Document 6RejVZJpbz5MZbj49ZBKz24rg

ir \ () Acute Inhalation Toxicity of Vinyl Chloride to Laboratory Animals MASTROiHATTEO, M.D., A. M. FISHER, Ph.D., 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 Introduction scribed as very slight. Elimination from the bufc was very rapid. These authors quoted tha wwt FIRST prcixired in 1833, vinyl chloride has come into increased use in the last decade in of Schaumaun1 with experimental animals. Mw.. rats and dogs ware able to endure repeated am- the production of polyvinyl chloride resins. Thecosis without any pathological evidence of b* fire and explosion liazard of the monomer and its or kidney damage. According to Schanmim, narcotic properties on acute exixwurc arc well known. As an industrial material, however, it luis concentrations of seven to ten per rent in 0 would be narcotic to humans in a short taaemd been regarded ns of moderate toxicity. A Thresh old limit Value of 500 ppm was established by 12 per cent would be dangerous. ' Vinyl chloride has been studied os a pueUb the American Conference of Governmental In anesthetic agent. Oster and associates' noted Ifatf dustrial Hygienists. incoordinated muscular activity of the extram No industrial fatalities associated with its use have previously been reported. It was therefore of special interest when two fatalities occurred in tics and cardiac anythmias of a serious astern were observed in all six dogs used in their apRS ment. Carr and others7 found that vinyl rhlondt a plant liandliug vinyl chloride. This plant is en gaged in the polymerization of the gaseous mono produced sensitization of the myocardium is three of seven dogs in which it was administrate mer with the aid of catalysts. One worker died while cleaning out a polymerization vessel and the as an anesthetic agent. Two cases of vinyl chloride gassing occurred is other while working in a pit. Details of these two a factory in Great Britain where polyvinyl rtt*- fatalities liavc lieen reported by one of the au idc resin was being made. These were reportedIf thors.1 Published information on the acute toxicity of the Chief Inspector of Factories.1 In one nte s process worker was standing outside a polyum vinyl chloride to experimental animals proved scanty. Patty, Yant and Waite* in 1930 reported on the acute tvsponsc of guinea pigs to vinyl zation vessel and washing it with a water stimm After ten minutes of this he suddenly coUapri across the open manhole. Artificial resuscitate* chloride. They found that exposure to 20 to 40 per cent in air killed guinea pigs in a short time; exposure to ten i>er cent was endured for several hours. Congestion and edema of the lungs with hyperemia of the liver and kidneys were noted. Peoples and 1/xikc1 found the minimal anes thetic range of vinyl rhloride in mice exposed for ten minutes was S to 12 per rent in air; 25 to 30 was successfully applied. Subsequent symptom* experienced by this worker were tightness of te chest, nausea, abdominal pain and hcadaclie. T!w second case occurred in a maintenance wwW who was overcome while repairing a yinvl dJratte leak. Both men were hospitalized. Another worim whose hands were accidentally sprayed vinyl chloride liquid under pressure devehqad* per cent was fatal in ten minutes. Dogs and rab bits were anesthetized within one minute when exposed to a concentration of a Itout IS per cent in air. Recovery was very rapid with no apparent bum. This latter case was reported by Hair** Such bums may occur with other highly vtdsth materials when sprayed onto the hands asa lajad - untoward effect even after prolonged anesthesia. under pressure. Lehmann ami Fluty* noted tluit vinyl chloride Filatova and Gronsberg1' In 1957 reported 0 was highly nan-otic but had a wide margin lie- hygienic conditions in a polyvinyl pmrwMS tween its narcotic and lethal concentrations. Its plant in the U.S.S.R. The plant was enpifsd * local irritating effect and its toxicity wen? de the polymerization of vinyl chloride bv mrenad 725182 tjtlyat. Air Sampang w& ne auu utc cuu,tion of vinyl chloride whs found to vary about 20 ppm to about 315 ppm. old Limit Value: 1 mg/liter or about 400 i). A spastic type blood vessel disorder was bed in workers from this plant. .use of the recent fatalities mentioned ive it was decided to undertake scute inhalastudies in laboratory animals with commcrly available vinyl chloride. This was done both comparison with earlier work and to provide formation on the acute resjxmsc and pathologichangos in more than one species of laboratory' lerimental Materials and Procedures Vinyl Chloride: The vinyl rhloridc was supplied s nietal cylinder under pressure. A commercial -Tjniflo with the following specifications was used: JljuriSe (wily n J0*C `vUstvr floswot *'BoiUo( non *C .SrSn>**B chloride content JrSMrim ' imclikliydo U '^Tcrtty (per cat) /J>lit (per cent) a.sn-o.Ms None -II to -9.1 None 10 ppm muimunt 01 ppm niaxiitium Eawntially Iran Ini 90.5 maximum 0.1 maximum Pure vinyl chloride is a colorless gas at room '..temperature; its Ijoiling point- is -- 13.9QC. It has < - v a sweetish otlor. Its flash point is given at -- 78C | *^ind its explosive limits in air from 4 to 22 per f"""rent. It lias the molecular formula CH-:CHC1. 1^% A mmols: Mice, rats and guinea pigs were used the study. Test and control animals were taken I the same laboratory stock. All were fed a 5^*andard commercial diet ami housctl in the same Jsjiay. All were of the same stage of development. ( Equipment: Tlic inhalation chamiter capacity ^J^*ss 56.0 liters. It .> equipiied witli a viewing dow and un inlet tube. Vinyl rhloridc was re in gaseous form through an adjustable Ive on the top of the containing cylinder, then Ough connecting rubber tulnng and a rccali- ", Fisher flow-meter. Fresh air was pumped r motor at an adjustable controlled rate through r. The streams of air and vinyl chloride i combined at appropriate rates of flow by a Y-tube leading through further rubber tub11'to the animal chamber inlet, to deliver a suing stream in the desired proportions. ons and adjustments were made to pro the following flow concentrations of vinyl "de in air for delivery: 10. 20, 30 and 40 per , All concentrations are expressed in this re1 os per cent by volume in air. No determina- UUiiA U4 VAMJfA i iiitn * in the test chamber during L-_ experiments. Experimental Procedures: Different groups of five mice, five rats and five guinea pigs were placed in the chamber and exposed for thirty minutes to concentrations of 10, 20 and 30 per cent vinyl chloride in air. Similar groups of con trol animals were maintained but not exposed to vinyl chloride. At the end of thirty minutes ex posure the tost animals were immediately re moved to fresh air. An additional group of five guinea pip was exposed to a concentration of 40 per cent vinyl chloride in air. In all 05 experimen tal animals were iuvolvcd. Observations were re corded on the animals during and after exposure. The animals which died either during the ex posure or after a delay period were auto|>sied soon after death. Two w<*cks after the exposure sur viving test animals and controls wen: sacrificed by a blow to the bead with the exception of four control rats which wen: killed hy exsanguiiuttion. 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 oil eases. The brain, adrenal, spleen, trachea, lymph nodes, and the eye were removed from represen tative animals in each group for stmly. Tin: tissues were preserved in formalin and sections made for staining with hematoxylin-rosin. pccial stains were made where indicated. Observation* Control Animals: No symptom* wen: exhibited by the 15 control animals and no deaths occurred. Ten Per Cent Vinyl Chloride: The response of anirauls exposed to this concentration is recorded below in summary form: Exposure Time ' minutes! 1 5 10 1& 30 39 30 Kcsjwiuc Slight irritation in mice and rats* Increased motor activity first in mice. then rat* and guinea idea. Inoeased motor activity in nil specie*; twitching of extremities in mint. Pronounced tremor, unsteady sail and muscular incoordination in all iliee and vats in ride position; muscular incoordination, tremors and twitching of extremities in guinea pigs. Hict and rats uneonarious, guinea pigs vry unsteady but still standing. Hio* and rets in deep nnreosn; guinea pigs in side iioritson with tremors one Exposure was stopixxl and the animals removed to fresh air. All recovered within five minutes. Twenty Per Cent Vinyl Chloride: The resixmse \ 725183 l) 336 October. /W of animals exposed to this concentration is re corded Itelow in summary form: xfiuri Tim# tminutvi) Ripm*w 1 Intwnluiip imftfim in iiimt and rat#. 2 Uuantkr itifiunitiutiiifl in nn#r and 3 it#* ami ration llieir till## with marked tvrmora and twifriijjic of th# ntmni* tn; itnitnuiiana amt timmiht incw orHittntimi in fuim* 10 Mira and rata iinniannu* with rapid irr**br brmthinc; cmn#n tries un* wwnoia but titowia* mnrktil twitcJi- ift*. 13 All aninmU in d##)1 nnrtoria; tmpinttinni irrretiUr and mind. 30 IVq itammt: lAiMhiu dw and alinl- km1. 13 RtvatUin* fnunl in on# frothin# at mouth and nnatril# in nntoand mu. 30 AU animals in (Wp narataia. Exposure wns stopptxt awl the animals removed to fresh air. Mice and rats recovered fader titan the guinea pigs and app-ared ttonnal within five minutes except for one mouse which was dead. Tltc guinea pigs continued to show muscular in coordination, unsteadiness on their fix-t until 20 minutes after removal from exposure. Thirty Per Cent Vinyl Chloride: The response of animals exposed to this eoueentnition is recorded below in summary* form: Ex(apioa*o"u, Ti)im. Rpor Rhe abow#J imiation iitHiiftliiMdy and tit# fata liaxml irritation quickly 1 MiaciiUi incoordination in miw and mts. 1 Mir* ami nti in aid# |<c#itkm with nwfkl imunn ami twurhiuc of llw Ntmitmn; niUMlllar iitrourdiiulioa in Riiitm inn with d#v#loptn< pnndylii of tlw S AU animal* uimnmouf: rapid irregular rrefnmiifi# in mir# and rat# with frothing about nmr qi{ mouth; tvitehin# of ftiivhniin Mill ocrtirm! otTUHtiulIv in iitinn imp. 10 RwinniiiAiiMtQfit#il in mi##; Itrmtliinc rb and thallnw in mu; #tun#n in## till Ptliihiinl nmaional twitching mov#fti#aa of lb# #\|r#imii##t u Brrethmc at<nii#*l in mu: crepitation* ion- tad ilnilmr m cmn#n ptgi; twitching #4 rttvmnitim anil |trra*ni in giiMinn pica so Mb# and mta atiU: guinm |ir tn dtop narratm with *4ow ilmllnv lirmtlung Exposure wns stopped and the animals removed to fresh air. The mice and nils wen* dead. The guinea pigs took 25 minutes to return to their normal appearance ami activity. One guinea pig from this group died within 2-1 hours following exposure. Tami.k I XmuiImmt of Dentils in DilTereut Gniti|n ..| law Mice, ltais ami Guinea I'ig- Kxfxised f..r D.ixj Minutes to Varying ('oneeiilralitiii- rtf fait Cliloritle in Air Vinyl rhlorwi# t t'1W1wUr'c.cMnrat imbyn vitlumtr in air* i j in iI a> ! at i 40 i Laboratory animal Mire j Rat# (suiiwa |*t* -i 0/S I/S |' O.i Or 5 i c.s i S_,S 1|J S/S -- i ! l.S* i.s* trtr ' fl > 1 'A u- Total | S/1S 11 V1& 'i 3,TD n f<-. ---- * A tlrbivniUnOiomarml wittunSt Forty Per Cent Vinyl Chloride: Only five tsaniii pigs were exposed to this roneentratiuu. irritation were immediately apparent, incoordination appeared within seconds. JUvriy five minutes all the guinea pigs were unriw>sws\v with slow siuillow breathing. At the end of ds.-.y. ox|>o*ure |xriod one guinea pig was dead and *i i remaining four were in deep narcosis. The* mn- ; vivors took 30 minutes to retum to tlieir went''; , apixairanec and activity, but one died withalls-j\, following 24 hours. / ? \, Tlie number of dentils occurring'in tfiSriw* V group* of five laboratory animals expusnt lt*V thirty minutes to varying concentrations of chloride in air is shown in Table 1. W'1 `* "'J 1 \J \ Pathological Findings Gross pathological and histological studies atw ` ; carried out. The findings are summarized 1W. Control .1 nimals: Tliese animals slum.d nr .-I gross or microscopic evidence of damage. . *-v Ten Per Cent Vinyl Chloride: All lest acinuk V survived this oxirosure, They were sacrificwl l weeks later. On gross examination there deiue in mite of slight hyperemia of the loot* ' This was less market! in rats. Guinea pigs d-d ? no difference front control animals. On liHtekc* examination the mice showed very slight rngieas ment of the pulmonary vessels. One mow* k showed degenerative changes in the tuliuUrrja- : thelium of the kidney with hydropic ssfSktg Tlie rats showed slight eongestion of the rspckries in the lung. Lungs in the guinea pig were W.... slightly more hypereinie than those of tlie nMr* ; animals. Tirenty Per Cent Vinyl Chloride: One wow died as a result of 30 minutes exposure tu tl* u. concentration. Pulmonary congestion wascvsksS on gross examination. Microscopically, tlicrr ws ; 725184 Industrial Hygiene Journal lJ 337 , 'neorgemout or the blood vessel* in the lung wit li | (ati-hy an-ii of atelectasis ami minimal islcina. I1 T1m* kidneys showed minimal degenerative changes in tlu* epithelium of the convoluted tu bules. Tlu* tost animals surviving till* ex]>osurv wore racrificcd in two weeks. On gross examination, oingcstion of tho lungs was present in all sjiecii-s, Isit it was more marked in tlio mioo and nits than J in tho guinea pigs. Histologically, there was evi- .* ilrnrc of pulmonary congestion in expwed aui maU, Some fatty infiltnition was pnss-nt in tho I livor of olio nit. All other tissues studied apixitred ; annual. i Thirty l`rr Cent Vinyl Chloride: Gross examinaj 1 tiwi of tho animal* wliieh died as a result of this exposure revealed congestion of tlie lungs with | hcmorrltagie arcus. Tlie mice and rats in addition thowrd congestion of tho livor and kidney. The one guinea pig death was dohiyod. In this animal there was nuirkod congestion of tlie lungs with . hemorrhages and tho liver was distended and very friable. Tlie microseopir cliaitgos in the animals which died inoludod marked engorgement of the pulmonary blood vessels with edema and hemor rhages in tho lungs. Tlie tmehoa of one rat showed sii|a.`rfioial desquamation of tho epithelium. Con cretion was also evident in the liver and kidney nf tlie mioo and rats. Tlie liver of the guinea pig whioh had the delayed death showed severe fatty legeneration of the liver confirmed with frozen wrtious stained with thulan III. The four surviving guinea pigs aero saerifieed two weeks later. Marked |Milmonary congestion was present with hentnrriiagie areas and edema, In one ease there was evident** of wvomlary late; trrial iiitiltration. Tlie liver in tliere guinea pigs gave the ap|iearaiire of fatty infiltration Iwt no fat was demonstrate*! on frozen section. Forty I'er Cent Vinyl Chloride: One of five i guinea pigs exposed to this eoneentration died i luring the exposure ami another died within 24 ; hours. Tlie two which died showed marked con gestion of the lungs with lieninrTiiagcs on gross examination. This was also evident on mirrowupie examination. Tlie liver of one of tliesr gave the apiwarancc of fatty infiltration, but no fat mold lx* demonstrated on frozen section. Tlie thus- surviving guinea pigs were saerifiecd twq weeks later. Marked congestion of tlie lungs with hcmoniiage was eviih*nt on both the gross and mieniscopie examination. In one guinea pig, the tracheal epitluiium was coni|>ietely a I ecut. Pathological studies which were mailc of the Inain, heart, spleen, adrenal*. lvni|ilt node* and (he eyes showed no difference Iirtween controls and animals dviug as a result of exposure or lietwtvn i-imtrols and tlie surviving animals sacri- fieetl two weeks after exposure. There was a tendency for the Wood to remain unclottcd in the animals dying during exposure. This feature was noted in the two humun fatalities mentioned ear lier Imt it Is not a specific characteristic of vinyl chloride. t Discussion Tlie resixinsc of guinea pigs to inhalation of vinyl chloride was similar to that reported by Patty, Yant and Waite. Tlie guinea pigs in our study, however, tolerated a greater exposure dur ing th' ex|M'riineutal jierind than either the mice or rats. The results in mice agreed closely with those re|Mirted by Peoples and Leake. Rats were similar to mire in their rnqxuisc. * Tlie |Mithological changes in animals which duxl as a result of exposure were mainly those of vascular engorgement of the lungs with hemor- rlrnges and edema. Tlie severity of these changes varied with-the severity of exposure. In the higher concentrations, pulmonary rhange was marked with severe damage to tlie tracheal epithelium. ' Congestion of the liver and kidneyB also occurred, in test animals. These changes are. similar to those reported by Fatty and associates. Evidence of pulmonary congestion was still present in surviving animals sacrificed two weeks after exposure. Patty and associates reported that such changes had disappeared in about eight days. Degenerative changes in the tubuiajepithelium j of the kidney were noted in one mouse dying as a,' result of exposure and in one mouse sacrificed* two weeks after being exposed. Such changes, however, were minimal and not shown by other animal* in the group. One nf the guinea pigs with delayed death fol lowing expoKUre showed severe fatty infiltration of tlie. liver. Clianges suggestive of fatty infiltra tion were olwcrvod in other exposed animals but not eonfinned by frozen sections stained with Sudan III. Summary Separate groups of laboratory animals com prising five mice, five rats and five guinea pigs were exposed in an inhalation chamber to concen trations of 10, 20 and 30 tier cent vinyl chloride in air for 30 minutes. An additional five guinea pigs were exposed to a 40 per cent concentration for a similar period of time. The response by each of the three species to these, concentrations is noted. Inhalation of these relatively high concentra tions produced narcosis and death. Mice were the most susceptible with guinea pigs considerably more resistant. Rats were similar to mice in their 725185 '398 ' October, 1960 response. Exposure :to. ten percent vinyl chloride in air produced deep narcosis in mice and rats but no deatlis; 30 jxt rout concentrations killed mice and rats. Ex|xsuro of guinea pigs to 20 per cent produced deep narcosis; blit three of five guinea pigs survived exposure to 40 |xw cent con centration. Animals dying ns a result of exposure were autopsied shortly after death. Survivors and con trol animals were sacrificed two weeks later. Gross pathological and microscopic studies were done and these findings arc dcsc.rilwd. The principal jiatliologieal changes in animals dying from cxixwure were congestion of the lungs with pulmonary rtlcmn and henwrriiagcs 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 eougestiou was not. Reference* 1. Dakzigk*, 11.: Acrii)raii) ?oiwoio| by Vinyl Chloride: lb port of Two C***4i*m JUrd, Jine. J. St; ih i.SpS I'jftO). 3. Patty, Y. A,, W. P. Vaxt, axp C- P. Waits: Aeove of Guinn Piff to V|iof> of Som* Ntw Comamtial Qtiue Compound! V. Vinyl Chloride, Pith. Htilth Rrpt. ll: Ite (Aufliub 1030). 3. I'ropuKA, A. S., a.vo C. D. L*aKe:TS* Aoooibttie Actbo^ Vinyl Chloride. J. A** 00331. 4. Lehmann, K. 0., 4 K. Flchy: TorkoUfy and /fwim /ndMAtn'of falr*nt$t Traittloted by E. Kinf end II. Y. fimik, Jr., Williams ft Wilkin*, Datliioom (1943), 3. Sciiavmahx, O.: Cited by Lohmonn, K- B. and F. Flixy. ft. OfTGi, R. H,, C. J. Cam, J. C. Kjuntx, axo 31 J. Sir* walo: Aneatlmitf XXVII. Xareoaia iritb Vinyl CUonir. .lttrftAr*(W#ir ft.* 399 (I94T), T. Cam, J., ft, M. BtinotAox, J, F. Vttctte, and J, C. K*um Jr.; Anallirwi XXIV, Clteininl Constitution of Hydn- enrbons and Cirdiu AutomaUeity, J. PWm. and TkVQV-97? I (1919). 9, A tual Rtport / Ik* Ckitf Imwpfdot / Factor*** f&t U* 1W- i$SIt London : H.M.3.O. Cmd. m (Mvob 19S3), 9. Harris, D. Hnltli Problems in tb Xanufrntui* and l> of Flatties, Bril. J. ini* Jfi. 10: OSS (19). 10. Filatova, V, S,, axd R. 8. GmkiiuQ: Hycftsnie Worinat Conditiona in Polyvinyl Chloride Tor Plant*. Ciritm yt'- 39-43 (January 1997). Abstracted in AM. / 1F*M JM. *' 09 (July 1997). Back Issues of AIHA Quarterly FOR 18 YEARS THE AIHA QUARTERLY was the publication of AIHA, then in 1958 it was clumped lo be the AIHA .lountal 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. For individual issues quantities on hand vary from a low of S upward. All issues except March 1946 (Yol, 7, No. It and June 1950 (Vol. 17, No. 2) arc available as we go to pre*s. Sonic issues are reprinted without cover. 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