Document oMBZajYGD9qj2ev817oLGKOZD

Acute Inhalation Toxieitv of Yinvl Chloride * * to Laboratory Animals E. MASTROMATTEO. M.l).. A. M. KMIKK. Hh.D., H. CHRISTIE. B.Sr.. ami II. 1IANZH.KK. M.l). Division of Industnal Hygiene, Ontario lh-p'U'm. >.i liDepartment of Physiological Hygiene, Schont i j II nt- - ' Toronto, Ontario; and Welland Welland. Qr.tnr,u U '< Or-tn--n. Introduction scrilsal ns irr - .giit 1.11 imrt:i11>>11 !.",n. 111> was very 1-1 pnI !`i <'!' .-1 ittin>1 nu'it.-.i (In- FIRST prepared in 1833, vinyl chloride lms come into increased use in the last decade in rats .uni dog- .able to 'mliire repeat' u the production of polyvinyl chloride resins. Thecosis Wit 1II '111 'li -i'll ll"l>)Clral i-\ ! 1' III I - .1 . fire and explosion hazard of the monomer and its or kiilncv .hiii. \1 .rilimi to iin'ii. narcotic properties on acute exposure are well coin cut rat it.nr. -.'n t.. tin '-i .>nf .1. known. As an industrial material, however, it has would lie ilai. nlii to i niiian- in a -hurt tine Ixicn regarded ae of moderate toxicity. A Thresh old Limit Value of 500 ppm was established by the American Conference of Governmental In dustrial Hygienists. Xo industrial fatalities associated with its use 12 per n ut would : .linger.11A irtyl chloride ans lieen -tudied as a | --.1 anesthetic agent. 1 saer and .issnci.-tii noted ri ineimnlinatod niusiailnr ui-ln it 1 of the r\ti.-!: tie* and cardiac arrytlunias ol a --rams nit', have previously been reported. It was therefore of special interest when two fatalities occurred in plant handling vinyl chloride. This plant is en were ot*.. r.ed in .1' ~i\ dogs used :n ll.iar .'\i ment. Carr and oti.. r': found tl.ai invl diloii produced -.nsitiznlion of the in\ociirdmrn gaged in the polymerisation of the gaseous mono mer with the aid of catalysts. One worker died while cleaning out a polymerisation vessel and the other while working in a pit. Details of these two fatalities have been reported by one of the au thors.1 Published information on the acute toxicity of vinyl chloride to experimental animals proved scanty. Patty, Yant and Waite* in 1930 reported on the acute response of guinea pigs to vinyl chloride. They found that exposure to 20 to -M) per cent in air killed guinea pigs in a short time; exposure to ten per cent was endured for several hours. Congestion and edema of the lungs with hyperemia of the liver and kidneys were noted. Peoples and Leake* found the minimal anes thetic range of vinyl chloride in mice exposed for ten minutes was 8 to 12 per cent in air; 25 to 30 tier cent wm fatal in ten minutes. Dogs and rab bits were anesthetized within one minute when three of -CU'II dog- 111 wluch it was aiiliiihi-t. 1 as an aiic-tlictie agent. Two eases ol vinyl chloride gassing m-eurri d a factory 111 < ircat Britain when' [xilyunyi i.0 ifle. resin was living made. These were reporte.1 the Chief Inspector of Factories.* In one on-, proeess worker was standing outside a jxil> in< iation vessel and washing it with a water SIP". After ten 110111111?. of this he suddenly eollaps nero.-s the open imitihole. Artificial resnscituti was siiecessiolb' applnal. Sulisequcnt synipto experienced by this worker were tightness of t chist, nausea, aUloininul pain and headuelie. 1 second ease occurred in a maintenance wmt who was overcome while repairing a vinyl eh lor leak. Both men wen* hospitalized. Another wort whose hands were accidentally sprayed w vinyl chloride liouid under pressure develo|'i bum. Tins latter case was reported by Harr exposed to a concentration of about 18 per cent Such hums min .K i iir with other highly volai in air. Recovery was very rapid with no apparent materials when -priced onto the hands as a li. j untoward effect even after prolonged anesthesia. under pressure. Ijhmmn and Plury4 noted that vinyl chloride Filatova and (Irousberg1* in 19.17 re|Hirtr.| was highly narcotic but had a wide margin be hygienic conditions in a polyvinyl proc.--- tween its narcotic and lethal concentrations. Its plant in the 1' S..fi.R. The plant was eng.Lge. 1 local irritating effect and its toxicity were dc- the imlyinenzution of vinyl chloride by incati- 394 r * i VC5780 ndustrial Hygiene Journal 39$ catalyst. Air sampling was done and the coni-utrution of vinyl chloride was found to vary -oni aliout 20 ppm to about 315 ppm. (U.S.S.R. 'hri sliolit l.inut Value: 1 mg/liter or aliout 400 pm). A spastic type blood vessel disorder was i-serds-d in workers from this plant. Because of the recent fatalitic* mentioned Ixive it was decided to undertake scute inhaluuin studies in laboratory animals with commer- mlly available vinyl chloride. This was done both >r comparison with earlier work and to provide ifnnnatinii on the acute response and |mtliologial changes m more than one species of lalunitory nimal. xperimental Material* and Procedures Yuujl ( Utrritlr: The vinyl chloride "a.~ -upphed l a metal cylinder under pressure. A ii inmcreml rade with the following specifications wa usnl: t^tic gravity at 2U*T Wf COfH*Dt oilmg rang* *(' ivdroxrn chloral* rontffOt c*tvlrne TlD nntv 'jwr rest) upuritit-t* (par ornli -i) - 11 r. - 1 VM* Id p*':- intt,`i, .'h .*0 JIJi" -tll*Ull Mil Ewnitiiiiv tnui fn 5 muii mu fl & ritftVi. .mi Pure vinyl cliloride is il color1 - ga> at riHim Iilnllp'Oc.nlUtuICre;. iItI- U.-WnMlOin>gh pI-o.MinIIt iI- 1 # ft t . It lias -weetish odor. Its flasil (Hunt i- IP -n it -7KC nd its explosive limits m air Inin 4 to 22 per lit. It lias the molecular formula ('II .('IK'l. .luiinn/s: Mii c, rats and guinea pigs were used l the studv Test and control animal' were taken oni the -ami- laliorotnry stock. All wen' fed ;t ,and,iid commercial diet and housed in the sitin' nv All Here of the sanjc stage oi development. h'i'iipmntl- The inhalation . liamU r lapacity as Vi i liter' It Has -<pli|i|h 11 Hitli a viewing oiil'ii' and an inlet tul'e, Vnnl ehiornle was rr- a si "i | mi gaseous lorm through an adjustable |vi on the top of the containing yimder. then louuh . OUIM cling rublier tubing and a rccali- i ill i 1'ishi i` rioH-metcr. Fre-h or was pum|>cd ; i iot or at all adjustable con trolled rate t linugh mill The streams of all' alld ;nvl i hloride re oiulimed at appropriate ran - Mow hy a ..'I ml. leading through lurtl" ml'ls-s tuh- - <!,' mini il rhaml h r llli'l ' Ifhtrr rt 'ilmi: !r .mi :tt tIm I |-Il,|d 1 -I i 1,11 l"ti * .m<l u nt* HI'IV Ml I'i Pi |>rM- '111 lit* iiitr tliiw . Mil. I'll lit 1 f 111 - `.1 \ ill) i . 1'' It' Ml !r itli\ t-ry ti 1, 2", 'il' II i.; Ml t'T \: - .1m* i :itr;t turns ;i| * \ -------- : u i * i' ? - -Mr `hf ?*v v < linin' in . t, f i tions of vinyl chlorklc concentration* were done in the test chamber during the experiment*. Experiment*1 Procedure*.- Difierent group* of five mice, five rats and five fl*TM-- pap were placed in the chamber and aagwedfor thirty minutes to ronccwtretiooa of 16, 30 and 30 per cent vinyl chloride in air. Similar group* of con trol animals were msintaiaerf hot pot txpoaed to vinyl chloride. At the end of thirty minute* ex posure the test animate m immediately re- mov- d to fiwte' air. 4a oridMoael gnrnp of five guinea pigs waa exposed to a concentred** of 40 per cent vinvl chloride in air. IniB 66 experimen tal animals owe involved. Obmrvoiica* were re- -in led isi the animal* dunn* aad after exposure. Th>- animal* which died other during the ex posure or after a delay period wove automated soon after death. Two week* after tfar exposure sur- ' iv ing tent animal* and control* naificed to- a blow to the head with th* soreptfon of four control rets which ware killed by ax**agma*tion. All animal* were examined for pa* pathologi cal change*. Tissues were motived from *11 ani mals for microscopic exMnmaiion. The hmgs, liwr, kidney and heart were removed in all cases. The brein, 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 end section* mode for staining with hematoxyiin-eosia. Special stains Here made where indicated. Observation* Control Animala- No symptom* 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 Tim* ifBinuteft) to Babobm " Slight trtifefctkm is aria* and fat*. lMMd Bator tftivitj fait is mice. tbs* IS* S*d CViMS plfBs Isatsssd Mtfyity is ail ipmn, twitching ot attnitias is coin. Prvsfttissad trur, unaiaaily ^it asd msseukr iaanowiissiioti is all apseiea. Mina asd ftU is aid* pemtifto; muacular iseoordisstion, tuition tbd twitehiag of olnmitiifi ts futnss pip. Jfier asd rat* uinrmariotia, guinea pita ary anal--fly but atilt ttastiing Mica asd rata is deep nsrama; guinea ptga is aide paaitpon with tnotora--(>oo usoon I. v i * t'-nrr was stopped and the animals rvnv 1.- !!'! i dir, f' -nt; l VC5781 jm miiiihA Uto OrtnO' ni animals excised to this concentration i- n corded ln*ii,w in summitry form: t piture Tim* miouto1 Response Imnwiiftte imuuuR ifl mu'- Mtiacukr incoordination I s it i> I uni*..i ' * iifi- in Mi,. |;- , ! < niiMM l*i|' tm 1 ; \! i * i M *< \ ,!\inc (`nhri'tit t .111 ii' *! \ ( h/.irMp <n Air i VioittentiM tbeir itteftwu'i tnmnre and twitching of tin* * .......... tics: uaatcadineaa and inumiLit nirdordination in fuint* pi** 10 Hie* ad rat* u&qdamaoui *ith rnpul innaular brnAtbinc; guinn pin un tsnateoua but showing ma/kwd twitch 11 AU uhmUia 4cp aaroorii; twnumtionimvuter and rapid. 10 Dap natton*; broathui* teow and IkiItew. Timlhin OMMd in on mouati fmthine * motllfe tod anmnk in rate* and i mu so AM --to d*p nanoait- Exposure was stopped and the animals removed to fresh air. Mice and rats recovered faster than the guinea pigs sad appeared normal within live minutes exoept for one mouse which was dead. The guinea pip continued to show muscular in coordination, nnstsartinwas on their feet until 20 minutes after removal from exposure. Thirty Per Cat! Ftmpf Chloride: The response of animals exposed to this concentration is recorded below in summary form: Ecipoou imm^lutriy ami bowtd irritation quickly .It, * t.(,4't is-r ,,ci \.x munU' m .. M1.1- Katw k.vli'iia i-id- \P . ^ ! 5 ` .'* i o^ u ;> it* h $ \ -'<* 4t| -- 2 A' *--------- ~ -------------- - TfLil 15 5 15 2' --- s * \*4lavw< .,<sin*>wurf#<l,thinlM honr*fojioi Forty Pn < - nt V III'll `t'hloriih < hilv nr ^ pigs wen1 i \11 to this eoneentrati1 m. Mu irritation in r- immediately apparent. Mu- mi-oordiiiutioi, apis-an-d within second- five minute- ill tin- guinea pigs wen1 uncon- mth slow -hallow lin'athing. At the end c\p,ISUTV one guinea pig was dead Mia remaimng ,--ur wen1 m deep narcosis. The,-< vivors p*>L a, mmiin-s to return to their n< ap|'arinci mil :a if. ity, l>ut one died with, following J I futiif Tlie mnnh r ul deaths oecurruig in dill group- of In.- la, oratory anunals exp,**- tliirtv minute- p, varying concentrations of chloride in air is shown in Tatilc I. inmofrti--turn id miiv m I mt i* mite r^iunn with I imtrbui* th* fetw \ wrt* k*topiai p*rJ i inpritR'' and au with UMJiltl,. I omrr**l 10 i itil. gmmm pn *a rteep > vltb 4m iteUm bfmUiiN Expoecrwwss Wnp|ii and thr animal* removed to freefcolr. The (nice and rat* were dead. The guinea pip tonk 3S minutes to return to their normal appearaare and activity. One guinea pig from this group died within 24 hoots following exposure. Pafhologieol Finding* (in>-s pathological trod histological studiei arnnl out Tlie titidings are summarized I* Coni nil l/o'ifi'j/n; These animals show gniss oi miemseo|iie evfilenee of damage. 7*eii Per <'< til I 'tag/ Chloride: All test an survivisl this evimsure They were sacrifice weeks later. On gross examination then1 wa denis- in mice of slight hyperemia of the This was ies- markisl in rat* (iumea pigs -I no difference fnml control animals (hi hist examination the tniee showed very slight cni inent of the pulmonary vessels. fine i showed degenerative rlianges in the ruhiili. thelium of the kidney with hvdropie s The rats showed -light congestion of the e.-i ies in the lung. Lungs in the guinea pig ci slightly more hyperentie than those of the i auimais. Twrnly Per Cmt Vinyl Chloride: One died as a result of 30 minute* exposure t concentration. Pulmonary congestion wuse on gross examination. Microscopically, the VC5782 .*: `4' .>&J i v.ia^i `iidustrial Hygiene Journal 397 ngorgcment of the blood vessels in the lung with mtchy areas of utelectasi* and minimal edema. Ilie kidneys showed minimal degenerative hainces in the epithelium of the eon voidted tu rnin'. The ti-st animals surviving this exposure were aeritieed in two weeks. On gross examination, >ngest ion of the lungs was present in all species, int it was more marked in the mire and rats than n the guinea pigs. Histologically, there was evil `nee of pulmonary congestion in exposed aninuls. Some fatty infiltration was present in the :ver of one rat. All other tisfiUis studied appeared lonnal. Thirti) I'er Cent Vinyl Chloride: (doss examinaion of the animals which died as a result of this \|n.Mirc revealed congestion of the lungs with lemorrlvagie areas. The mice and rats m addition liowed congestion of the liver and kidney. The me guinea pig death was delayed. In this animal here was marked eongestion of the lungs with leniorrhages and the liver was distended and very nablr. The mieroseopic ehanges in the animals iliteli dieil 1111-111111x1 marked engorgement of the iiilnionarv blood vessels with edema and licnior* hage~ in the lungs. The traehea of one rat showed uperheial des(|Uamation of the epitlniiuni, Con.estHin was also evident in the liver and kidney I tin- iniee and rats. The l^ver o! the guinea pig liinii had the delayed death showed severe fatty ;egi neration of the liver eontirnied with frozen itions stainetl with Sudan ill The lour surviving guinea pig- were saeritieed wo weeks later. Marked pidnionarv . iigestinn -as present with liemorrhagie area- and edema, n one ease there was evidenee of seeondary bncerial inhltradon. Tin- liver m these guinea pigs ale tile apisaranee of fatty infiltration hilt no it was demonstrated on frozen seetion. I'mti/ /'it Cent l ini/l ('hloriiit1 One of five innea pig' e\|>owsl to this eoiieentiation died uruig the exposure and another died within 24 .out- Th< two vvliieh died showed marked eone-ii-u of the lung' with hellion I iagi - on gross lamination Tills was also evident on nnero- . ..pa examination. The liver ot one .a these gave ippeai.mii- of tnttv mfiltiatioM. hip no lat . n;il is- demonifratisl on frozen lion T;e rhri'*'-nrv tv mg giimea pig- w.-iv -aerifieed 0 wi'ik- lat- I Marked < iingt--11-Ml >M the lungs rli u* morrh ige vva- '-inli-nt on T - - T! i the gro-s 1 n111 iosi opie exanniial ion In mn guuieu pig, - I: -II lie-i, i mtheniuu was i ouiplel* 1 ah-ent. I'Ilhoiogli al -t Ui lie- will, h w*o- III ide ol the II l.riil -ohen. adlei.aU, l\ni|*i| n-'ile- and . . -iioW 1-d UO dilTereuee I s I w * * ii i `lit 1 oiI imm o- <tv mg a' a re-nlt ni - x:.oo,t. .u I,, in! .' .Mid the -mi iin fired two weeks after exposure. There was a tendency for the blood to remain unclotted in die animals dying during exposure. This feature was noted in the two human fatalities mentioned ear lier hut it u not a specific characteristic of vinyl chloride. Discussion The response of guinea pip to inhalation of vinyl chloride was similar to that reported by Patty, Yant and Waite. The guinea pigs in our study, however, tolerated a greater exposure dur ing the experimental period than eilherthe mice or rata. The results in mice agreed closely with those reported by Peoples and Leake. Hats were similar to mice in their response. The pathological changes in animals which died as s result of exposure were mainly thoee of vascular engorgement of the hinge with hemor rhages and edema. The seventy of theae changes varied with the eeverity of exposure. In the higher concentrations, pulmonary change was marked with severe damage to the tracheal epithelium. Congestion of the Uver and kidneys also occurred in test animals. These changes are similar to those reported by Petty 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 I ^generative changes in the tubular epithelium of tin- kidney were noted in aoe mouse dying as a result of exposure and in one mouse sscrificed two weeks after being exposed. Such changes, however, were minimal and not shown by other animals in the group. , One of the guinea pigs with delayed death fol lowing exposure showed severe fstty infiltration of the liver. Changes suggestive of fatty infiltra tion were observed in other exposed animals but not confirmed by frosea sections stained with Sudan HI. Summary Separate groups of laboratory animals com prising five mice, five rate and five guinea pigs wen- exposed in an inhalation chamber to concen trations of 10, 20 and 30 per cent vinyl chloride in air for 30 minutes. An additional five guinea pigs were exposed to a 40 per cent concentration lur a similar period of time. The res|K)nse by each ill the three species to these concentrations Is iii ited lulinlution of these relatively high concent ruMuiis produced narcosis and death. Mice were the iin.'i susceptible with guinea pigs considerably :,imi, ri 'ist.uit. Rats were similar to nin e m their VC5783 .* & fj$ wKvr-yfs' *^- .V .7, -v* Oi v*.. ^*1 .m October. lf)i response. Exposure to ten per cent vinyl chhit i.i< in air produced deep narcosis in mice and r.itbut tin deaths; 30 per rent conccntratimi* sill'-1 mii<- ami rots. Exposure of guinea pigs to jo | > rent produced deep narcosis; but three nt lm tsuim-a pigs survived exposure to 40 per i-ent < nn centration. Animals dying as 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 are described. The principal pathological changes in animal> 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 dot was also observed. One of the three guinea pig! which died following exposure showed severe fatty infiltration of the liver. Survivors mcrifioed two weeks after exposure showed little difference from the control animals. Pulmonary congartwn was still evident but liver and kidney congestion was not. References 1 t. If U* je.-r id I wit .. ( hy \ nvi f n]*.r.G. \f*d J 4f >2* \ t ft' hn> I \ P Vvsf.AM'fM* Wtfti, \r<ir* *.{ * .Mtu' I l\ff* * \ of ` <`im .<>'.ti'U ^ 'ttnl ( M'lfiiUf. t'nli, H-'i'lh f{`& t ftv .. I'HitM.r-. \ > Mil' D l.ithF n*r XiumIm1'!* Vilivl t J **! .'kl 4 l>tilM4S\, h U. A, t*. V'Lrm T.tTit.-'. 40 Hh-l llit-.i indmt'nnl **>1 * fx, 1 hy King sii'l M 1 * Jr.. UtlU.sro* *v IWUmw* *,l*^ 5, Sf'H.t( MsVS.'l, l.'lti-'lId'UtniDO, K K .ill-l Y \ I'llV ft OtTRM 15 II., r .1 I'AM.J f' likVNT/.. AND M .1 7"* VAitl \m*li**j* XWll. SffreOVlN will: Vmvl AmHUtst-lxHt * *194*>. 7 CtHK, J.It M hntctwoN', J F. ViituA, *> J c 1\ka Jil: Vnrwthowi* XXfV. Oirrmrl Conttituunn cf H- carbon* kmi C*rImc Atifvfinucity, J. <ns > t Tkrriv u`- I ftfIvi ft. Amnttni Uepf<rt it/ tiit rkv,/ Inip*dor of I\trh,tu$ /.* iM;, UntUm HMfin Omd. *772 (Mafti. *43- 9. Harri*, l> K Jlmtltlt ProbJrin* m tl* Mntuuat't.re Vaeof Huur*. Bnf J. tnd. Mtd. IQ: 25$ 'FJS31 10. Filatova. V S , and K. S. UmoktsehO' Hygienic Wi>r Cotulitioni to Fulyttayl C'ltlooiie T*r PWntr fbtunn 3tM3 tW) Motmeteil in World .V-* m -July 1967 Back Issues or AIHA Quarterly R 18 YEARS THE AIHA QUARTERLY was the publication of AIHA, then K11058it was changed to be the AIHA .loum.il with six issues per year instead of four. Now limitation of storage space is ioreme >o di.po^e of all hark issues in the Quarterly. For individual issues quantities on hand vary from a low of ' upward. All MSOes except March 1046 (Vol. 7, No. 11 ami June 1<J56 (Vol. 17, No. 2) are availshis as we go to pram. Some issues are reprinted without cover. Tlie cost iIlfiO par issue ($1.00 each when more than three i=?ue< .are ordered) from 1'ohime7 throogb 18. Erom 1M0 to 1946 AIHA Quarterly ap|>earod ,a.< a >ection in Industrial Medicine and Surgery, however these iwues of thoxr <-ctinm liave been reprinted and are available as s unit. The complete reprint, Yob 1-7, costs $10.00 to member;;, and $5QD0 to companies or departments of government. Handsomely bound, complete astsof Yels. 1-18 with cumulative index are available fur $230.00 per set. Address all orders to: George D. Clayton, Executive Secretary, AIHA, 1412,') Prevoet, Detroit 27, Michigan. (Back issues of AIHA Journal, 1958 to present, m.-n be obtained directly from our publisher, The Williams it Wilkins Company, 428 E. l'reton, Baltimore 2, Maryland at SIJO such imne.) :3 RCi-tT-. : "if? VC5784