Document ExDerq4NZOz9mvxak8wLX1wxR

\ b > t> i r PUBLISHED REFERENCES TO THE BIOLOGICAL EFFECTS OF VINYL CHLORIDE INCLUDING CHEMICAL ABSTRACTS 1962-JANUARY 14, 1974 AND BIOLOGICAL ABSTRACTS 1962-1973 Assembled in chronological order by: THE DOW CHEMICAL COMPANY January, 1974 Although this compilation contains most of the references to the biological effects of vinyl chloride as related to mammalian toxicity, the compilation should not be considered as exhaustive. BOR 009648 THE TOXICITY OF VINYL CHLORIDE VAPOR A Brief Summary of the Published Literature February 7, 1974 % The following articles and abstracts, compiled by The Dow Chemical Company, are believed to include most of the significant scientific information on the toxicology of vinyl chloride in man and animals. The articles and abstracts are arranged in chronological order. Articles published in the last half of 1973 may not be included if they have not been abstracted by Chemical Abstracts or Biological Abstracts. Important review articles which summarize much of the old literature have been used to cover the literature prior to 1961-1962. Therefore, copies of certain articles and abstracts described in these early reviews are not included in this compilation. Since vinyl chloride (chloroethene, CH2=CHC1) is a gas at room temperature and pressure, the common route of toxic exposure is by inhalation. As with many liquified gases, contact of the skin or eyes with escaping compressed vinyl chloride can produce freezing and frostbite. (Torkelson et al, 1961). Vinyl chloride has long been considered to be very low in toxicity by acute inhalation. Lehmann and Flury (1938) summarized the literature and reported work by Schauman who considered vinyl chloride to be a candidate surgical anesthetic. Schauman reported little pathological changes even after repeated exposure to anesthetic concentrations. BOR 009649 2. W. tT. von Oettingen (1955) of the U. S. Public Health Service summarized the available toxicity data on many halogenated hydrocarbons in an excellent monograph. - According to von Oettingen, several authors had reported vinyl chloride to be rapidly absorbed and excreted* through the lungs and to cause anesthesia. The following is von Oettingen's summary of the toxicity of vinyl chloride in animals and man: "As to the toxicity of vinyl chloride, Patty, Yant, and Waite (1930) studied this in guinea pigs. They found that exposure to 20 to 40 vol. percent kills the animals in a very short time, that concentrations of 10 vol. percent are dangerous to life with exposures for 30 to 60 minutes, and that 0.5 vol. percent is the maximum allowable concen tration for several hours' exposure without causing acute disturbances of severe nature. Animals exposed in this way showed some edema of the lungs and hyperemia of liver and kidneys. They considered vinyl chloride less harmful than chloroform or carbon tetrachloride and of a similar order of toxicity as ethyl chloride. Schaumann (1938) found that mice and rats tolerate repeated light narcosis for 4 hours daily on 5 to 8 consecutive days and for 1 hour daily for 4 weeks without showing kidney or liver injuries. Dogs which had been narcotized for 3 hours with 10 vol. percent on 7 occasions in the course of several weeks showed no consider able changes in kidney and liver. Higher concentrations (20 vol. percent) caused in dogs marked salivation, respiratory arrest, and vomiting after narcosis. Peoples and Leake (1933) determined the lethal range for mice with 10 minutes' exposure as 10 to 12 mM per liter, and Schaumann (1934) determined the vinyl chloride level in the blood at the time of cardiac arrest as <40 mg percent and at the time of respiratory arrest as 27 to 30 mg percent, the same value for chloroform being 60 to 70 mg percent. BOR 96S0 3 Regarding the toxicity of vinyl chloride -for man, Patty, -Yant, and Waite (1930) expressed the opinion that the gas ' does not possess adequate warning properties because of its odor or irritant action, but that it gives warning by producing symptoms of dizziness and disorientation in advance of harm, except when present in exceedingly high concentrations which would cause almost immediately help lessness and unconsciousness. Inhalation of 2.5 percent will soon cause dizziness, disorientation, and a burning sensation in the soles of the feet, which symptoms disappear immediately after discontinuation of the exposure except for a slight headache which may last 30 minutes. These authors suggested the use of vinyl chloride for narcosis in man." As a result of two deaths in Canada, the acute inhalation toxicity of vinyl chloride was studied by Mastromatteo et al (1960) who reported that exposure of mice, rats, and guinea pigs to 10, 20, and 30 volume percent vinyl chloride caused the following mortality: NUMBER OF DEATHS IN DIFFERENT GROUPS OF FIVE MICE, RATS AND GUINEA PIGS EXPOSED FOR THIRTY MINUTES TO VARYING CONCENTRA TIONS OF VINYL CHLORIDE IN AIR Vinyl chloride concentration (percent by volume in air) 10 20 30 40 Mice Laboratory animal Rats Guinea pigs 0/5 1/5 5/5 " 0/5 0/5 5/5 0/5 0/5 1/5* 2/5* Total 0/15 1/15 11/15 2/5 Total 6/15 5/15 3/20 14/50 * A delayed death occurred within 24 hours following exposure. BOR 009651 4 k4 * Some pulmanary hyperemia and engorgement was observed by these investigators, but liver and kidney injury were remarkably low. Deaths were due to narcosis. The first report of studies to determine the effect of long-term repeated exposure (6 months) were summarized by Torkelson, Oyen and Rowe (1961) as follows: "Repeated exposures of laboratory animals to several concen trations of vinyl chloride in air were conducted to determine the chronic toxicity of this material towards animals in order to assess the hazard to humans. Vinyl chloride was found to have a slight capacity to cause liver and kidney injury on repeated exposures. Male and female rats showed micropathological changes after repeated daily 7-hour exposures at 5t'0 ppm for 4.5 months. Repeated 7-hour exposures at 200 ppm for six months resulted in micropathological changes in the livers of rabbits and statistically significant increases in the average weight of the livers of male and female rats but no detectable changes in dogs and guinea pigs. Repeated 7-hour exposures at 100 ppm resulted in slight increases in the average weight of rat livers, the other species were not affected. All species studied tolerated repeated daily 7-hour exposures to 50 ppm for six months with no detectable injury. Repeated daily 1-hour exposures at 200 and 100 ppm of vinyl chloride were without effect, longer exposures caused a slight increase in liver weight. BOR 009652 5 The standard for evaluating regular daily 7 to 8-hour exposures may be defined as the concentration below which practically all analytical results must fall. The value of 100 ppm is suggested as this standard for vinyl chloride, with a timeweighted average for all exposures not to exceed 50 ppm." Lester, Greenberg, and Adams (1963) took strong exception to the conclusion of Torkelson et al (1961) that 50 ppm should be a maximum time weighted average exposure for workers. On the basis of 3 months exposure of rats to 2 " 4* volume percent and 19 days to 5 volume percent, they concluded that 500 ppm was acceptable as a TLV despite minor changes which they observed in rat livers and which they considered "were within the normal range and were not pathologic in nature." Because of these conflicting reports, the TLV Commitfee of the ACGIH in 1963 chose to change their TLV from 500 ppm as a maximum time-weighted average for industrial exposure to 500 ppm as a ceiling value. (American Conference Governmental Industrial Hygiene, 19631* Since 1962, numerous European articles on vinyl chloride have appeared, particularly in the Russian literature. For several reasons, these articles are difficult in interpret in terms of chronic toxicity since the reported exposures were to mixtures or were otherwise ill-defined, the exposures are often acute, or the criteria of effect was a minimal change in response or behavior, such as a subtle change in a conditioned response. BOR 009653 6 In 1967, reports appeared in the literature describing a * condition known as acroosteolysis in workmen engaged in polymerization of vinyl chloride to polyvinyl chloride. Harris and Adams (1967) reported on two cases in Europe. Wilson et al (1967), reported on 37 cases in the B. F. Good rich Company. Basalaev (1970) described the use of large frame photofluorography for diagnosis of acroosteolysis in Russia. Basalaev et al (1972) described studies in rats and rabbits and claimed to have produced the disease in these . species. Fethiere and Kerzner (1972) discussed the disease as did Juhe et al of the University of Bonn (1975). Jfthe et al (1973) described a syndrome consisting of (arranged in decreasing order of occurrence) thrombopenia, splenomegaly, liver damage, obstruction of ventillation, circulatory obstruction, and skin and bone alteration. As a result of this problem, the University of Michigan in 1967 was retained by the Manufacturing Chemists Association.to investigate this disease in sponsoring American companies. The results of a large scale epidemiological study of workers then currently employed in vinyl chloride and polyvinyl chloride production were reported in three publications by this group (Dinman et al, (1971) Cook et al, (1971) and Dodson et al, (1971)) . Dinman et al summarized the study as follows: "An epidemiological study was performed covering 5,011 employees with 21,510 man-years experience in various phases of vinyl chloride (VC) and polyvinyl chloride (PVC) manu, facturing in 32 plants throughout the United States and Canada. The total number of definitive cases of acroosteolysis BOR 009654 7. v 1 (AOL) was 25; 16 other individuals were under suspicion. *' This condition is clearly associated with the hand cleaning of polymerizers. Workers engaged in other phases of VC or PVC manufacturing do not appear to be at risk of developing AOL. The importance of Raynaud's phenomenon as a con comitant of AOL is emphasized. Several statistical approaches for rapid medical survey are suggested. Acroosteolysis appears to be a systemic rather than local disease. Presently, neither the etiological agent nor its portal of entry is known." Cook et al describes the polyvinyl chloride production process in considerable detail. They concluded that although no etiological agent could be identified, "There appeared to be a correlation, between the extent of degassing prior to entry into the reactor" ard the incidence of acroosteolysis. Mutchler and Kramer present*c" a paper at the 1968 Gordon Research Conference wnich was subsequently published (1972), which reported on "The Correlation of Clinical and Environ mental Measurements for Workers Exposed to Vinyl Chloride " The authors drew the following conclusion: "Our findings suggest that repeated exposure to vinyl chloride at TWA levels of 300 ppm or above for a working lifetime together with a very low level of vinylidene chloride may result in slight changes in certain physiologic and clinical laboratory parameters. The possibility of some impairment in liver function tests must be considered, even though ho overt clinical disease was evident in any of the individuals studied. We shall continue our study, but suggest that similar studies to help clarify the effects of this material be performed for other worker populations exposed to vinyl chloride alone." BOR 009655 8 -r The MChr sponsored studies by Dinman et al and Mutchler and Kramer appear to be the only two significant eqidemiological studies on vinyl chloride reported in the literature. P. L. viola, in an attempt to produce acroosteolysis in animals, exposed rats 4 hours per day, 5 days per week to 30,000 ppm (3%) vinyl chloride vapor. (Viola, March, 1970). In his first report on the results of 12 months exposure, he described metaplastic changes in the bones which he con sidered similar to the human disease acroosteolysis. He made no mention of having observed cancer in these animals until the Tenth Internationa] Cancer Congress in May, 1970. In the abstracts of this meeting, (Viola, 1970), and sub sequently in May, 1971, Viola, Bigotti and Caputo (1971) reported tumors of the skin, lungs and bones occurring first after 10 months of exposure. The authors summarized this work as follows: "Rats (Ar/IRE Wistar strain) exposed for 12 months to vapors of vinyl chloride developed tumors of the skin, lungs, and bones. The cutaneous tumors, which always appeared in the area in which submaxillary and parotid glands are located, have been histologically recognized as epidermoid carcinomas, papillomas, and mucoepidermoid carcinomas. The morphological characteristics of lung tumors, which occurred in a lower percentage, were mainly of the adenocarcinoma type, with the exception of a single epidermoid tumor originating from the epithelial covering cells. In a minor number of rats, a large proliferation of cartilaginous tissue diagnosed as osteochondroma developed in the metacarpal and metatarsal regions of the four limbs. BOR 009656 This report by Viola et al is apparently the earliest and only publication in which carcinogenic activity has been ascribed to vinyl chloride. Although there are possible deficiencies in Viola's study, such as his very impure sample, the presence of food and bedding in the exposure chamber, excessive exposure concentration as well as in the statistical evaluation and interpretation of the lesions, the report is of serious concern and has resulted in additional animal and epidemiological studies which are currently underway (MCA Press Releases). BOR 009657 Lehman, K. B., and F. Flury. Toxicology and hygiene of industrial solvents. 1938. As translated by Eleanor King and Henry F. Smyth, Jr. 1941 Von Oettingen, W. F.f M.D. The halogenated aliphatic, olefinic, cyclic, aromatic, and aliphatic-aromatic hydrocarbons including the halogenated insecticides, their toxicity and potential dangers. Public Health Service Publication No. 414, U. S. Department of Health, Education, and Welfare, Washington, D. C. 1955. Mastromatteo, E., M.D., A. M. Fisher, H. Christie, and K. Danziger. Acute inhalation toxicity of vinyl Chloride to laboratory animals. American Industrial Hygiene Association Journal, Volume 21, No. 5, October, 1960. Torkolson, T. R., F. Oyen, and V. K. Rowe. The toxicity of vinyl chloride as determined by repeated .exposure of . laboratory animals. American Industrial Hygiene Association Journal, Volume 22, No. 5, pp. 354-361. 1961. Gabor, S., M. Lecca-Radu, and I. Marital Certain biochemical indexes of the blood in workers exposed to toxic substances (benzene, chlorobenzene, vinyl chloride). From.-/Toksikol. i Klinika Prof. Zabolevanii Khim. Etiol. Sb. 221-223. 1962. Irish, D. D. Vinyl chloride, CH,=CHC1 (Monochloroethene). Industrial Hygiene and Toxicology, Volume 2, pp. 1303-1305. F. A. Patty, Editor. 1962. Lester, D., L. A. Greenberg, and W. R. Adams. Effects of single and repeated exposures of humans and rats to vinyl chloride. American Industrial Hygiene Association Journal, pp. 265-275, May-June. 1963. Gabor* S., M. Radu, N. Preda, S. Abrudean, L. Ivanof, Z. Anea, and C. Valaezkay. Inst. Hyg. Cluj., Romania. Bucharest 13(5), 409-418. 1964. Hardie, D. W. F. Chlorocarbons and chlorohydrocarbons: vinyl chloride. Kirk-Othmer Encycl. Chem. Technol., 2nd Ed. 5, 171-178. 1964. Kuebler, H. The physiological properties of aerosol propellants. Aerosol Age 9(4), 44, 47-48, 50, 90-91. 1964. BOR 009658 Mamedov, M. Vinyl chloride. Baku: Azerb. Gos. Izd. pp. 127. 1964. Grigorescu, I. and G. Toba. Vinyl chloride? industrial toxicologic aspects. Rev. Chim. 17(8):499-501. 1966. Harris, D. K. and w. G. F. Adams. Acroosteolysis occurring in men engaged in the polymerization of vinyl chloride. Brit. Med. Journal, 5567, pp. 712-714. Illus. 1967. Wilson, R. H., W. E. McCormick, C. F. Tatum, and J. L. Creech Occupational Acroosteolysis, report of 31 cases. The Journal of the American Medical Association, Volume 201, No. 8, pp. 577-581. 1967. Vazin, A. N., and E. I. Plokhova. Pathogenic effect of chronic exposure to vinyl chloride on rabbits. Farmakol Toksikol, 31(3):369-372. 1968. Vazin. A. N., and E. I. Plokhova. Pathogenesis of a disease, developing during chronic action of vinyl chloride on tne organism. Farmakol Toksikol 31 (3):369-372. 1968. Vazin, A. N., and E. I. Plokhova. Creation of an experi mental model of "toxic angioneurosis" developing from the chronic action of vinyl chloride vapors on an organism. GIG TR Prof Zabol 12 (7):47-49. 1968. Antonyuzhenko, V. A. Occupational poisoning by vinyl chloride. GIG TR Prof Zabol 12(3):5Q-S2. 1968, Baretta, E. D., R. D. Stewart, and J. E. Mutchler. Monitoring Exposures to vinyl chloride vapor: breath analysis and continuous air sampling. American Industrial Hygiene Association Journal, Volume 30, pp. 537-544. 1969. Vazin, A. N., and E. I. PLokhova. Dynamic changes in epinephrine-like substances in rabbit blood following chronic exposure to vinyl chloride fumes. GIG TR Prof Zabol 13(6):46-47. 1969. Clapp, J. J., C. M. Kaye, and L. Young. Metabolism of allyl compounds in the rat. Biochem. Journal 114(1), pp. 6-7. 1969. Vazin, A. N., E. I. Plokhova. Changes in adrenaline-like substances in rabbit blood following chronic exposure to vinyl chloride fumes. Gig. Tr. Prof Zabol. 13(6), pp. 46-47. 1969. BOR 009659 Vazin, A. N., E. I. Plokhova. Changes in the cardiac activity of rats chronically exposed to vinyl chloride vapors. Farmakol Toksikol, 32(2):220-222. 1969. Schottek, Wolfgang. Toxicology of vinyl chloride. Chera. Tech., 21(11), pp. 708-711. 1969. Smirnova, N. A., and N. P. Granik. Long-term side effects of acute occupational poisoning by certain hydrocarbons and their derivatives. GIG TR Prof Zabol 14(5):50-51. 1970. Basalaev, A. V. Experience with the use of large-frame photofluorography in examining skeletal bones of persons occupationally dealing with unsaturated hydrocarbons of the ethylene series (olefins) and their chlorine deriva tives (vinyl chloride, trichloroethylene). GIG TR Prof Zabol 14(11):34-37. 1970. Kudryavtseva, 0. F. Characteristics of electrocardio graphic changes in patients with vinyl chloride poisoning. GIG TR Prof Zabol 14(8):54-56. 1970. Viola, P. L. Pathology of vinyl chloride. Medicina del Lavoro, Volume 61, No. 3. March, 1970. Translated from the Italian. 1970. Viola, P. L. Cahcerogenic effect of vinyl chloride. Presented at the Tenth Int. Cancer Cong., Houston, Texas. Regina Elena Inst, for Cancer Research, May 22-29. 1970. Dinman, B. D., W. A. Cook, W. M. Whitehouse, H. J. Magnuson, and T. Ditcheck. Occupational Acroosteolysis: I. An Epidemiological Study. Archives of Environmental Health, Volume 22, pp. 61-73, January. 1971. Cook, W. A., P. M. Giever, B. D. Dinman, and H. J. Magnuson. Occupational Acroosteolysis: II. An Industrial Hygiene Study. Archives of Environmental Health, Volume 22, pp. 74-82 January. 1971. Dodson, V. N., B. D. Dinman, W. M. Whitehouse, A. N. M. Nasr, and H. J. Magnuson. Occupational Acroosteolysis: III. A clinical study. Archives of Environmental Health, Volume 22, pp. 83-91, January. 1971. Viola, P. L., A. Bigotti, and A. Caputo. Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Research, Volume 31, pp. 516-522, May. 1971. BOR 009660 Vinyl chloride. Documentation of the Threshold Limit Value, American Conference of Governmental Industrial Hygienists,Third Edition, 1971. Kramer, C. G., and J. E. Mutchler. The correlation of clinical and environmental measurements for workers exposed to vinyl chloride. American Industrial Hygiene Association Journal, Volume 33(1):19-30. 1971. Meyerson, L. B. and G. C. Meier. Cutaneous lesions in acroosteolysis. Arch Dermatol 106 (2):224-227 . 1972. Jiihe, S., and C. E. Lange. Long-term exposure to vinyl chloride. Dt. tried. Wschr. 97*1972. Basalaev, A. V., A. N. Vazin and A. G. Kochetkov. Pathogenesis of changes developing due to long-term exposure to the effect of viuyl chloride. GIG'TR Prof Zabol 16 (2):24-27. 1972. Markowitz, S. S., C. J. McDonald, W. Fethiere and M. S. Kerzner. Occupational acroosteolysis. Arch Dermatol 106 (2):219-223. 1972. Jiihe, S., C. E. Lange, G. Stein, and G. Veltman. Uber die sogenannte Vinylchlorid-Krankheit. Dtsch. med. Wschr. 98, pp. 2034-2037. (German). 1973. Jiihe, S., C. E. Lange, G. Stein, and G. Veltman. On the so-called vinyl chloride disease. Deutsche Medizinische Wochenschrift, 98_(43) , pp. 2034-2337. English translation. 1973 Levina, M. M., V. S. Filatova, E. G. Belaya, S. A. Ashirova, Y. P. Tikhomirov, A. L. Levin, R. Z. Mostinskaya, and B. E. Kuznetskii. Hygienic certification of the building projects development, and reconstruction of plants pro ducing organochlorine products. Gig. Sanit (4):86-87. 1973. Filatova, V. S., V. K. Vinogradova, and L. S. Bashkirova. Hygienic evaluation of working conditions in some chemical plants operating in the open air. Gig. Tr. Prof Zabol (8):8-11. 1973. BOR 009661