Document ZJNqn8ZGVyX2ybXRRG8JoBM5V

.; y/j//r R&S 115438 INTERNATIONAL CONFERENCE UNIVERSITY OF PRETORIA SOUTH AFRICA ON AIR . ' '* POLLUTION MUTAGENIC AND POTENTIAL MUTAGENIC INDUSTRIAL CHEMICALS * BY ' \ X Dr L. FISHBEIN SESSION ON MEDICAL ASPECTS WEDNESDAY, 28 APRIL 1976 1-J S3 CO cn cot* CO 1 ,J `: t ?! i nm'iiiimni r I \ iif .rf-iv-* jn*i>-fi iy v^ 44 > -M . i i. t ' it ' rt! 4* n * ' ' I. j This paper has been duplicated in the fora and language as submitted by i . the' authoEi without alteration or editing by the Organizers. Hicrdie referaat is herdruk presies soos deur die skrywer voorberei sender enige varandering van forraaat of taal deur die Organiseerders. I4 * R&S 115440 1. MUTAGENIC AND POTENTIAL MUTAGENIC INDUSTRIAL CHEMICALS by Lawrence Fishbein B.Sc. (Brooklyn), M.Sc. (Georgetown), Ph.D. (Georgetown) Asst, to Director for Environmental Surveillance National Center for Toxicological Research Jefferson, Arkansas USA Synopsis A spectrum of industrial chemicals (predominantly chlorinated aliphatic hydrocarbons) was reviewed in terms of the production ........... ..... -**.> i in terms .1; i:-.- ..V'-o quantities and/or use patterns, occurrence in the environment ' a.cr'or cse pr.r.e-r.r , oct:uw>:;.'Cu m the .:r.'-r.r* as well as germane aspects of their mutagenicity and/or carcino * ` * -i * .Tir - .'.CCT*. tl- : ttsi'Jr genicity. The agents considered included: vinyl chloride, . The - ;.Vitj-c?r.--.VKrcc< :r.viwuai. v;r.y. -Lii vinylidene chloride, trichloroethylene, tetrachlcroethylene, carbon v:,-yiicc`.*c chlc. i.r^-, iricbiero*..ti:yjonr, te^racniorocti y:.',u*. earner. tetrachloride,.chloroprene, haloethers (chloromethyl ether, .;.t;.icr:cc,. ci-icccprcr.*.*, r.:-.'cet!.*-*:rs (cnl.-tomel;-,/* . ` -,.-r, bis (chloromethyl) ether,- bis(2r,chloroethyl.ether.), phlorine^nd ohu-.-Tuitca-.chj.orv.v-iv.'.-yi., cspor'inc-,.,*.r.d chlorodioxins (2,3,7,8-tetrachloridifcer)zq-.p-;d?0kin)-v ***"`**"*-t * - * w. * `Cv..! -tv. . .. , ' The potential mutagenicity of a number of vinyl analogs (e.g., " : * >' *-- -Ciiy o; a nv.noor of vir.j 1 anaj.vr.s acrylamide, acrylonitrile, acrolein, acrylic acid, styrene) via " . .. :n, .-.ervjic ae:i, srvrc-r.e) via the intact molecule per sc or via an oxide or epoxide-intermediate or metabolic product was also noted. -n i.,i..vrt5-*'r r,in-*. v.m*; r-.-Tvr Int. Conf. on. Air Poll. .--. t : .r.. 2. The spectrum of chemical burdens that man is subjected to is very broad indeed and can include use. categories such as food and feed additives, drugs, pesticides and industrial chemicals (including their trace synthetic and/or degradation impurities), in various formulations including solid, liquid, suspensions, dusts and aerosols. The potential toxicants can enter the environment via air, water and soil as well as indirectly or directly into food. , It is estimated that about 500 chemicals are introduced each year*, adding to the burden of the more than approximately half million chemi cals currently in use of which about 10,000 or so are produced annudk1 in amounts between 500 and 1 million kilos2 . It should be noted that more than 2 million chemicals have been registered for use, mostly in the last 3-4 decades*. 'One striking feature of the chemical industry during the past two and a half decades has been in the enormous growth in the production of organic chemicals. For example, in 1950 world production (excluding Eastern bloc countries) totaled only approximately 7 million tons. By 1970 it had grown to 63 million tons and it is estimated that in 1985 it will total approximately 150 million tons^ . The majority of organic chemicals (approx. 75%) are further pro- cessed either in their place of manufacture or elsewhere. Over two thirds of the latter are used in the preparation of end-products such as plastics and resins, synthetic fibers, synthetic rubbers, and surf t Int. Conf. on Air Poll. ,,s 3. coatings. (These are no longer "chemicals"in the usual accepted sense of the term.) Of the remaining 25%, which consists of chemicals used as such, the largest part is further processed within industry itself to produce, either alone or in admixture with other materials such as detergents, glycols (e.g., antifreeze, brake fluids) and solvents (e.g., aerosol propellants). - Arising from these types of cnd-products, it has been speculated that at the present time a total amount of up to 20 million tons of manu- 3 factured organic chemicals may enter the environment annually . It is not known with precisipn what percentage of these chemicals may be hazardous in terms of their potential carcinogenicity, mutagenicity, and teratogenicity. Although the etiology of human neoplasia, with rare exceptions, is unknown, it has been estimated that 50% to 90% of cancpr in roan is caused by exposure to chemicals 4 ' 5 , Most of the known chemical carcinogens are considered to be the product of increasing agricultural ( and technological sophistication^. Not all chemical mutagens have been demonstrated to be carcino genic, although most chemical carcinogens (several of which cause cancer in man), have been found to be mutagens when tested in one of the mutagenicity test procedures that combine microbial, mammalian, or other animal-cell systems as genetic targets with an in vitro or in vivo metabolic activation system6"-ft . Int. Conf. on Air Poll. T, R&S 115442 I \ ' 4. In recent years there has been recognized concern over the envi- romnental and toxicological effects of a spectrum of halogenated hydro carbons, primarily the organo chlorine insecticides, and related derivatives, e.g., DDT, dieldrin, Mirex, chlordane. hcptachlorepoxide and polychlorinated biphenyls (PCB's), This concern has nov/ been extended to practically all of the major commercial chlori nated hydrocarbons, numerous members of which have extensive utility as solvents, aerosol propellants, degreasing agents, dry- cleaning fluids, fire extinguishers, etc., and hence are manufactured on a large scale. Chlorinated aliphatic hydrocarbons have constituted and pro bably will continue to do so in the foreseeable future the most impor tant class of organic solvents. Estimated world production capacities (1973) of th<i chlorinated aliphatics (Table I) illustrate the practical significance of this type of compounds, for economics as well as for toxicological and ecological consideration. TABLE 1 ESTIMATED WORLD PRODUCTION CAPACITIES (1973) OF MAJOR CHLORINATED HYDROCARBONS, IN 103 TONS/YEAR (a) Trichloroethylene Perchloroethylenc 1,1,1-Trichloroethane Methylene Chloride Trichlorofluromethane Dichlorodifluoroinelhane (b) * 1010 Vinyl Chloride 10.500 1050 1,2-Dichloroethane 19,500 480 Carbon Tetrachloride 1,000 400 Chloroform 245 485 Methyl Chloride 570 350 * . ,` Int. Conf, on Air Poll. j 5. Of the compounds in column (a), tlie fluorochloromethanes arc extensively used as aerosol propellants -and are almost completely lost after use. The others are employed principally ap solvents in industrial or domestic applications. The products listed in Table I are characterized by high volatility and low solubility in water. They enter the environment primarily by evaporation to the atmosphere. Some chlorinated hydrocarbons r will, however, be found in aqueous effluents from factories handling them and even in household sewage, and hence will pass into muni cipal drainage systems and ultimate sinks. The aliphatic chlorinated hydrocarbons listed in Table I have been found to exhibit a rapid transfer both from air to water, and from water to air. Irrespective of whether the initial loss of chlori nated hydrocarbon is to the atmosphere or the hydrosphere, the transfer processes will lead to a wide distribution of these compounds. In terms of worker exposure, the predominant routes of exposure arc via inhalation and dermal absorption and secondarily from ingestion of food and water. Vinyl chloride (chlorocthylcne; ethylene monochloride) (VC; VCM) (vinyl chloride monomer), has attracted a considerable amount of attention since 1973, because of the recent discovery of its carc cinogcnic action in man . Thirteen deaths due to angiosarcoma of the liver have been linked to occupational expsoure to gaseous vinyl chloride during polyvinyl chloride (PVC) production operations in * Int. C nf. on Air Poll. a + the plastics industry in the U.S.^*^. The total VCM work population in the U.S., past and present has been estimated to be about 20,000^. Thousands of companies, both large and small, and hundreds of thousands'of workers are engaged in the manufacture of, and/or of, plastic products made from PVC^. The hazard of vinyl chloride was originally belived to primarily concern workers in the plastic industries who may receive a particularly high exposure of VCM in certain operations (e.g., cleaning of polymerization kettles), or a long-term exposure to relatively low concentrations in air of VCM at different factory sites. It is now believed that much larger populations are at risk due to (a) signi ficant losses of VCM to the atmosphere at selected sites with subsequent atmospheric transport, (2) populations within proximity of the VCM and PVC production areas per se. (3) consumption of food products containing leachabie amounts of unrcacted VCM from PVC packaged materials, and (4) ingestion of water containing unreacted VCM leached from PVC pipes. World production of VCM in 1971 in various areas was estimated as follows (in millions of kg): United States 1,969; Western Europe 2,497; Japan 1,275; Eastern Europe 817; other areas 499' or a total of 7,057 million kilos^. Polyvinyl chloride (PVC) is produced in the U.S. at a yearly rate of 2.4 billion kg (about one-third the Western Worlds' supply) via four major processes. (1) Suspension polymerization (78% of Int. Conf. on Air Poll. Wsf ' --M  ! e t 8' 1 f iI ;. i ii ii ! \ j r A I l St I * ,t ( - "T t- 7. total production); (2) Emulsion polymerization (12% of total production); '(3) Bulk polymerization (6% of total production); and (4) solution (4% of total production). The U.S. consumption of PVC resins in 1972 was as follows: building and construction industries (42%), household uses (15%) , consumer goods (12%), electrical applications (11%), packaging (9%), and transportation (6%), with miscellaneous uses accounting for the remainder. Irr , nation concerning VCM emission data from both VCM and PVC resin plants is scant. VCM loss estimates of approximately 6% have been reported, based primarily on material balance studies^. VCM is distributed into the atmosphere surrounding the emissions source in patterns that depend on the amount of VCM released, the nature of the plant area from which it is rele's-cd and meterological ' : <u , i , < .... ,. conditions. Currently, emissions of vinyl chloride from VCM and PVC plants are estimated to exceed 90 million kg annually with 90% of all vinyl chloride atmospheric emissions believed to emanate from PVC plants^. (Monomer plants emit less then 10% of the total). While monomer plants emit Jess VCM per kg of product than polymer I plants, this may partially be offset by the tendency for monomer plants to have larger production capacities than polymer plants. This can be manifest in absolute VCM emission levels from polymer plants being in the range of 2 to 5 times those of monomer plants^. Although emissions of VCM from fabricating plants and from fabricated w Int. Conf. on Air Poll. /* R&S 115446 8. __ products may also occur, there are apparently no current data to quantify these emissions. The concentration of residual VCM monomer in PVC powder that is fabricated into final products is also an important determinant of VCM in the ppm range. The entrapped concentration is dependent upon the production process and can range from 0.1 to 5.8 thousand ppm, which can be liberated during fabrication, particularly when heated*. * An additional feature of the VCM and PVC industries (in the U.S.) that are of significance in terms of potential VCM concentration levels in the. atmosphere are the "clustering" of plants, (e.g., on the Gulf Coast in the Pasadena-Deer, Texas and Baton Rouge, La. areas)*. It has been difficult to estimate the areas and quantities of VCM losses which come primarily form vent streams, the storage and transportation loading systems, and seepages from pumps. Limited ! atmospheric VCM concentration measurements have been made in the vicinity (0 to 8 km) of VCM/PVC production sources. In over 90% of the cases, the peak concentrations have been below 1 ppm. A few 24 hour average values of 1-3 ppm. at distances of 0.8-S km measurements were below 1 ppm*. However, because of the sampling and analytical procedures used, the accuracy of these measurements may be no better than + 100%*. The principal route of exposure to vinyl chloride is believed to be via air inhalation, although exposure could occur from skin contact Int. Conf. on Air Poll. t~- ; f.' 1 r t** " /t V 1 c # i . - Jjf* MCvjn-tl / s ;.'r>WlU1.VllH1 JnUi1 HI -- f' * i' * J* / 1 . ;i ':: \ k i i . * ` 9. as well as from ingestion of food and water. Occupational exposure studies have revealed a wide range of VCM concentrations, dependent \ i \) i f ; t` .i i; ! v *** ;H i 5' i l! 1 `4 ;\ on the manufacturing processes involved. Air concentration of VCM in a polymerization reactor prior to ventilation has been reported to be of the order of 7800 mg/m3 (600-1000 ppm). 13 Concentrations of 1560<-2600 mg/ni^ (600-1000 ppm) of VCM in a polymerization reactor - after washing has also been reported 14 . Concentrations of 50-800 3 3 uig/m (20-312 ppm) of VCM, with peaks up to 87,300 mg/m r ' (34,000 ppm) in the working atmosphere of plants producing PVC have been reported^"*. PVC leaving certain manufacturing plants 3J fio ttl 4S* 00 - i * : may contain 200-400 ppm VCM; oh delivery to the customer, the level .of VCM is. about 250 ppm and after processing, levels of 0,5-20 ppm t \ i i !` . t '` t| ` i l! 1. i . t' ^# - i * i1 | i * \ * r .i '! * { *i V `f - ' ' *- - are reached, depending on the method of fabrication. A number of potential non-factory exposures to VCM exist. Until . recently, vinyl chloride has been widely employed as a propellant in i. ^ 17. 18 .aerosols for hair sprays, pesticides and room deodorants * , The use of aerosol products in enclosed spaces, even in short bursts (c.g., 30 seconds) could result in air concentrations of VCM as high 3 as 1000 mg/m (400 ppm) and these levels could persist for several hours after spraying v "l4 * .. * 4. ' , i * 1 * ' '* \ ` 't l ! - , * 5, * 41|1, . . I' H| i*! *. 4 t: . The mutagenicity of vinyl chloride and/or its metabolites (e.g., 'cKlovocthylcne oxide, chloroacctaldchyde, chloroethanol) has been demonstrated recently in vitro20-22 t utilizing the reverse mutation system of S. tvphirmirium of Ames ct al23 (e.n.* strains TA 1530* * * ,* Int. Conf. on Air Poll. :`Vi ' T ............-"V- . 1 -* .* : !"' 3 '!["" :i ' * *^ . . / . 1 J .j i . ' ' ' * * - 4l ' * i" ' \ .. 10. '\ " - ' tii \ 1 33 R c/> 'i 1 - * S l 1 >t *` I t i i . - -. \: * i I , . -. i* r *. **. i* / i i * -> t* -` * I 1 ` * V ' * *" 1 i. : *> .* ;* ` i* -- ' . 11 * \ 4 ' 1 ; * )< t. '* 1 *. J TA 1535, and G~46 were specifically reverted to Kis+ prototrophy by single-base-pair substitutions orby base-pair insertions or deletions, "frameshifts" utilizing TA 153o, TA 3537, and TA 1533). 24 Lopvieno et al demonstrated that vinyl chloride in the presence * of purified mousc~liver microsomes was converted to an active meta~ bolite(s) producing gene mutation(s) in the yeast S. pombe and gene * conversion(s) in two loci of a diploid strain of S, cerevisiae. V, ` Vinyl chloride has also been found mutagenic in Drosophila mclanogastcr^ and the mutagenicity in Chinese hamster V 79 cells of two vinyl chloride metabolites, chloroethylene oxide and chloroacetaldehyde has also been shown26 . Chromosome aberrations in a small number of vinyl chloride exposed workers has also been demonstrated 27 * 2C Vinylidene chloride (1,1-dichloroethylenc; Cl^^CC^) is used as a monomeric intermediate in the production of plastics, parti- cularly the Saran type and has been reported to be an impurity in vinyl chloride monomer 29 The mutagenicity of vinylidene chloride (DCE) has been reported by Bartsch ct al21 in the previously described S. typhimurium strains of TA 1530 and TA 1535, DCE exhibited a higher mutagenic effect than that observed with vinyl chloride, when the compound was 30 metabolically activated by rate or mouse microsomal liver enzymes ` It is quite possible that analogous to vinyl chloride21 , DCE may 4 'l ' !" -. ., , 1; !*V* V`I*<1 * ,/l . ** ` ..... .................. V; r-r- -r*r * ` ' . * '. * . * * W -if R&S 115450 11. be mutagenic following activation to an epoxide intermediate, e.g., CH,-C-Cl->. \7 o Trichloroethylene (trichlorocthene; C1CH=CC12) and tctrach- loroethylene Cperchloroethylene, C12C=CC12) are both widely employed as solvents, dry cleaning and degreasing agents, and in the manu facture of a variety of organic chemicals, such as polymeiized resins of phenol-formaldehyde, urea-formaldehyde and epoxides in the * production of special fiber glasses, Tetrachloroelhylene is also used in comparatively small amounts as a commodity fumigant, and for food extractions including de'eafeinating coffee, and removing oleoresins from spices^. . ., Preliminary evaluation tests at the National Cancer Institute in the U.S. indicates that trichloroethylene (when fed) induces tumors in mice, predominantly hepatocellular carcinomas with some metastascs to the lungs^*. Mammalian metabolic pathoways of trichloroethylene and tetrach- loroethylene in the mouse and rat are belived to involve the inter mediate epoxides, O /\ C12C------- CHC1 O /\ and Cl2-C'------- CC1. respectively32 ' 33 , Urinary metabolites found for trichloroethylene include: trichloroacetic acid, chloral (trichloroacctaldehydc) trich- lorocthanol and chloroform 32-35 . Chloralhydratc has been reported to induce point mutations in Drosophila^, bacteria^ and chromosome aberrations in Vicia faba38 . Int. Conf. oh Air Poll. *. t m T, *ulf lr. '*. . .-i f i i 11 iM ..* i.xi j.i -- -- "**1 '* *** fc*" - - * - ' - * *" ktv.fwi * V** 12. It should also be noted that the possibility exists of trichloro ethylene per se and/or its oxide being mutagenic via considerations 21 22 previously demonstrated above for vinyl chloride * . It is generally acknowledged that emissions of commerical organist solvent vapors into the atmosphere have been increasing dramatically in the last decade 39 . McConnell et al39 estimated the loss of trich loroethylene and perchlorocthylene to the global environment in 1973 to be each over 1 million tons. Solvent emissions, for example, are believed to account for over 20% of the total hydrocarbons emitted into the atmosphere in Los Angeles County and these emissions averaged about one-sixth pound per person annually in this county. The release rate of industrial effluents into the air over Los Angeles County has been estimated at 500 tons/day. These emissions arc believed to be mainly solvents of v/hich 25 tons are dry cleaning fluids and 95 tons are degreasing solvents; the remaining 380 tons are surface coating and miscellaneous ' 40, 41 compounds , . Carbon tetrachloride is produced in enormous quantities, e.g., over 1.0 billion pounds in the U.S. in 1970. In the U.S.. the majority of the CCl^ produced in 1970 was employed in the production of fluorocarbons, e.g., approximately 700 million pounds (69%) for dichlorodifluoromethane (CF_C1 ) and about 260 million pounds (26%) for trichlorofluoromethane (CFCl^). The remaining 5% of the pro duction in the U.S. (in 1970) (approximately 50 million pounds) Int. Conf. on. Air Poll. rr :r R&S 115452 i fcjlTri.t. WiVh. <-* a-H?.-.,ij imuiAiaiut 13. was used as : (a) grain fumigants (mixed with other chemicals); (b) fire extinguishers; (c) solvent for oils, fats, resins, and rubber cents; (d) cleaning agent for machinery and electrical equipment; (e) degreasing metal fabricated parts; and (f) organic chlorination processes. Losses of carbon tetrachloride to the global environment were estimated by McConnell et al to be in the order of 1 million tons in 1974. Carbon tetrachloride has produced liver tumors in the mouse, . hamster, and rat following several routes of administration, including inhalation and oral ingestion^. A number of cases of hepatomas appearing in men several years after CCl^ poisoning have also been rcporlcd^'^. Bartholmess^ in his survey of chemical mutagens in the environment has listed carbon tetrachloride as a chromosome breaking agent. Chloroprenc (l-chloro-2,3-butadiene; Cf^C-CH-Ci^) is the Cl monomer for neoprene, the specialty rubber. ' . High rates of skin and lung cancer have been recently' reported among workers in U.S. and USSR plants who have handled ehloro- prene and its derivatives46 ' 4?". Currently about 2500 workers in 47 the United States are exposed to chloroprene i Halocthcrs represent an interesting category of alkylating carcino- I gens, as well as potential mutagens, of increasing interest. The Int. Conf. on Air Poll. *t f R&S 115453 .14 carcinogenicity of the a-chloroethers, chloromcthyl methyl ether (CMME), and bis(chloromethyl)eth`cr (BCME) in mice and rats has been reported^ Suspected cases of lung cancer due to occu- pational exposure to CMME has also been cited51 ' 52 . CMME and BCME are widely used in the chemical industry as intermediates in organic synthesis and in the preparation of ion-exchange series. Commercial CMME contains 1 to 6% of BCME. BCME is very carcino genic and CMME is also active but less so^'^. Conflicting information exists as to the formation of BCME via the spontaneous reactions between HC1 and formaldehyde in both gas and liquid phases^ NIOSH has confirmed the spontaneous formation of BCME from the reaction of formaldehyde and hydrochloric acid in some textile plants and is now investigating the extent of possible worker exposure to the carcinogen . Bis (2-chloroisopropyl) ether and bis (2-chloroethyl) ether (appar ently arising from industrial outfall) appear to be rather widespread halocther pollutants in the rivers of the United States^**^. Innes et al^ reported the induction of hepatomas in mice fed bis (2-chloroethyl)-ether and bis (2-chloroethyl) ether has been found to be mutagenic in Drosophila^. . Approximately 250 million pounds of chlorinated hydrocarbon byproducts, known as still bottom material, accumulate each year from organic chemical manufacturing in the U.S. 62 A procedure which has been recommended for the decomposition of the above materials (as well as 2,4*5-T and DDT) is chlorinolysis, Int, Conft on Air Poll.  ' *'*'frf`-"%***t*'** * * I R&S 115454 ; ! / ./ - y.r r- r 15. whereby chlorine is added to the chemical residues, producing high yields of carbon tetrachloride, hydrochloric acid, and carbonyl chloride. Recent concerns have been raised about the use of chlorination as a disinfecting technique63 . An estimated 1,000 tons of chlorinated organic compounds, some of them known to induce cancer in labor- atory animals (c.g., chloroform and carbon tetrachloride) are t discharged annually into the U.S. waterways as a result of the chlorination of waste water. (It should be noted that the wastewater industry relics almost exclusively on chlorine as a disinfectant.) Recent Environmental Protection Agency (EPA) studies have indicated the presence of small quantities of 66 organic chemicals (many of them chlorinated hydrocarbons) in the nation's drinking water supply^. " ' -H' v The chromosomal effects of chlorine per se on mammalian cells in vitro have been reported by Mickey and Holden 65 Chlorodioxins (polychlorinated dibenzo-p-dioxins) include a large number of compounds, (some extremely toxic) which occur primarily as contaminants in technical products such as tri-, tetra-, and pentachlorophenol and a number of other related products. 2,3,7,8-Tctrachlorodibenzo-p-dioxin (TCDD) or other ck'orinated dibenzodioxins or chlorinated dibenzofurans may be present in the waste products from chlorination of benzenes, phenols and polyphenyls since traces have been found in the commerical products^. Conditions which enhance TCDD formation (as well as other chlorinated dioxins) are high temperature, high pressure, and Tnt. Conf, on'Air Poll. r vr ^ ktr 'ir----------r~ 16.alkalinity, are analogous to the conditions required for the production of pcntachlorophcr.ol (PCP) from hexachloroben2ene or in the - . production of tri-, tetra-and pentachlorophenol by the direct chlorination of phenol. The mutagenic effects of TCDD.on bacterial systems e.g., Salmonella typhimurium strain TA 1532 have been noted by Hussain 67 et al It is also important to note a number of vinyl analogs which have . significant industrial utility as solvents, plastic and polymer monomers and synthetic utility may be potential mutagens via analogous consi derations as described for vinyl chloride, vinylidene chloride and trichloroethylener e.g., the intact molecule per se or via an oxide or epoxide intermediate or metabolic product. These agents include: acrylamide (CH-j-CHCON^); acrylonitrile (CH-j-CHCN); acrolein (CH2=CHCHO); acrylic acid (CH2=CHCOOH); styrene (C^HjCHCH^; styrene oxide (C^HgCH-CH2), vinyl bromide (CH2=CHBr) and vinyl- O benzyl chloride (CH^CHC^HgCl^Cl}. 17. BIBLIOGRAPHY 1. Council of Environmental Quality Probe, "Toxic Substances", Council of Environmental Quality, U. S. Govt. Printing Office, Washington, D.C. 1971 2. Goodman, G, T., How Do Chemical Substances Affect the Envi ronment? Proc. Roy. Soc. London B., 185, 1974, 127-148 3. Iliff, N., Organic Chemicals in the Environment, New Scientist, 1972. 53, 263-265 4. Anon, Conference Explored Occupational, Cancer Chem. Eng, News, 1975, 53_, 16 5. Boyland, E., The Correlation of Experimental Carcinogenesis and Cancer in Wan, Progr. Exp. Tumor Res. (Basel). 1969, H, 222-234 r 6. Stoltz, D. R., Poirier, L. A., "Irving, C. C., Strich, H. F.. and Wcisburger, J. H., and Grice, H. C., Evaluation of Short-term Tests for Carcinogenicity, Toxicol. Appl. Pharmacol., 1974, 29, 157-180 7. Committee 17, Environmental Mutagenic Hazards, Nature, 1974, 187, 503-514 8. Miller, E.C., and J. A*. (1971) The Mutagenicity of Chemical Carcinogens: Correlations, Problems and Interpretations In: "Chemical Mutagens: Principles and Methods for their Detection", A. Hollacnder, editor. New York, Plenum, 1971, pp. 83 9. Creech, J. L. and Johnson, M. N., Angiosarcoma of Liver in the Manufacture of Polyvinyl Chloride, J. Occup. Med., 1974, 16. 150-151 10. EPA. Environmental Aspects of Vinyl/polyvinyl Chloride, U.S. Environmental Protection Agency, Research Triangle Park, 1975 31. Heath, C. W. Jr., Falk, H., and Crccch, J. L., Characteristics of Cases of Angiosarcoma of the Liver among Vinyl Chloride Workers in the U.S., Ann. N,V. Acad. Sci., 1975, 246, 231-236 12. 1ARC, "Some Anti-Thyroid and Related Substances, Nitrofurans and Industrial Chemicals", Monograph No. 7, International Agency for Research on Cancer, Lyon, 1974 R&S 115456 *1 lu. 13. Cook, W. 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