Document RJQMYzj3G9mp2DJrBeM0B4Y3n

*- .3 ii id a I 'I i j 1 i r> --r Indus Acute Inhalation Toxicity of Vinyl Chloride to Laboratory Animals E. MASTROMATTEO, M.D., A. M. FISHER, Ph.D., H. CHRISTIE, B.Sc., and H. DANZIGER, M.D. Division of Industrial Hygiene, Ontario Department of Health, Toronto, Ontario; Department of Physiological Hygiene, School of Hygiene, University of Toronto, Toronto, Ontario; and Welland County General Hospital, Welland, Ontario l i i $ t * t f f Introduction scribed as very slight. Elimination from the body FdfnkbotogohatmfwihhaneraaulaftdheeheoptegNovrssaicrerItncelelwptaaheRolsLoArordiewnti.nnermitiapSmc1cewmdeiii.ticnnllrigteeTaspehAehhdeiaHalrtirvtasipulxrohinnheiypicdtnnVprosedaiaitgaorennltodutawenouveipnrgd|telslepsiHciroueaininleoinaaatnyroreCjligillsskctoriusdvxndieofrteil*tntmoounaveisdneeshwafgfosaib.nfeeonaehstfmip5ornirlfzyireneiinri0oecnztaalocdnpi0lnraaerdlyjaceodM1cttuatsemhmpiapw8elopscyjrolplo3roeeaaynaouivlf3mtrcorstsrtt.tie,iieieotdnestfdfnzhsaDorfdyeatwvei.Gtocbea.ltte.taiahhiinxyxlOamotoclT,sIeeapiiytvtnhtncehhoioioleegelelildsonisnoatwvassrsyuwcoeenrsstoawwi.arhsmempdoetsefsboolAoicveloedettealufrtcehhirleakrshnnsTuierratdchereae,tthsrichnaameterrsrneiesireddelstdideondwedfth1v-ossetnIiwaibehmeian.hrtsioniunnosdeeysleslTheooaiciwtptaircwwi1tnntdihhaosoen2rfraoocecroeftssnVTeseSarsoauupdiescskrwiencoclenuCteavdteai.htrohdrocysowneoahndn&beCeinlcdrnnrlftdiimeisueetdyryeetaeiaasehmccfwnyadcssretirnhortrniaoet&avatvslaoealhuussgeoreagdwenpndredGssdtnrneannco1isoiitjdKad*ndmrioisafmcudewie.*centitnowvolta.ioiaoeduuaicTyfgzigOtartgtainsghohtheaseltl>crhaesysBpolremet.roeusiinltaysasonrreeoavlhtsbdeitciatAn.rtexxlhdfh7ualihawreencapemoamndlifFochon.neoaolguotaonioadirtTruoafecctgoicigwnrhdnhmhrsstadstisoeoieohodtcvsithetuunnrsieuraoesiigsteinssnedttgrdeolfnhayee.tuwcsiaqesdweaaari.mavlas|utpoeKdteoisisitaoesfdnynorevhIenertroleganasyeietor8itscnnhd6mihrdvcocorlaccemoynatieelac|uanreunoltntciditslh*nuoyeriestcuitpmieorexiilu.lerstnduindtfcrliedmnxtMninsea*awenp-!drtsdtininra:;iuiuev-i*i*:-nvlrd:h.-r!vnm:.i-:'>e-**.:r:,: Published information on tin; acute toxicity of vinyl chloride to exi>eriinentnl animals proved process worker was standing outside a imlvim-r: zation vessel and washing it with ;t water stri *::;- scanty. Patty, Yaut and Waite2 in 1930 reported on the acute response of guinea pigs to vinyl After ten minutes of this lie suddenly collai^ across the open manhole. Artificial resuscitate ' chloride. They found that exjjosurt; to *20 to 40 per cent in air killed guinea pigs in a short time; ex [insure to ten )>er rent was endured for sev eral hours. Congestion and edema of the lungs with hyi>orcinia of the liver and kidneys were noted. was successfully applied. Subsequent sympt*~ ' experienced by this worker were tightness ul t chest, nausea, abdominal pain and headache. * .second case occurred in a maintenance who was overcome while repairing a vinyl chi""-' Peoples and Ijcake/1 found the minimal anes leak. Both men were hospitalized. Another wor-.* thetic range of vinyl chloride in mice exposed for ten minutes was S to 12 per rent- in air; 25 to 30 whose ha mis were accidentally sprayed vinyl chloride liquid under pressure develops ]>er cent was fatal in ten minutes. Dogs and rab bits were anesthetized within one minute when exposed to a concentration ol aUmt IS per cent hum. This latter ease was reported hy lhr~-~ Sueh Imnis may'occur with other highly vo1:-T ill air. Recovery was very rapid with no apparent materials when sprayed onto the hands :ts a bl Untoward effect even after prolonged anesthesia. under pressure. D'hmann and I'hirv4 noted that- vinyl chloride Kdatovn and Gronsherglu in 1957 rejtorteo was highly narcotic hut. had a wide margin 1m*- hygienic conditions in a -jHilyvinyl pmce.''" - tween its narcotic and lethal concentrations. Its plant in the IbS.S.R. 'The plant was cng:i.-''`- local irritating e|]cc(, ami its toxicity were de the polymerization of vinyl ehloridc hy i j a cat: centre from Hires ppm) i loser Be* abov* tion i-ially fur <* infor cal cl aniir. r ma grad. WhC- Ily.i- Iron * `i;ri* ; I:up Jj ri ten 3 - -v ? am : mi fro st a * V:i J W; ' wi ; i BFG02597 v.JuxIrial Hygiene Journal non . Air sampling was done and tin* con.ntraiion of vinyl chloride was found to vary r.mi about. 20 ppm to alnmt. 2la ppm. (W.S.S.It. Threshold Limit- Value: l mg/liter or about 4(H) A spastic type blood vessel disorder was Scribed in workers from (.bis plant. because of (be recent fatalities mentioned ;Uive it was decided to undertake acute inhala- itm studies in laboratory animals with com mor ally available vinyl chloride. This was done l>otb ;.r comparison with earlier work and to provide ^formation on the acute response and pathologiil changes in more than one s|>eeios of lal>or:itory ,nimal. experimental Materials and Procedures Vinyl Chloride: The vinyl chloride was supplied r.a metal cylinder under pressure. A commercial :m<lc with the following specifications was used: gravity at 20*C iitrr content r-Uinc range *C dragon chloride content wtyWnc `^taWcliydo Nn ` jity (per cent) . purities (pdr cent) 0.9S3-0.9R5 None -II to -9.5 None 10 ppm maximum 20 ppm maximum Essentially iron free 99.5 maximum 0.5 maximum Pure vinyl chloride is a colorless gas at room :iiporaturc; its boiling point- is -- 13.9C. It has >\ivctish odor. Its flash point is given at -- 7SC A its explosive limits in air from 4 to 22 per :it. It has the molecular formula CIb:CHCl. Wiimo/s: Mice, rats and guinea pigs were used .;he study. Test ami control animals were taken 'in the same lalxuatory stock. All were fed a *.in<lnrd commercial diet and boused in the same y. All were of the same stage of development. Equipment: The inhalation chamber capacity 5G.G liters. It was equipp'd with a viewing :nlow and an inlet tube. Vinyl chloride was re nd in gaseous form through an adjustable ire on the top of the containing cylinder, then rough connecting ruhlx'r tubing and a recaliatid lusher flow-meter, 1'rcsli air was pumped ; motor at an adjustable controlled rate through meter. The streams of air and vinyl chloride re combined at appropriate rates of flow by a Y-tul)e leading through further nihlier tub; tu the animal chamber inlet, to deliver a .tinning stream in the 'desired projxirtions. ^illations and adjustments were made to pro. c the following flow concentrations of vinyl "hdc in air for delivery: 10. 20, 30 and 40 per \t. All concentrations are expressed in this rert.is per cent by volume in air. No determina tions of vinyl chloride concentrations were done in the test chamber during the experiments. J^.r/H'rinirriial Procedures: Different groups of five mice, five rats and five guinea pigs were placed in the chain)>cr and excised for thirty minutes to concentrations of It), 20 and 30 per cent vinyl chloride in air. Similar groups of con trol animals were maintained but not cxjioscd to vinyl chloride. At the end of thirty minutes ex posure the lest animals were immediately re moved to fresh air. An additional group of five guinea pigs was cxi>oscd to a concentration of 40 percent vinyl chloride in air. In all fi5 exi>erimeiital animals were involved. Observations were re corded on the animals during and after exposure. The animals which died either during the cxI insure or after a delay period were autopsied soon after death. Two weeks after the exposure sur viving test animals and controls were sacrificed by a blow to the head with the exception of four control rats which were killed by exsanguination. All animals were examined for gross pathologi cal changes. Tissues were removed from all ani mals for microscopic examination. The lungs, liver, kidney and heart were removed in all eases. The brain, adrenal, spleen, trachea, lymph nodes, and the eye were removed from represen tative animals in each group for study. The tissues were preserved in formalin and sections made for staining with hematoxylin-cosin. Special stains were made where indicated. Observations Control Animals: No symptoms were exhibited by the 15 control animals and no deaths occurred. Ten Per Cent Vinyl Chloride: The response of animals exposed to this concentration is recorded below in summary form: Exposure Time (minutes) 5 10 15 20 25 30 Response Slight irritation in mice and rats. Increased motor activity first in mice, then rats and guinea pigs. Increased motor activity in all species; twitchine of extremities in mice. Pronounced tremor, unsteady gait and muscular incoordination in all species. Mice and rats in side iKwition; muscular incoordination, tremors and twitching of extremities in guinea pigs. Mice ami rata unconscious, guinea pigs very unsteady but still standing. Mice and rats in deep narcosis; guinea pigs in side position with tremors--one unconscious. Ex]>osurc was stopped and the animals removed to fresh air. All recovered within five minutes. Twenty Per Cent Vinyl Cidoride: The response ; f ! Iri tI i j ii i }I 20244002 BFG02598 396 October, !&< Indust of animals exposed to this concentration is re corded below in summary form: Exposure Time (minutes) 1 2 5 10 15 20 25 30 Response Immediate irritation in mice and rats. Muscular incoordination in mice and mts. Mice and ruts on their sides with marked tremors and twitchinR of the extremi ties; unsteadiness and muscular inco ordination in guinea pigs. Mice and rats unconscious with rapid irregular breathing; guinea pigs un conscious but showing marked twitch ing. All animals in deep narcosis; respirations irregular and rapid. Deep narcosis; breathing slow and shal low. Breathing ceased in one mouse; frothing at mouth and nostrils in mice and rats. All animals in deep narcosis. Exposure was stopped and the animals removed to fresh air. Mice and rats recovered faster than the guinea pigs and appeared normal within five minutes except for one mouse which was dead. The guinea pigs continued to show muscular in coordination, unsteadiness <m their find, until 20 minutes after removal from exposure. Thirty Per Cent Vinyl Chloride: The response of animals exposed to this concentration is recorded lxrlow in summary form: Kximxurc Time f minutes) Response Mice showed irritation immediately and the ruU* allowed irritation quickly thereafter. 1 Muscular incoordination in mice and rata. 2 Mice und ruta in aide position with marked tremorn arid twitching of the extremilicH; muscular incoordination in guinea pigs with developing paraly sis of the extremities. 5 All animals unconscious; rapid irregular respirations in mice ami nits with frothing til>out nose ami mouth; twitching of extremities still occurred occasionally in guinea pigs. 10 Respirations atnpiicd in mice; breathing stow mid ahullow in ml*; guinea pig Mill c\liilul<d oeen.iiohal twitching moia-iMciit* of the eMrcmilic*. 15 1 ti'i-aihing M<i|i|n*d in rut*; respirations sluiv and -hallmv in guiin-ti pigs; twitching id cMii-uiilic* still present in guinea pigs. 30 Mice aud mts si ill; guinea pigs tu deep linicii.-u* with sluw shallow breathing Exposure* was stopped and the animals removed to fresh air. The mire and rats were dead. The guinea pigs took 2f> minutes to return to their normal appearance and activity. (hie guinea pig from this group died within 21 hours following exposure. Table I Number of Deaths in Different Groups of Kin Mice, Rats and Guinea Pigs Exposed for TUiuv Minutes to Varying Concentrations of Vinyl Chloride in Air Vinyl chloride concentration (l>cr cent by volume in air) 10 20 30 40 Laboratory animal Mice 0/5 1/5 5/5 " Rats 0/5 0/5 5/5 -- Guinra [ti^s I1 C/5 0/5 1/5* 2/5* Total 0/15 1/15 11/15 2/5 Total 5/15 5/15 3/20 | H/M * A delayed death occurred within 24 hours following expos err- Forty Per Cent Vinyl Chloride: Only five guim-= pigs were exited to this concentration. Signs irritation were immediately apparent. Muscuhr incoordination ap]X'ared within seconds. Alb: five minutes all the guinea pigs were imconscimu with slow shallow lava thing. At the end of tin* c.\|Mismv period one guinea pig was dead and ti c remaining four were in deep nareosis. These sur vivors took 30 minutes to return to their normal ttpjH'arance and activity, but one died within the following 24 hours. The mnnlHT of deaths occurring in different groups of five laboratory animals exjKised i"f thirty minutes to varying concentrations of vinyl chloride in air is shown in Tabic 1. Pathological Findings Gross pathological and histological studies wen' carried out. The findings are summarized Ixrltnv. Control Animals: These animals showed n gross or microscopic evidence of damage. Ten Per Cent Vinyl Chloride: All test animal' survived this exposure. They were sacrificed t'" weeks later. On gross examination there was evi dence in mice of slight hyperemia of the Uing' This was less marked in rats. Guinea pigs sinned no difference, from eontrol animals. On histol"--1 examination the mice showed very slight engorge- inetit of the pulmonary vessels. One showed degenerative changes in the t id mlar epi thelium of the kidney with hydropic swrlhag. The ruts showed slight congestion of the rapdia'- les in (he lung. Lungs in the guinea pig were a slightly more hyperentir than those of the nmtm. animals. Tu'enty Ptr ('ent 1 tityl (Itlaride: (hie meiev died as a result of .*10 minutes exposure to th'> concent ration. I hilmouury l ongest iou was evaicta on gross examination. Microscopically, there wie riigorg' patchy The 1 cliang* hides. The saerihrouge: hut it in the deliee mals. liver < norm: TU. tion < e\p< I: hrm< show one g then hcm< iriah whir (min rhng supe gest of \\ Wilt* deg. j i sect i '1 t Wi In ten gn\ l at i gm, du In i 4* 'u oO a t t! 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J.)|jo s'j.m.u oa\| po.H) q Jia\ 9uiq oq] m sjossoa pK|q otp .1 (uotuo^jo. i KiV Ii I'Munof V'!Jiyui BFG02600 20244004 398 October, Id- response. Exposure to ten per cent vinyl chloride in air produced deep narcosis in mice and rats but no deaths; 30 per cent concentrations killed mice and rats. Exposure of guinea pigs to 20 per cent produced deep narcosis; but three of five guinea pigs survived exposure to 40 i>er cent con centration. Animals dying as a result of exposure were autopsied shortly after death. Survivor's and con trol animals were sacrificed two weeks later. Gross pathological and microscopic studies were done and these findings arc described. The principal pathological changes in animals dying from exposure were congestion of the lungs with pulmonary edema and hemorrhages in some, and congestion of the liver and kidneys. Failure of the blood to clot was also observed. One of the three guinea pigs which died following exposure showed severe fatty infiltration of the liver. Survivors sacrificed two weeks after exposure showed little difference from the control animals. Pulmonary congestion was still evident but liver and kidney congestion was not. References 1. Danziger, H.: Accidental Poisoning by Vinyl Chloride: port of Two Cases, Canadian Med. Assoc. J. $2: $2$ 1960). 2. Patty, F. A., W. P. Yant, and C. P. Waite: Acute of Guinea Pigs to Vapors of Some New Commercial Orc^ Compounds V. Vinyl Chloride, Pub. Health Kept, j; (A liftust 1930). 3. People, A. 8., and C. D. Leake: The Anesthetic Act Vinyl Chloride, J. Pharmacology 48: 234 (1933). 4. Lehmann, K. B., & F. Fluky: Toricology and //Mi(w , Industrial Solvents, Translated by E. King and II. F. 5:... :. Jr., Williams & Wilkins, Baltimore (1943). 6. Senaumann, O.: Cited by Lehmann, K. B. and F. Flury 6. Oster, R. H., C. J. Carr, J. C. Krantz, and M. J. Sun wald: Anesthesia XXVII. Narcosis with Vinyl Ch!or. IAnesthesiology 8: 359 (1947). 7. Carr, J., R. M. Burowos, J. F. Vitciia, and J. C. Riant: Jr.: Anesthesia XXIV. Chemical Constitution of IKA-* carbons and Cardiac Autonmticity, J. Pharm. and Therap. 97: 1 (1949). 8. Annual Report of the Chief Inspector of Factories for Ike IV:* . JB$t, Ixmtlon : Il.M.S.O. Cmd. 8772 (March 1953), 9. Hajuuh, D. K.: Health Problems in the Manufacture Use of Plastics, Brit. J. Ind. Med. 10:255 (1953). 10. Filatova, U. S., and E. S. Gronsukko: Hygienic WorUn Conditions in Polyvinyl Chloride Tar Plants. Giqitna ; ? 38-42 (January 1957). Abstracted in Abet, of World $I*d. tl. 69 (July 1957). Back Issues of AIHA Quarterly ]70R IS YEARS THE A1IIA QUARTERLY was the publication of AIIIA, then J- in 1958 it was changed to be the AIIIA Journal with six issues per year instead of four. Now limitation of storage space is forcing us to dispose of all back issues of the Quarterly. 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(Bark i-.-ues of AIIIA Journal, 1058 to present, may 1x` obtained directly from our publisher, The Williams A* Wilkins Company, *128 10. l'rcston, Baltimore 2, Maryland, at $1.50 each issue.) N O N O 0 01 Introdi TS, and b Lunv thallh The p to its used also v; optica tion v An numb thalli rides >*n le r: the d labor tribu (TP" tinat ei>11 eunt ti aeul `\n \ eral poui litre Exp T tain Co. u:d are1. re hi l -1 1: BFG02601