl chloride in the air for 3 hr and mated to Muller 5 females. A significant increase in recessive lethais uas obtained both in the first and second generations', this indicated That the induction of recessive lethal mosaics took place. These results are in accordance with previous findings That Drosophila exhibits a metabolic conversion of indirect carcinogens, resembling the metabolic activation in mammals. (No refs) 00005374 VINYL CHLORIDE PAGE 146 274 AU - Loprieno N ; Abbondandolo A ; Barale R ; Baroneelli S ; Bonatti S AU - Brcnpetti G ; llim A ; Corsi C ; Corti G ; Frezpa D AU - Leporini C ; Mazzaccaro A > Nieri R ; Rosellini D > Rossi A AD - Laborat orio di MuTagenesi e Differenziamento , CMR e IstiTuto di Genetica de11'Uni vers i Ta> Pisa, Italy TI - MUTAGENICITY OF INDUSTRIAL CONFOUNDS: VINYL CHLORIDE, STYRENE ANO THEIR FOSSIBLE METABOLITES (MEETING ABSTRACT). SI - CARC/77/00353 SO - Mutat Res! 33(2):114-115 1976 LA - ENG A3 - Nutacenicity methodologies were appliad to the study of vinyl chloride. styrene, and their metabolities (2-chloroethylene oxide, 2-chloroethanol, 2-chioroacetaldehyde, and styrana oxide) to correlate tha mammalian metabolic fata of The compounds uith thair biological activity. Tha compounds were studied by liver microsomal assay and host-madiatad assay uith tha yeast S pomba and S ceravisiae. Preliminary experiments were also dona uith somatic mammalian calls (V79 Chinese hamster), on which tha induction of S-azaquanine resistant clones was assessed. Vinyl chloride was found to be mutagenic in tha presence of liver microsomal preparations and in Tha host-mediat ad assay; moreover, tha possible in vivo metabolite, 2-chloroathylane oxide, was responsible for mutagenic activity. Styrene was found to be inactive on yeast (*- microsomes ) or slightly active on hamster cells', stvrene oxide was found to be active in different biological systems. (No refs) 275 AU - Maricq HR I Johnson NN ; Whetstone CL ; LeRoy EC AD - Div. Rheumatology Immunology, Dept. Medicine, Medical Univ, South Carolina, 30 Barre St., Charleston, SC 23401 TI - CAPILLARY ABNORMALITIES IN POLYVINfL CHLORIDE PRODUCTION WORKERS. EXAMINATION BY IN VIVO MICROSCOPY. SI - ICD8/77/02755 SO - JAMA', 236(12 ): 1368-1371 1976 LA - ENG AB - To determine whether symptomatic vinyl chloride (VC) workers have fincjer-sk in-cap i llary abnormalitias, whether tha abnormalities are similar or different from those In patients with idiopathic scleroderma and Ranaud syndrome, whether microvascular abnormali T i as are related to tha t''pa of VC associated abnormalitias (especially 11ver ), whether microvascular abnormalities are related to the nature and duration of VC exposure, and whether mlcrovascular abnormalities are found in workers not exposed to VC, the hands of 152 VC-exposed workers were examined by ulde-field capillary microscopy. Examination revealed scattered scleroderma-1'ke mlcrovascular abnormalities in 21 workers and isolated capillary abnormalities in another 27, as compared with only Three isolated abnorma11ties in 50 manual workers not exposed to VC. Thirteen of 17 VC workers with objective evidence of VC-assoc1 atad abnorma1ities (anqiosercema or fibrosis of liver, acroosteolysis, or scleroderma-like skin lesions) also had microvascular abnormalities. Since c '.:v' "''' ' ', c C . . c .7 * .^4 -t 30 99 C/5 03 00 <0 CD cn 00005875 VINYL CHLORIDE PAGE 147 mi crovascular changes occur nor? frequently than overt VC-associated pathologic conditions, they may represent an early manifestation of the VC effect. Thus, capillary microscopy may become a useful mass-screening procedure in the early detection and prevention of VC-associated disease. 276 AU - Rannug U ; Ramel C A0 - Environmental Toxicology Unit. Wallenberg Lab.. Stockholm, Sweden TI - THE MUTAGENICITY OF WASTE PRODUCTS FROM THE VINYL CHLORIDE INDUSTRIES (MEETING ABSTRACT). SI - ICQ3/77/01850 50 - Mutat Res; 33(21:113 1976 LA - ENG AB - Vinyl chloride has been shown to possess carcinogenic and mutagenic properties. There is a risk that byproducts also possessing these properties may be formed in industrial processes involving this compound. The manufacture of vinyl chloride from acetylene and/or ethylene has given rise to a waste product, the EOC tar that contains ethylene dichloride as one of its main components. (This waste product has been dumped into the sea in large quantities.) It was tested for mutagenicity with one of the strains in the Salmonella test system (TA153S). which responded to base-pair substitutions in DMA. Ethanol, dimethyl sulfoxide, and Tween 80 were used to dissolve or emulsity the tar. They produced a mutagenic effect which was approximately of The same magnitude. However, when a microsomal fraction from rat liver plus an NADPH-generating system was added, the EDC tar exhibited a considerably stronger mutagenic effect. These results suggest that there are direct as well as indirect mutagenic components in the EDC tar. 277 AU - Robinson JS ; Thompson JM ", Belcher R ', Stephen HI AD - Dept. Anaesthetics. Univ. Birmingham, Birmingham. England TI - VINYL CHLORIDE: THE CARCINOGENIC RISK (LETTER TO EDITOR). 51 - IC0B/77/Q1742 SO - Br Med J; 2(6039):S15 1976 LA - ENG AB - Vin>'l chloride behaves as a non-ideal gas aT room temperature and, as such, a given mass occupies less vol at any particular temperature and partial pressure than predicted bv The ideal gas laws. Although the resultant error arising from The use of parts per million (ppm) as opposed to the ideal v/" may be Small, precision is essential In establishing The threshold and ceiling limits. It is simpler Tp use microg/llter for air pollution Thresholds because the monitoring instruments are most easily and reliably calibrated in mass/vol units. C C C ( c c c c c L c c VC, /,._>. ^V.'-d 00005876 VINYL CHLORIDE PAGE 148 273 AU - Schlatter CH AD - InsTitut fur Toxikologie, Schorenstrosse 16 CH-8603 Schwerzenbach bei Zurich TI - THE RISK Or CONSUMERS AND PVC WORKERS TO VINYL CHLORIDE. SI - CARC/77/00617 SO - Schweiz Med Uochenscnr; 1C6(19 ):647-650 1976 LA - GER A3 - The signs and symptoms of vinyl chloride intoxication* the epidemiology of hepatic hamjnqicsarcowa. the results of animal experimentation* currant estimates of occupational risk* and the danger of polyvinyl chloride packaging to the general population are topically reviewed. 279 AU - Lloyd JW AD - NIOSH Center for Disease Control* 5500 Fishers Lane* Rockville* MD 20352 TI - OCCUPATIONAL CANCER. SI - CAEC/77/00 366 50 - Proceedings of the Eleventh Canadian Cancer Research Conference, Natl Cancer Inst Canada Toronto Ontario 6-8 Hay 1976* 1976. LA - ENG AB - There is usually an exceedingly long delay before The first indications of an occupational cancer hazard and the definitive analysis of excess risk that is required before The institution of workplace controls. Brief discussion is given of The excesses of: bladder cancers in dye and rubber workers ar.d in workers exposed to 4-aminobiphenyl * a rubber antioxidant; skin cancer among workers in copper smelters and Tin refineries and among persons exposed to arsenic* such as sheep dip workers; lung and nasal sinus cancers among nickel and chromium workers; lung and digestive tract cancers and pleural and peritoneal mesotheliomas among workers in the asbestos industry; leukemias among radiologists; lung cancers among uranium millers; bone cancers among radium dial painters? cancel' of the nasal sinuses in woodworkers ; and angiosarcomas of the liver in workers exposed to vinyl chloride. 280 AU AD TI SI SO LA AD Fox AJ Medical Statistics Div., St. Catherines House* 10 Kingsway* London UC2B 6JP. England VINYL CHLORIDE AND MORTALITY? (LETTER TO EDITOR). IC03/77/00227 Lancet; 2(79821:416-417 1976 ENG An analysis of the data on worker's exposed to vinyl chloride indicated that an unbiased measure can only be obtained from studies of men who had left the industry during a fixing period and were still alive at the end of that period. These calculations provided little evidence to support the suggestion of an excess risk of lung and brain cancer in workers exposed to vinyl chloride. However, there was an excess of deaths due to cancer of the liver, particularly angiosarcoma. R&S 138968 ( 00005877 VINYL CHLORIDE PAGE 149 c 281 AU - Barry G ; Rossi ter CE AD - Llandough Hasp., Penarth, Glamorgan CF6 1XW, United Kingdom TI - VIHYL CHLORIDE ANO MORTALITY? (LETTER TO EDITOR). c SI - ICD6/77/00226 SO - Lancet; 2(7932)1416 1976 LA - ENG AB - Analysis of the results provided in an article and the followup letters and replies indicates that there is little evidence of excess mortality* either overall or from cancer, in Workers exposed to vinyl chloride. Furthermore, there does not appear to be a trend corresponding to increasing duration of exposure. These findings are in contrast to the inverse and exaggerated trends given in previous articles. e. 282 AU - Muller KT ; Buchter A ; Gross R I Bolt U AO - Med. Univ.-K1inik , 5 Koln 41, Joseph-STelcmann-Str. 9, West Germany TI - RESULTS OF A STUDY OF 17 CASES OF LONG-TERM EXPOSURE TO VINYL CHLORIDE. 51 - CARC/77/00312 SO - Med Welt; 27(1).'21-24 1976 LA - GER AB - A discussion of the physicochemical properties of vinyl chloride (VC) and its toxicology precedes a review of 17 patients with VC intoxication. Liver pathology and positive Raynaud signs occurred in 11/17, esophageal or fundlc varices in 8/17, splenomegaly in 8/17, thrombocytopenia in 10/17, and acro-osteolysis in 8/17. Six probands presented with granulo cytopoiesis and marrow stimulation bv sternal puncture. Five patients had various changes in antibody composition, and six were leukopenic. All patients were otoiaryngologically negative. A suspicion of hepatic hemangioendothelioma in one subject was disconfirmed on laparoscopy, although the patient had elevated serum iron and distal hypalgesia. The subjects were men, with a mean 9-yr VC exposure. 283 AU - Corbett TH AD - US Veterans Admin. Hosp., Ann Arbor, MI 48105 TI - CANCER AND CONGENITAL ANOMALIES ASSOCIATED WITH ANESTHETICS. i SI - CARC/77/00153 SO - Ann NY Acad Sci ; 271:53-66 1976 LA - ENG A3 - Certain anesthetics in general use may be carcinogenic, embryolethal , teratoqemc, and/or mutagenic. Spontaneous abortion rates as high as 33Z hawe been reported among nurse anesthetists, Coi.ipared to a rate of 9X among general duty nurses, and 16.4/ of 434 children born to nurse anesthetists who had worked during pre cnanev had birth defects, compared to only 5. 7'/. of 261 children born to nurse anesthetists who had not worked while pregnant. Three studies have indicated an increased cancer risk In operating-room personnel; a recent survey involving 50,000 such personnel and 30,000 non-operating room female medical c (' v c ( c ( L. 00005873 VINYL CHLORIDE PAGE 150 284 AU AD TI SI SO LA AB 285 AU AO TI SI SO LA AB personnel controls revealed an increased prevalence of cancer in the former, ranging from 1.3 to 2 times the control rate. Halogen ether anesthetics such as isoflurane, methoxyflurane, and enflurane are similar in chemical structure to the proved carcinogen bis(chloromethyl) ether, and trichloroethylene is likewise similar to the carcinogen vinyl chloride. Isoflurane has been shown to be carcinogenic in mice. When pregnant Swiss/ICR mica were exposed to 0.5'/. isoflurane for 2 hr on days 12, 14, 16, and 18 of pregnancy and the offspring were exposed to 0.1'/. isoflurane every other day from age 5 days for 25 exposures, 10/37 male offspring killed after IS mo had hepatic neoplasms, with three animals having multiple tumors. No neoplasms were observed among 23 control animals. Isoflurane, and the structurally similar halogenated ether and alkane anesthetic agents, must be regarded with suspicion and studied for carcinogenic properties as soon as possible. Kotin P Health, Safety 4 Environment Dept., Johns-Manvi1le Corp. , Denver, CO 60217 DOSE-RESPONSE RELATIONSHIP AND THRESHOLD CONCEPTS. CARC/77/00144 Ann NY Acad Sci; 27H22-23 1976 ENG The author examines the concepts of dose-response and threshold levels in cancer induction. The applicabi1ity of the dose-response concept has been clearly demonstrated for the tumorigenic effects of carcinogenic agents in animal models over Certain concentration ranges. This has been verified in man, and dose-response data and no-effect levels have been determined for carcinogenic organic and inorganic chemicals (specifically for vinyl chloride and asbestos), metals, and for non-ioniping and ionicing radiation. In the absence of evidence to the contrary, the applicability of the threshold concept in considerations of acceptable levels of carcinogens within the environment cannot be denied. Ma11 oni C Inst. Oncology and Tumour Centre, Bologna, Italy PREDICTIVE VALUE OF CARCINOGENESIS BIOASSAYS. CARC/77/00123 Ann NY Acad Sell 27H431-443 1976 ENG Bioassays provide an important means of predicting the oncogenic risk of particular occupational and envi ron.nen t al agents to man. In fact, the three most important occurrences of environmental and occupational tumors discovered after 1970 were directly or indirectly predicted by animal studies. The first was the adolescent clear-cell vaginal adenocarcinoma found in girls born to mothers treated during pregnancy with synthetic nonsteroid estrogen therapy. As long ago as 1933, it was demonstrated that stllbestrol had carcinogenic properties, with mammary tumors arising in male mice treated with the compound', several years R&s 138969 33 0 </) a co (D o c c c c c Wk.IjV,. :JrV V'-XA rcyyy yv-.'V-'C'; 00005879 VINYL CHLORIDE PAGE 151 286 All AD TI SI SO LA AB later, the same hormone was shown to produce a variety of tumors among different animal species. The second occurrence was that of pulmonary carcinoma among workers exposed to bis(chloromethy1) ether, which had previously been shown to produce sc f1brosarcomas and skin carcinomas when injected sc into rats or applied topically to mice. When the compound was inhaled by rats, it induced squamous Cell carcinomas of the lung. The third example was provided by the identification of liver angiosarcomas in workers occupationally exposed to vinyl chloride (VC), after the carcinogenicity of the compound had been demonstrated in rats. Data from inhalation experiments with VC in rats, mice, and hamsters and from ingestion experiments in rats are reported in detail. Sixty Swiss mice of both sexes were treated by inhalation of VC in air at 10,000 ppm for 9 hr/day, 5 days weekly for 30 wk. After 01 uk 55 developed pulmonary tumors, 13 had mammary careinomas , 6 had liver anqlosarcomas, 9 had vascular tumors, and 3 had epithelial tumors of the skin! of 150 untreated mice, 8 developed pulmonary tumors and 1 a vascular tumor after the same length of time. Sioassays can also be used to predict the carcinogenicity of inorganic substances. Various inorganic materials were tested by sc injection of 30-mg quantities into Spraque-Dawley rats. Of 90 animals in each group, 9 developed rhabdomyosarcomas and fibrosarcomas with neochromium, 8 with chromium allumen, 26 with chromium yellow, 27 with molybdenum orange, 16 with cadmium yellow, and 1 with iron yellow, after 125-150 wk. None of 190 control animals developed neoplasms. Of 99 male and 98 female Sprague-Dawley rats, 39 and 31 developed peritoneal mesotheliomas following the endoperitoneal injection of 25 mg of crocidolite. Lilis R J Anderson H ; Miller A I Selikoff IJ Mount Sinai Sch. Medicine, Mew York, NY PULMONARY CHANGES AMONG VINYL CHLORIDE POLYMERIZATION WORKERS. CARC/77/00015 Chest; 69(21:299-303 1976 ENG Pulmonary changes uncovered during clinical examinations of three groups of exposed vinyl chloride (VC) polymericatlon uorkers are discussed. The examination included chest x-rays, smoking history, a chronic bronchitis questionnaire, and pulmonary function tests. The first group was from a plant known to have high exposure levels to VC and polyvinyl chloride (PVC) . The second plant was the first PVC polymerisation facility, so that long exposure effects could be expected. The third plant had a relatively low exposure le,,el. In the first group, the overall prevalence of small linear reticular and/or rounded opacities was 22.7/1 x-ray changes Increased with length of e'posure. In the second group the prevalence of chest x-ray changes was 19.9/. The third group had a much lower prevalence of chest x-ray abnormalities (9.3X1. The prevalence of positive smoking history was higher in workers with abnormal chest x-ray films in the first two groups , perhaps indicating a multiple factor effect of smoking and VC-PVC exposure. No significant differences were 00005880 VINYL CHLORIDE PAGE 152 found between the groups with abnormal and normal chest x-rays with respect to chronic bronchitis or age. Pulmonary function tests showed a relatively high prevalence of obstructive changes* but there was no consistent correlation between abnormal chest x-ray and pulmonary function abnormalities. It is possible that chest x-ray changes and obstructive pulmonary function abnormalities reflect differenl pathologic processes* the chest x-ray changes being mainly related to parenchymal damage* while the obstructive pulmonary function changes reflect airway changes. 287 AU - Owen R AD - London* England TI - vinyl chloride: epidemiological studies and preventive measures. SI - CARC/76/04520 SO - Adv Tumor Prev Detect Charact! 3:233-241 1976 LA - ENG AB - Epidemiological studies are being made to assess the effects of occupational exposure to vinyl chloride in Great Britain. Cancer and mortality rates of 6.000-8.000 past and present workers in five polyvinyl chloride plants are being related to vinyl chloride exposure in terms of time and concentration. A retrospective study of cases of angiosarcoma of the liver is underway to evaluate the association between this disease and occupation. The medical and social histories of these cases are also being compiled. The United Kingdom has lowered its interim standards for vinyl chloride exposure to a ceiling value of 30 ppm and a time-weighted average of 10 ppm. 288 AU - Montesano R ; Bartsch H AD - Unit Chemical Carcinogenesis. International Agency Res. Cancer, Lyon. France TI - MUTAGENICITY AND METABOLISM OF VINYL CHLORIDE. SI - CARC/76/Q4519 SO - A.dv Tumor Prev Detect Charact'. 3:242-245 1976 LA - ENG AB - Studies on the mutagenicity and metabolism of vinyl chloride are reviewed. The mutagenic and/or carcinogenic effect of vinyl chloride appears to be mediated through the formation of electrophilic metabolites by microsomal mixed-function oxidase. The pretreatment of rats with drugs That modify the activity of the encym*e results in changes in The in vitro mutagenicity of vinyl chloride. This supports the hypothesis that the carcinogen has to be converted into electrcphi1ic and mutagenic metabolites. Pretreatment of rats with phenobarbitone increases the mutagenic response* whereas the admInlsTratlon of pregnenolone-16a-carbonitrile and am I noacetonitrile reduces The 1iver-modiaTed wutaceniciTy of vinyl chloride. Experiments involving The trapping of chloroethv1 one oxide in vitro bv 4-n1trcbencvlpyridine, follouinq activation of vinyl chloride in the presence of mouse liver microsomal encs'mes > an MAOFH generating system, and oxygen, support the hypothesis That monochloroethylene oxide is a primary reactive and mutagenic metabolite of vinyl chloride. R&S 138972 i'' 3 C 00005881 VINYL CHLORIDE PAGE 153 (' 289 AU - Pregaglia GF AD - Dept. Res. and Technology, Petrochemical Div., Montedison, Milan, Italy c TI - PRODUCTION AND USE OF VINYL CHLORIDE: IMPACT OF THE LINK BETWEEN VINYL CHLORIDE MONOMER AND CANCER. 51 - CARC/76/04518 SO - Adv Tumor Prev Detect Charact; 3:209-215 1976 (. LA - ENG AB - Exposure hazards associated with the production and use of vinyl chloride monomer (VCM) are reviewed along with some possible solutions. VCM has recently been associated with the cancer deaths of production workers exposed to the compound, and the Occupational Safety and Health Adminlstration has recommended that the exposure level be reduced to 1 ppm (averaged over an 8-hr periodl starting in 1976. Exposure hazards to VCM in polyvinyl chloride manufacturing plants include: VCM loss from valves and pumps to the ambient air at concentrations ranging from a few to a few dozen parts per million; the need for workers to enter reactor vessels periodically for cleaning! monomer escape from the polymer during storage and processing of the latter; and monomer losses through vent gas streams. Possible means of reducing VCM exposure include: the scale-up to larger reactors, resulting in fewer leaks and easier cleaning; remote Control operation and the use of highly sensitive vapor detectors! and new processes for the removal of VCM from vent gases, such as the adsorption of VCM on activated carbon and its regeneration with steam. 290 AU - Anonymous AD - No affiliation given TI - VINYL CHLORIDE: THE CARCINOGENIC RISK. SI - ICDB/76/29393 SO - Br Med JJ 2(60281:139-135 1976 LA - ENG AB - Previous studies have indicated the carcinogenicity of vinyl chloride monomer in workers exposed to the gas. It appears that 12-29 yr latent interval exists between the exposure and the onset of symptoms, with a mean duration of exposure of 18 yr. The threshold value for exposure has recently been lowered to 10 ppm. c. It will take future studies to decide whether this threshold value will have eliminated the risk of cancer, 291 AU - Lopr i eno N ; Barale R ! Baroncellt S I Broncetti G Cammellini A AU - Corsl G ; Leporini C ! Nieri R ; Rossi AM TI - THE MUTAGENICITY OF THE CARCINOGEN VINYL CHLORIDE AND ITS COMPARISON WITH A KNOWN ALKYLATING MUTAGEN. 51 CARC/76/09106 SO Screening Tests In Chemical Carcinogenesis; International Agency for Res. on Cancer. (Brussels, Belgium, 9-12 June 1975, no. 12, 1976. LA ENG AB The authors compared the mutagenic activity of methyl v. c: (>; c c i.. c c 00005882 VINYL CHLORIDE 33 0) co 00 CO -s| GO c PAGE 154 I ;.j methanesulfonate (MHS), used as a reference chemical, with that of vinyl chloride (VCM). The mutagenic activities were determined by use of the genetic systems of tuo eukaryotic yeast cells (Schizosaccharomyces pombe and Saccharomyces cerevisiae), uhich allow the evaluation of forward mutations on the five-loci system of S pombe and mitotic gene conversions on the two-loci system of S cerevisiae or the one-locus system of S pombe. From the experimental data available, the biological effect of VCM has been attributed mainly to its conversion by microsomal enzymes to reactive metabolites of the alkylating type. For this reason, the alkylating compound MM3 was chosen for comparison. In the present experiments, it was found that 1 mmol of MMS is equivalent to 41,7 mmol of VCM. Mitotic gene-conversion data gave a similar ratio: VCM is 10 to 40 times less effective than MMS. The "alues of the specific mutation rates and of the dose required for doubling the spontaneous mutation frequency indicated that VCM is converted to a highly reactive mutagenic metabolite. 292 AU - Bolt HM ; Kacpus H ! Buchter A ; Bolt U AD - Institut fur Toxikologie der Uni versitat. Wilhelmstr. 56. 0-7400 Tubingen, West Germany TI - DISPOSITION OF tl,2**-14 CJ VINYL CHLORIDE IN THE RAT. SI - CARC/76/04103 SO - Arch Toxicol (Berl); 35(31:153-162 1976 LA - ENG AB - Three male Wistar rats, 200-250 g, were exposed to (1,2*#-14 C)-vinyl chloride in an all-glass closed system of 10.3 1 volume. To avoid saturation of the metabolizing enzymes, concentrations below 100 ppm were applied. In preliminary experiments, it was found that only about 40k of inspired vinyl chloride Is absorbed by the lungs. Uptake of vinyl chloride by the rats was completely blocked by acute pretreatment with potent inhibitors of cytochrome P-450-dependent microsomal drug metabolism (i.e, by 35 mq/kg 3-bromopheny1-4(5 )-imidazole or 50 mg/kg 6-nitro-1,2,3-benzothiadiazole in 0.6 ml/kg dimethyl sulfoxide. DMSO). A weaker inhibition was observed after pretreatment with 2-diethylaminoe thy1-2,2-diphony1valerate!HCl (SKF-525A ) or 5.6-dimethyl-1,2,3-benzothiadiazole (50 mg/kg in 0.6 ml/kg DMSO). Metyrapone did not causa inhibition. Uptake of vinyl chloride was increased by pretreatment with 1,1,1-trichloro-2,2-bis(p-chloropheny1 )ethane (DDT) and, to a lesser extent, with clotrimazole. No significant stimulation of uptake was observed after pretreatment with phonobarbital 3-methylcholanthrene, rifampicin, or chronic ethanol treatment. Immediately after exposure, highest radioactivity levels were observed in liver and kidney) the radioactive metabolites were rapidly excreted, mainly in the urine (69.4k 6 2.6k within 24 hr). c c c V (. c c L L L v. R&S 138974 ' i 3........................................................... c 00005883 (If, VINYL CHLORIDE PAGE 155 c 293 All - Van Ouuren BL ; Banerjee S AD - Haw York Univ. Hedical Center, New York, NY 10016 TI - COVALENT INTERACTION OF METABOLITES OF THE CARCINOGEN ( TRICHLOROETHYLENE IN RAT HEPATIC MICROSOMES. SI - CARC/76/04102 50 - Cancer Res-, 36(7):2419-2422 1976 LA - ENG c AB - Trichloroethylene (TCE), a structural analog of vinyl chloride, induces hepatocellular carcinoma and other tumors in B6C3F1 hybrid mice. TCE epoxide, a possible metabolite, is expected to be highly reactive toward cellular nucleophiles! e.g, proteins and nucleic acids. Hence, the microsomal metabolism of TCE and its covalent binding to microsomal protein were examined. Rat liver microsomes from male Sprague-Dawley rats were incubated in vitro with **14 C-TCE. The results showed that TCE binds covalently to microsomal protein, since extensive organic extractions and Pronase digestion do not dissociate the TCE-protein complex. The binding was decreased by 7,8-benzoflavone> blocked by (. 2-die thvlaminoe thy1-2,2-diphenylvalerateIHCl (SKF-52SA) > and enhanced by ip administration of phenobarbital , The possibility that TCE epoxide, once formed, could be converted to watei--soluble product" through enzymatic hydrolysis by epoxide ( hydrase was also investigated. Addition of 3,3,3-trichloropropene oxide, a potent inhibitor of epoxide hydrase, to the incubation system markedly enhanced TCE binding. These observations support the view that, in order to bind to protein, it is necessary for TCE to be metabolized to its epoxide, a reactive intermediate that is most likely involved in TCE careinogenesis and toxicity. 294 AU - Wegman DH ; Peters JM \ Jaeger RJ ; Burgess WA ; Boden LI AD - 665 Huntinqton Ave., Boston, MA 02115 TI - PUBLIC-HEALTH ROUNDS AT THE HARVARD SCHOOL OF PUBLIC HEALTH. VINYL CHLORIDE: CAN THE WORKER BE PROTECTED? 51 - CARC/76/03S40 SO - N Engl J Med! 294(121:653-675 1976 LA - ENG AB - The toxicology, economic and engineering aspects, and regulation of occupational exposure to vinyl chloride are reviewed. Well V before 1974, when three cases of a rare neoplasm, angiosarcona of the liver, were reported in workers exposed to vinyl chloride over a 20-yr period, there was sufficient evidence to Support the presumption of a serious occupational hazard. Toxicological studies as early as 1933 indicated that vinyl chloride has little acute lethal action and negligible short-term toxicity but is a potent carcinogen in rodents under work-like exposure of 50 ppm and less. Useful toxicologic screening should be carried cut in locations other than the workplace and in species other than man. The manner In which workers are exposed to vinyl chloride '/cries greatly, depending on their occupation in one of three stages: (a) production of "inyl chloride monomer (VCM); (b) reaction of VCM to form polyvinyl chloride (PVC)! and (c) The fabrication of 00005884 VINYL CHLORIDE PAGE 156 plastic products from PVC. Major exposure and the cases of angiosarcoma of the liver occur in the second industrial stage. The most common exposure in the first stage occurs from leaks and faulty equipment maintenance. In the third stage> exposure (1,000 ppm) occurs uhen workers periodically crawl into the reactor to clean the inside surface. The Federal occupational standard for vinyl chloride exposure (issued in October 1974), although accepting in principle 1 ppm as the maximum possible exposure, permits temporary exposures of up to 25 ppm without respiratory protection. 295 AU - Pelfrene AF AD - Univ. Nebraska Medical Center, 42nd and Dewey Ave., Omaha, NB 68105 TI - CARCINOGENIC ROLE OF VINYL CHLORIDE (LETTER TO EDITOR). SI - CARC/76/03813 SO - Nouv Presse Med; 5(15)=999-1000 1976 LA - FRE AB - The author disagrees with the interpretation of current vinyl chloride data given in an earlier review. The carcinogenicity of this gas is well-documented, in man as well as in laboratory animals. Since January 1, 1975, the maximum permissible limit in American industry has been 1 ppm (a time-related average value for an B-hr day, 5-day work week). There is also a ceiling of 5 ppm for a maximum of 15 min exposure. The 1-pom value is well above the capacity of present detection techniques with a sensitivity of 0,1 ppm. Reduction and control of exposure thresholds are therefore possible. It is an exaggeration to assert that American vinyl chloride workers are generally exposed to concentrations of 600 to 1,000 ppm. Only some (in the polymer i cation units) run the risk of overexposure. The figures quoted seem abnormally high if one recalls that, in 1953, The discovery of neurotoxic and anqiotoxic effects in vinyl workers led to the lowering of The highest permissible limit to 500 ppm. Laboratory animals not only develop ecto- and mesodermic tumors after exposure to 50 to 200 ppm, they do so at lesser doses, and also after inhalation and ingestion. Extrapolation from rat to man is difficult, but one should not ignore laboratory results. It is preferable to limit human exposure to Toxic products on the strength of animal experiments than to wait for The same conclusions from studies of human epldemiology. 296 AU AD TI SI SO LA AB - Smith PM ; Williams DM ', Evans DM - Llandougn Hosp., B.P. Chemicals International Ltd., Penarth, Glamorgan, Wales HEPATIC ANGIOSARCOMA IN A VINYL CHLORIDE WORKER. - CARC/76/0 3453 - Bull NY Acad Med! 52(4)1447-452 1976 ENG An unusual case is presented of a 36-yr-old man who developed angiosarcoma of the liver after exposure to vinyl chloride monomer gas (VCM) for only 3 1/2 yr. The mean duration of exposure for previously reported cases of angiosarcoma was 16 yr. 00005885 VINYL CHLORIDE ( PAGE 157 The latent period from the first exposure to VCM to diagnosis was 8 yr, contrasting to the previous mean interval of 17 yr. A liver biopsy 15 mo prior to death showed striking focal dilation of the sinusoids. There is some evidence that this may be a precursor to tumor formation. 297 AU - Mi Ivy P ; Garro AJ AD - Mount Sinai Sch. Medicine, Fifth Ave. and 100th St., New York, NY 10029 c II - MUTAGENIC ACTIVITY OF STYRENE OXIDE (1.2-EFOXYETHYLBEHZENE), A PRESUMED STYRENE METABOLITE. SI - CARC/76/03996 SO - Mutat Res; 90(1):15-1S 1976 LA - ENG 30 AB - The possible mutagenic effects of styrene and some of its metabolites were studied in various strains of Salmonella (/) typhimuriurn. Only styrene oxide induced mutations in strains TA1535 and TA1C0, showing an activity similar to vinyl chloride end its presumed metabolites. The mutants were not clustered around the gone of inhibited grouthi but randomly distributedi suggesting that the styrene oxide was dispersed by vaporisation 03 03 ID -4 CD rather than by diffusion through the Agar. IT is concluded that styrene vapor may metabolise To a potentially carcinogenic compound, and current acceptable levels may pose a health threat to Workers. 298 AU AO II SI SO LA AB - Barnes AW ICI Plastics Div.i Welu\<n Garden City, Hert f ordshi re , England VINYL CHLORIDE AND THE PRODUCTION OF PVC (MEETING ABSTRACT). CARC/76/0300S Proc R Soc Med; 69(A):277-201 1976 ENG Tlie polymerization characteri s t i cs of vinyl chloride are described, and the process for producing polyvinyl chloride (PVC) is outlined. Interfaces of exposure of humans to PVC are outlined, and Theoretical exposure levels for workers at various staqes in the production process and tor the average U.K civilian are calculated. Average annual dietary ingestion is calculated as 0.0001 g/yr , Atmospheric exposure for polymerication workers has decreased from approximately 1,000 ppm in 1990 to approximately 5 ppm in 1975, although certain workers might have been exposed to as much as 3,000 ppm in 1990, The daily dose of the polymerization plant worker who had been exposed To 1,000 ppm is calculated at 0.16 g/kg, the dose for The polymerization plant worker presently exposed To 5 ppm is 0.0018 g/kg, and that of the average citizen 0.000000009 g/kg. c L L L- 00005386 VINYL CHLORIDE PAGE 158 299 AU AU AU AD TI SI 50 LA AB 300 AU AD TI SI SO LA AB Loprieno N ! Barale R J Baroncelli S ; Bauer C Bronzetti G Cammellini A ; Cercignani G ; Cors i C ; Gervasi G ; Leporini C Nieri R ; Rossi AM ; Stretti G ; Turehi G IsTituTo di GeneTica, University, Pisa, Italy EVALUATION OF THE GENETIC EFFECTS INDUCED BY VINYL CHLORIDE MONOMER (VCM) UNDER MAMMALIAN METABOLIC ACTIVATION: STUOIES IN VITRO AND IN VIVO. CARC/76/03399 MutaT Res; 90:85-95 1976 ENG Trie mutagenic activity of vinyl chloride monomer (VCM) was observed on yeast in the presence of a pure preparation of mouse (Swiss albino) liver microsomes and in the ''host-mediated assay1'; the gene conversion inducible by Saccharomyces cerevisiae was also observed. VCM in The presence of purified microsomes (sedimented at 105,000 g) was converted into an active metaboliTe(s ) that produced gene mutations in the yeast S pcmbe (foruard mutation) and gene conversions in two loci of diploid S cerevisiae. No mutagenic activity was found when yeast cells were treaTed with VCM, a phosphate buffer, or microsomes alone! this demonstrates that the enzyme necessary to metabolize VCM into a biologically reactive compound is not presenT in the yeast. Moreover, the compound was active in the host-mediated assay, when mice were treated with an oral dose of 700 mg/kg of VCM. These results have demonstrated That VCM is mutagenic for eukaryotic organisms and that it produces other genetic changes! this activity is 1iver-microsome dependent and dose dependent. It is recommended that reliable methodologies, like this mammalian metabolic activation one, for assessing the Toxicological values of many industrial compounds before They reach production, be made available. Weinbren K Royal Postgraduate Medical Sch., Du Cane Road, London W12 OHS, England MI5T0PATH0L0GY OF LIVER LESIONS ASSOCIATED WITH EXPOSURE TO VINYL CHLORIDE MONOMER (MEETING ABSTRACT). CARC/76/03503 Proc R Soc Med; 69(9):299-303 1976 ENG An ouTline of the cell character 151iC3 of angiosarcoma of the liver and changes that have occurred, with and without Tumor development , in patients exposed To vinyl chloride monomer are presented. The tumors appear as dark hemorrhagic nodules with distortion and fibrosis in the intervening tissue", frank necrosis is often present. There are three types of involvement: the sinusoidal pattern, the papillary Type, and the cavernous Type. The cells are usuallv associated with vessel walls and vascular spaces. Near the tumor and sometimes in the absence of tumors, perisinusoida 1 reticular fibers are prominent and fibrosis in The porTal tracts is often reported. Subcapsular flbrosl3 may also occur. The relevance of these nontumorous changes to the 33 8 (/) 03 CO CO ^1 c c \ l c L L c ' ii c c ( 33 C/3 00 CO to 00 00005S37 VINYL CHLORIDE ( PAGE 159 subsequent development of angiosarcoma is unknown at this time. **## END OF OFFLINE PRINT ###*# c c c c c e e L