Document 34w3jJ76ao8ZzJraY84NN6XJ

Effects of Single stud Repealed Exposure? of Iiuuuuis and Rats to Vinyl Chloride a LESTER, rhJ),* L. A. GREENBERG, PkJ*,* ni W. ROBERT ADAMS. MJXt I -L--f'r~r / AfftitA Tab tfirmilr Department */ PntkaUff, Srkant nf ileiituu, )'<!> Vuimii;, A'r timrlm, Cimm 0 Rats exposed ciebi Um dotty "*jl AWA at Wwawi-- of W far dim Mailu aa4 K (at If dan exhiWwd tl(t> la Ban and when sreiefct and ia tad and white cril canau. Eseept ia'ikc caw at User. tiania alutaiiaaa did at accompany thaw ibata The ahentiam ia twar motpholoei wata <Ma ike aatotal range and ware act faiMitic ia chancier. Became osher {acau al Be eaimak" response. taali aa ,ata at growth. ana iraasamhuce aad ' emoglobin, are aaebaaetd. it a metad shat the atawat dmMI limit aala* af ROM aacd aat he lowered. Introduction together with a trace of air and carbon dioxide. ihrcihold limit value of 500 ppm it baled on limited data4 using vinyl chloride ten pure Taaut I Analysis af Vinyl Chlarid* Mon- mar than that now obtainable* the effects of cute exposure in man and rati and long term expotutc in rati was iaveiti]p.ted by ui Mid AMtlM er* SmUW in 1959 and it described here. Our data do not support the conclusion of Turkelson. ei af.* that the tlireihold limit value thotild tXvm.uV.L ere* Mm be/educed ten-fold; indeed their data indi- . cate need for further studies prior to any Methods revision of the threshold limit value. Experimental Malarial The vinyl chloride monomer was supplied by the Perkins Plant of Solway Process Di vision. Allied Chemical Corporation, in four 100 B>. cylinders with the characteristics shown in Table I, presumably differing ma terially from die vinyl rhloride used by Tnrkrlsnn, el af.* only in die presence of GO iqmt nf tlu- inhibitor, pliennt. Cas chro matography of tltc ik|uid pivase iudteated the 'presence of more titan ")% vinyl clikirtde, INwoJ m As Tn#tf.AM AbmiI W tfc# WrvM Iwlaiiiial IUbwm A ***-- IVjiIhbiub, D. CL. Mb*. VP 'S. Tbn % Mpfii'M m pwi lif irfurb |im Men .Mbs J ( InaHtal ('MtMltM Mbi hM bf P. |. CoMf llr-ebb Wstnr (rfan> l V'lioM #Urf. l>wobrosnwy a^ Nfkso iMut IJm/mn. Kms co-Jfef IMr Iwifintf, .> ftitNMirk, |r<r%. 1|4rtgNfi W l> h. I'oUk tlsolib litM* It lilt Hiflib *u *1 *97. Desired eonrentrations were obtained by metering air and vinyl chloride through flow meters ealibratrd for these gasrs and pass ing Utc ajipropriatc flows dtrotigh a 2-liter mixing chamber. The concentration was also enminuously monitored by a thermal romluctivicy meter calibrated for vinyl chlo ride versus air. The desired emicemration of sinyl rhloride was maimainnl with less titan y/a deviation. Tlie tcual gas flow was almut 50 liters per minute (lpm) in ail but one of tlte experiments. Five experiments were conducted: (1) a flsr.tiuiune exposure of human livings to rnneciitratums id vinyl ehtnrkle ranging from 0.0 to 2.05; ; (2) an exposure of rats (Slierman ittain rats from Jiixll.ind Farm, New City, N. Y.) fur as.lung as two luniri with ctwmtiratiora up to I5'c; and (3, 4, and S) 765 0558001 l BFG03940 ' '1 ) I 266 Mtfjone, 19C3 opeuta lit cats to concentration* of 8 to slides of die Rvrr, spken, and kidney vre-n- 10% tor IS di)i, 5% tor 19 consecutive examinvd and cbssifiesl, tln-n recosied and day* and 2% for 92 diji. re-examined; in this manner sa nrasute f fstialogiesl the consistence and reliability of die patlmiogisi'a technique was obtained. litis eon- . The experimental and control- animate were killed by ctlicr inhalation after expos ures to 2, 5 and 8 to 10% vinyl chloride ' earn completed. Each animal was auloptied according to ctandard practice. In addition dstency was nearly jierfrct in the case of fiver slides, and only slightly less so for qdern and kidney. The results of these examinations are reported in the appropriate fellow, ing sections. lo the pow examination of all animals, all the liver*, kidneys and spleens wrre examined micrescojncally and snne animate reerhrd Results Experiment f a complete uiicrosco|nc examination. llrart, lieeaine the main objective was the deter* lunC, liver, spleen, urinary bladtkr, testes, minatinn of tlie efTeet of long term nqmsnre prostate, ovary, brain, spinal coni, pituitary, to vinyl chloride, die maximum eoncrnlm- tibia, pancreas, stontarh, small and large tion of the gas to which humans might intestine, adrenals, kidneys, uterus, fallopian conceivably be exposed without any imme tubes, tltymtis, thyroid, parathyroid, c-r, knee diate acute effects was determined; this cou* joint, bone marrow, skeletal muvle, salivary centration then became die basis for deter glands and skin were removed from each mining the concentration used during die animal and preserved in 10% buffer.*] for* 92-day exposure of rats. nsalin. AO tissues were examined grossly both at autopsy and after formalhi lixation. Following fixation, representative samples of all tissues were processed according to stand, aid histological procedure and stained with Three men (26, 33, 30 yean; 86, 78, 73 Kg.) and dtree women (23, 40, 55 yean; 64, 52, 61 Kg.) were exposed twice each day, separated by a 6-liour interval, for dtree successive day* to six different con- hematoxylin and cesin; separate; specimens ccntrstians of vinyl chloride: 0.0, 0.4, 0J, of liver were stained for fat with the FUm* 1.2, 1.5 and 2.0%. The eeneemrations were big (fed technique. The animals receiving such complete examination of Use tissues listed included two males and one female rat that had brrn exposed 13 times and one female rat exposed ten times to tlse 8 to 10% level; eight experimental and nine control animals surviving the 3% cx|>ostirc; and 20 randomly srh-cted rats, equally di presented in a different order to each sub ject to make it possible to factor out any possiblc adaptation to either die gas or tlw experimental situation; the 0.0% concentra tion was included so that sotnr assrsnnntl of suggestihility could lie made. Until its conclusion, the- subjects were told neither the effects to expect from die rx|n*- vided as to cxpci inn-mat and control groups urc nor tlie puqxnr of the rx|ieiimem; nnr and to sex, exposed to 2% vinyl chhuidr. was information vouchsafed as to the con The marked inerrasrs in liver weight ac centrations tliat were used at any time, `llir companying the cxjimiires to 3% and 3% subjects each sat in a rliair separated from of die gas, the dem-ase in spleen weight in die gas mixing equipment by a sertrii, a die 2% rxpsoure ami the rqtnnrd kidney simple plastic breathing mask affixed wit changes in cxjmvurr to 300 ppm1 U*l us to tlir face, rovrrmg die mouth and iwsr. IV examine these parlirtikir imms with a blind rate of air nr air-gas mixture passed through technique, tiius excluding tiu- nyiriatiou of the tuad, was sufficient (30 )|mu) In |m-vi-ni any bias or prejudice from die judgmentt. any dilutiun effect* from tin- aiuimphi-re. All slides, including dupli> an-v. were ran- After five mimilrs cif In rattling tlw inivtm*-. dosnly niiiuhrrixl mi ilut it was iitt|WMsili|r liu- i*x|imur was Irtminaiid ami llu- vil-* to distinguish. willMMil iIm- nslr, uhiili li.it! jin I. wine mini lo riHiiji.ui' tlu-ir fs-rliir" ) been ex|avimemal aiul wiiiah rimtiui. Hie at this lime In tlie time iittiurdiure-ly BFG03941 Muar'st Hygiene fountel 267 |iriar to putting on the mash; no ngniim of up Vine! were made. The icsponacs if llie subjects are summarized in Table II. It it apparent that the maximum concentra tion causing no effect in any subject Gcs be tween 0.8 and 1.25c. From the responses it it evident that vinyl chloride causa, clearcut intoxicating symptoms which out serve as adequate warning signs of its presence. thesia for turn hours; on removal to air, there was aa uneventful and profbpt races cry. Experiment 3 * Some notion of the distinctive and specific padtology that might be caused by vinyl chloride was our object in exposing rats to a concentration of 105*. Taste II 8nposwi sf llumsfi Subjects to V*ryi*j _______ .Canesatiatism ut Vuirf ChlerWs . hrCm M WUtlWtl ItMtWV g. snoao w es a o ssa 11 iis t llntiiw njwml la SaCrw I, t t i u m4 4 IJijw it N* diffwtww Hwitwd 4*wWW?t*.*. }, 4 -1. 1 haptl t WMM. tf>ief *urt * Mm's** f WNmt. kdpfl 4 inlMf, MsHbaaef hri., tt| imh. ,V rtftre wpit< to l %. A> bn r. m Wfti--| *||HH Mr****** viali tls^Mt^U. J**.tM* Wljrtin, MM MirCl. i* MiRutd im> v uriimin ! iM mtiMsti. U At iwfcfccte friwifj sitreviuitt tltaa. h^cn 1 Winii) * W4irb ifcit vnMtd TAhWmmhmmha4miMw>fftlH#rnJirr MmuU4 Experiment 2 To gain further insight into the intoxicat ing effects of vinyl chloride rats were re posed to varying concentrations of vinyl chloride for periods up to two hours. The effluent gas Imtn the mixing clumber, at the desired concentration, was |dwi1 through a 10-liter all-glass ex|tostire rhamlier contaming two rats. At a 5'} concentration in toxication is moderate but the righting re flex is Inst; intoxieation is more intense at 65b but the righting reflex is still present. This reflex is lost at a concentration of the cornea! reflex diiup;tears at a concentra tion of lO^f. On removal from die chamber, the animab return to die pre-exposure state rapidly. One animal eras sacrificed after ex posure to die I05r concentration and sltosvcd no visible grow padtology. Ex|tosurc to a concentration of i35J> rvMilted in deep anew, lltesia within fnt minutes. F.fTnsinn of fluid front die tiKMith ptrredixl respiratory failure bl one rat after -12 minutes: amo|y rrvraled rdettia and rimgestinn of the Jungs. The ireend rat was maintained under dti tlrrp ancs- Thirty-six rau, equally divided as to sex, sucre divided randomly into an experimental and a control group; the 18 experimental rats were exposed to die gas in a 1100-Utsr steel chamber. The concentration was initial ly raised rapidly la die desired level by ad mitting vinyl chloride without admixture with air until die effluent from the chamber attained the desired level as noted on the thermal conductivity meter. A fan within die chamber, connected by a flexible cable to an electric motor outside of the chamber (thus avoiding die hazard of an explosion), mixed die vinyl chloride with die air with in the chamber. Thereafter, die effluent bom the 2-Uter mixing vessel was admitted to the chamber; to conserve gas, the through put of this highest concentration was 20 1pm. The experimental rats were exposed daily from 0830 to IS30 hours white die control animab were exposed from 0000 to 0800 hours. At the concentration, as already noted, rats lose conteinuinras, regaining it five to ten minutes after removal to air. After two consecutive 6-hmtr exposures, how ever, die appearance nf the animab mggested dial dim would Ik* no survivors if this concentration were maintained for die con templated 13-day |>vriod; consequently, be ginning with die third exposure, the con centration was reduced to 8%. The test urns interrupted for one day after die xvcmli daily eqmirr because of a mccltanical breakdown. Of the grntip rxpusrd in this fashion, direr frmale rats dirt!, after tlx; sec ond. fifth anil fourireiiili rx|x<surrs; die two animals that dull earliest were rr|tbtCtxl with sidrstiiiilrs fur llic remaining exposure pcriml; eight female rats were thus alive at llv* end uf die fifteenth ex|Miwtre. Female rats exposed 10 and 13 times were autnjrsrcd 20550003 BFG03942 36S IK.1 % Tim Til Clwitmim rf Marpiixlawir Owner* in lams CfuHfiotMii 4 Tnu IV Onwei* m KMarn IS rib*. m 11>--in. wwiw<ii 1U4 Met**** ml wK Mi* 4 k iMt MHMI s liwnit Mtfct W vH. la* M m4m * umIw. .___ ___ _ 4 MtiWJ graving 4 arlk, Im* m <irir m****, mmmmi 4 s frill frb 4Mifra ` " I4 i Gt4t wl wwii*<. VirwiMM* mmd ' >4mmV mi 4 si the termination of the exposure; the re* maining sis rats were autopsied 15 days later, fee of llacae rats having been exposer! 15 time* and the sixth rat 13 times. The mortality teas greater among the male rats: only two mates survived 15 exposures, the remaining males, and their mslaecmcnts, surviving only an average of eight .'xposures. The two male rats exposed 15 tunes were autopsies] at the termination of the -xposure. There was no weight gain in the initial days of the exposure to tills eoncauiraiion, al though after the ninth day some resumption of growth seemed to occur, possibly an in dication of the development of tolerance to the efforts of the gas at the exp saute con tinued. Upon termination of the exposure, growth resumed promptly at the same rate as site control animals. Roth at the 16th and at the 30th days, there appeared to be no differences in liver: body weight ratios between exiirrimmtal and control rats, al though too few livers were weighed at the termmatinn of the experiment to make mean ingful comparisons of this ratio. The external appearance, roat and tail, of aO the animals was within normal limits. About a third nf the animals liad parasitic Ever cysts. No differences in appearance, color, randstenry or ikgnv of congestion weir observed betwi-ni the livrrt nf rs|irri. mental and rontrnl animal*. Tlir lungs nf there experimental annuals sarrifiiTtl im* mrsliatrly ti|mn s-matiun of tin- rx|vsuire had numerous focal filniiuiu* plrural exit. dates nsTilaying noilular ytiluw-lnmm |nrmrhymal lesions whisit hail the a|tpearanrr of regions of arutr luvruti/ing fm-al )mruinonia. Of the six rx|irrmirtii.il animals sarrilirrtl two wirks after the rxpowur, llie lungs of iwu rcvrahsl a few atllimrit filmm* pleural adhesions wliieh were interpreted as representing regions of healed pneumonia. All other organs and tissues were within normal litnits, with no differences between experimental and control animals. The experimental animals sacrificed at the termination at die exposure reeavet a com plete histologic examination. The lesions in the lungs of the three animals in this group showing gran pleural pathology wire sent to be due to acute focal necrotizing juictimonia in varying stages of organization. Some pulmonary edema was present as wt-11 as diffuse infiltrates of mononuclear erlls in the alveolar srptae. Seme areas of metaphtsia were present in and near the regions of pneumonia and were interpreted as secon dary to the pneumonia. The parasitic liver eysts seen grossly were confirmed microscopically. The liver sections stained for fat revealed individual variation of some degree but no rignifieam deviation from normal. The reded slides of die livcix were classed arronling to die descriptions in Table IH while kidney and spleen were judged according to the criteria in Tables IV and V; Figures 1, 2, 3, 4, and 5 are * TaaiaV CIsMiSraiiw nf Mi|ilwlnfir Chances hi Spiral* I * * 4 (3m BMptipii--______________ I frUM M#r WlifK fctelr * ffll'liiw. ImLmtv hriWSH |MMfrV|t*s gtffiwil *ENhrbMB Md Mff* witigl tMtraf. 1 (Mmmmo g--mi i. mm rfraaar frt Uirtrs mm ppitWIm Mb tafrmr <d trstm.il trtN*tt Im iUm nlw 4 povipfrtVsfil hllJlWMW. 1 tfriMMl ro**** ainomuniirir mm* smhmmr m M* Wtol Ismpbmttm, >i sbuti rugwu. 4 IfWiVll a iwlft *4 |*Mlsbnra*M. hsiMglsii* at IMHill IMtrti IhsE MlwM ml pettfArtol hudumret, I At loses ht|eefd.Mr J rl*M ml |||4Mil*t. (I) m* MtwMuitrh omomsI iwionel presto** Mii*iniM win* hiplasttm sosmmwM It* 1*1 Mttffrfiil M* ml mssH du| humfeotim I lainpiootlV Intat (Juij Othodrag It Mfltfr *Ml ml liar MrHtMxM. f * W 08SS02 BFG03943 InJuUtiol llygirne Journal 30 Ihlttuiaf lb* morphnimct. Ml claim Soeribrd in Tabic 111: (1) Clau I: (3) Clau 2: (J) Cbm 3: (4) Claw 4; (3) CUM 1. H 4 E (lain. S 200. illustrative of the clau descriptions in Table III. There were no significant differences in the scoring of the grou|, 'although there was a`class "5" and no class '*3** in the rats killed at the termination of tL.r exposure, whereat there were no livers in clau "3" among the control animals. There were no class "5" livers among the cx|tcritticntal rats killed two svrrks after the exjsosure; Use slides were evenly divided between scores of 3 and 4. Kidney slides from tlic experimental ani mals were not graded differently titan from the controls but all spleen slides from ex perimental animals retrived the highest score, differing significantly from the con trol spleens, although some controls also received such high scores. tI Experiment 4 Tlicsc preliminary trsts vrtmxl to indicate dial vinyl clilntictc was an anrsllu-lic gas which might also art as a lung irritant, fn Orslrr to ani this feature uf its anion, to highlight Munifnant |iutlinlngu'al fi-aliitrs and 1st avoid tin* (tileiiiulily of tLiiu.igr arising from sniMliivis almw, live hiu.ile ami live male rats, iiiauln-d with rnnliols, wete rxpostal for right Imtus daily to live per cent vinyl chloride in air for 19 consecutive days. The experimental animals were p aced with in tiie chamber at 03.10 and removed at 1030 and die control animals from 0000 to 0000 hours. To prevent contamination of food or svatcr, both gmu|is of animals \.ere piacesi within the rhamlier in empty cat,et; lienee experimental and control animals were de prived of food and svatcr for eight hours daily. The requisite concentration of die vinyl chloride was attained initially as in Ex periment 3, but the chamber was ventilated at 30 Ipm. Ahliougli die body weight of the experi mental rats decreased initially, this trend was res-erwd hy the fourth exposure, die rate of growth thereafter being no different than the controls. The drop in weight at the start and the subsequent resumption of growth was |iaralh'lrd hy an .ipparmt inerrasing tolrranre to tlie gas as the rxpnsiiir* continued. At die stait. the itHoxie.nion of thr rau was mnikrtl, imtahility of iIm* hind legs In-tog a promitH-nt fratnre uf die r*|imiirp. With rarh exposure, however, lliete was ait uln-ious limiiimimi of these symplonis, lluit hy the (ifth or sixth ex|*tsute. it w;ts not (tossihlr In di-liiiguislt any i-vitlt-nt symploiits nf nettrologiral ili-lirit. t Imns-.lnliitt dctt-rmituiimu during tlte ex- t N O cn tn .8 O BFG03944 X 270 Mtpjunr, 1963 Tams VI Formed Elements of Ui Bleed at Termination at Eapooum to I aad 2% Vinyl Chloride pcaure period revealed ao difference between experimental and control group*. On the twentieth day experimental and control aaimala were anesthetized with di ethyl ether, blood wot drawn by cardiac puncture and 1/9 volume of i.i.M sodium oxalate was added to the blood. The ani mals were then hilled with an overdose of the anestltetic and autopsied. Measurements of hemoglobin, prothrombin timi hemato crit, red cells, white cells, differential white cells and serum transaminase were performed on the blood drawn. Semin transaminase, hematocrit values and prothrombin times were normal for both groups. Table VI lists the values for some of the formed ele ments of llie blond. Monocytes and cosine* phils formed only a mull proportion of the white cells; no differences betwe-tn control and experimental animals occurred. The red cells were somewhat elevated and the whincells lower in the experimental group. Table VII shows dial the liver:body w-eight ratio of the experimental animals was significantly elevated. All five male experimental animals ex posed to ir/e vinyl chloride had coats which were somewhat thinner than normal; the tails of these animals were scaly. Hie three fe male expei internal animals and all the con trol animals had normal coats and tails. One male ex|ieriiurmal animal had fibrous pleural adhesions on the left side: the fibrous nature of these adlmions suggestrd that tlir Taduc VII U*rr and Splmi Wright* ( Rala Expound to Vinyl Chloride 20558006 Mil *>- *c BFG03945 inJuUriet Hygiene Jonrnel 271 porai m nvtnl wcvks old and |icohably dumber to 2.0% vinyl chloride fur eight not tdatcd to tie rx|msurc ilmlt >|ni> hums prr day (OHIO lu lull)) cm Monday Mental and control animal* had ;uraiitic thruugil Friday for a iirriusi of tliriv niontin. . fi*r cysts. No differences in appearance, Tl*e control animals wrre expmed to 0.0% color, consistency or degree el cengestitm of tlie test gas, that is, to a flow- of 30 Ipm were noted between the livers ,el the two of air, in die same durnher as die experi . (roupa. The other organ* and time* wen mental group lor eight hours per day on within normal limit* in their (ret* appear- die same days of the week. No food or water , ante, with no dilTcrenccs between experi- was present in die cages during cither ex ' mental and control group*. posure. All rat* were weighed at approxi With die deception el the pleural adhedons in one animal, the microscopic appear ance el all Uit organs and tissue* was nor mal. The pat* observation oI pamittc Brer eystes in ah animals wit confirmed micro scopically. Liver sections (ran all animals mately weekly intervals; hemoglobin deter minations, from sail blood, were nude at monthly interval*. In nridier body weight nor in hrmoglohin values were dic.e any sig nificant differences between the n ntrol and rxjicrisucnial groups. were stained Ice fat, but none rcvi-aled evi 1Turing the course of the rximtunr, time dence of inrreased fat nor were there any were five deaths; of tliese, four nrrurml in differences in intracellular fat between die the control group. Ms data from time ani - two (roup*. mals are included in any of the table* Classification of the liver slides for the On die 89th day blood was wididrawn morphological designations of Table ' III from die control animals under anesthesia showed differences between the control and as previously described (Experiment 4); diese experimental group*. The mean score of the animals were then killed with ether and control group wa 2.93 and that of the autopsied. A similar procedure was followed experimental group wo* 4.56,. with only one on the 92nd day for the experimental ani control animal being graded "4" and no mal* The livers and spleens of all animals experimental animal being graded less titan were weighed prior to fixation in formalin. *4**. The differences between the means The mean values of the tissue: body weight was thus highly significant, yielding a "p" ratios are shown in Table VIL The dif of less than 0.001. ferences in the means were in all instances No differences in kidney or spleen slides significant, the livers larger and site spleens between experimental and control animals smaller in the experimental as cninjiared with , were noted. .the control animal* No significant differ ences between the grou|i* ap|>eaml in the Experiment S snhies fnr hematocrit and (irolliroiiibm. The scriiii transaminase was not determined. Setause human exposure to vinyl chloride Monocytes and rouiMipliiU sliowed no dif. seems unlikely at conrmtratirm* of the ga* (rrrncf* iietwern die gruM|is; values for die much greater titan the concentration causing oilier blood elements are diown in Table VI. . signs of intoxication, that is, at 1.2 to 1.6%, the long term exposure of rats was conducted The external apjiearanee of all animals at a concentration of 2.0%. was nonnaL Parasitic liver cysts were pres Sixty rats, each weighing about 73 grams, were separated randomly into two group* of IS mates and 15 females and placed in eight separate cages. In the week before die ex posure was started, the rats were observed, weighed twice and blood withdrawn fnr ent m all animal* Tlicre were no differ ences in appearance, color, consistency or degree of congestion Iwtswit die livers of else tuts group*. All other organs and tis sues were similatly normal, no differences between tlie groups being a|i{urenL hemoglobin determination. The ex|icriincn- All tlie oigans and tissue* rsautiiwd histo tti animals were exposed in the 1100-liter logically were wiiliip noinul limits, no padi- * 20558007 BFG03946 i ..............(A w t- ) V in Ihy/ssi, 1X3 riog beins cndrat in either experimental to product some singular or characteristic or control animals. patliolngy. It cannot be said dial this gnat Tlie paimitic Ikrr ryiit arm grossly were wot achieved, the results being questional4c confirmed microscopically. liver aectiem and uncertain. Lung latent were certainly stained for (at revealed normal variation. but present but these could not be ascribed with no animab had increased imraceflular (at nor certainty to any irritant properties of lc gas were there differences between tin expert* since they might well have arisen from the mental and control animab. Cruled in fang-continued anesthesia; there was aa ap accord with die mnqtlmlpgy in Table III, parent regression of these lesions in rats al the liver slides mvalrd iliffcirnres between lowed a 14-day recovery period. The pret the groups. The mean score of the control ence of pneumonia certainly raises the pos group was 1.58, that of the experimental sibility of an acute toxic effect on lung tis group 3.6X No Ever in die control group sue at these concentrations; however, die scored mete than 2 and none in the ex pneumonia could just as well be caused by perimental group srorrd lew than 3; one Be secondary infection during the severe cen er scored 5. Because there was no overlap tral nervous system end respiratory depres the differences between die means ato high sion, an interpretation favored somewhat by ly significant. the diffuse lesions mad ./ the irregular oc There were no differences in score (or the currence of the pneumonia. spleens in the two groups, but the kidney The kidney and Ever changes described slides of the experimental animab scored by Masuontattco, t aV in rats exposed for . significantly less than their controls. 30 ptinutes to 20, 38 and 40% '* vinyl chloride, were not observed here, ^'though Discussion 13 repeated 8-hour exposures to aa snesthcde concentration is alto a relative1? severe The data from the. present investigation stimulus. Tlie findings in the he y. agree confirm the arutc effects to be cxprrtrd (rout with Uk relative lack of effect friuxl by various concentrations nf vinyl chloride: Nfastramatteo rt *L in rats expose*, for 30 concentrations below \r,i, when exposure minutes to 10% vinyl chloride, rxe.pt that b limited to five minutes, cause no ob continued exposure, for days, dors esult in servable intoxicating effects; five minutes, mortality. The relative lack of patliolngy as however,* h shorter than die time necessary the result of 30 minute exposure at 10% to reach an equilibrium level in die circula found by Mauromattce ei sf. would teem tion; from behavioral observations in tlie to support the view that lung lesion: found rat, it may be estimated that in five minutes after repeated exposures could well arise some two-thirds of die equilibrium level is from the anesthesia and not from tome ac reached; consequently a concentration of 0.6 tion peculiar to vinyl chloride. Tlicrc was to 0.7%, if long continued would not pro no indication at either the 2% or 3% level duce intoxication. As die concentration rises of any untoward or otiicr effects upon the above this level die intensity of die intoxicat lung tissue. ing signs increases until at a concentration of As an overall measure of general hraldi, 7% tlie righting reflex is Inst; at 10% tin: body weight ami rate of growth are sensitive corneal reflex dfvqipean and at mhrnitra- indicants. Kvm in die exposure to a eon- tions of 137* Ad abovr rrqiirainry failure rcntmifan of 3%, which at lint [imducrs a takes place. Vinyl rlihirkle thus arts at an marked and tt-vrrr Suioxkarimi, tlie sliarp anedietir gas, its tlqsntim ariicm inrtvasing dmp iu tlx* weight nf male rx|ierimnital with increasing ronri-niraiMm uf tin* ga* in animals arm at da* start of tlir rx|imiirr was the air hrearimt. llir iiurrs)-vuling innras. anrm irwrvsl vi dial liy llx- rral nf llir I!), htg nrutnlngiral ikTiriis ending in ilraili at ikiy rx|airr tlim* was tm diffrtmrr law conrentratinm gmilir llbiu l."i%. Tlie |nir- twvnt ni|M-iiim-ntal ami rontnl rats of pose in rx|wing rats to iinartilraliieis ram- cilltrr wx. Ihsly weight ami tatr nf grnwlli mg anrstliesia (H in 10%) was an attein|it similarly slwnn-d no tliffctvmxt lietwern die 20558008 BFG0394T " * '1  > lajatftiml Jtjxirmr /wnW m giuups in llr 2ft ex|Wkurc. It mint tar mv view of die whir range flat die Ihvr: Irdy ptoml again th.il die enmdi of tlic rats wvtglil ratio may rnmnipaw (Talde VII). during the .Vi rxpesiur uijijiurt tlx* iJmiis. li.itlu-r this inrirss* may signify a nrewspiw Ural of tile rat's In-ltavior which bulit-alnl riiir irsjioow in metalsdir dnangrtMlMs OC- tiiat dim was rapid development e( tolcr- rasMUM-sl liy nuhl and mmk-ralr uitmicalinn snoe to tin; intoxicating effects pi tliis con. for daily IMmur (irrioils. from die data ob cremation. tained here, it h not certain dial liatopatho- Neither the 29 nor die 3ft concentrations logical change would have ocrum-d had ex , caused changes in the prothrombin time, posures been carried out for longer times. hematocrit or hemoglobin values. At both In the paper by Torkchnn rt tl., histo- the 2ft and die 3ft concentrations, the patlwlngical diangcs in die liver and in- white cell count was lowered significantly, . creased livrrtlxxly wriglil ratios are realthough still wen within tlir normal range. pnrlcd in male rau exposed in 390 ppm The increase in ml cells, although ugnifi- vinyl cbluridr for 43 months. That there is candy elcvausl in tlie 3ft exposure, was not correlated with changes in the larmoglohin content. The inerrase in eoncctnation oi no ranral iriatinn her. ant die rrponrd bis. tofnlliology and the isrnwi ir. Cvcrtlmdy weight ratio is evident front die extensive die vinyl chloride is associated with a greater data gathered by those investigaton. Female (all in the white cells and a greater (and rats exposed to 300 ppm vinyl ritlxkle for significant) increase in the red cells at die 43 months showed no statistical) - significant 3% level. Aldiough Kmpliocytes and neu increase in hver weight but arc reported to trophils arc incrcared, only die change at have histepadtological changes in die liver. the 2ft concentration unlike the previous Female rats exposed to lower e* neentntions cell changes, reaches the ssatisueaily signifi (100 and 200 ppn) for six titna'la had tig- cant IpvcL It is difficult to know if time nifirantly increased liverthody weight ratios changes have any toxic significarce, since no but no patliology. On the other hand, rab tissue changes were seen upon microscopic bits of both sexes exhibited Iw; pathology examination that would account or be as widtout showing any increase in fiver weight sociated with a drop in the whim cells or an after exposure for six mondis to a concen inerrase in red cells. The decrease in spleen: tration of 200 |>pm. The audtori correctly body weight ratio is in a direction opposite to point out dial organ'.body weight ratios may diat usually associated with a severe drop- well be ancfnctiiai, illustrating lie point by in white evils; although the white cell count iIh- signiiieaiit dem-ax; in kidney weight did not suffer a severe (Imp, the decrease was Itxmd in fnnalr rats npmsl to 30 pjsu for substantial at die termination of die ex. six. mondis; such ruts exhibited no rlianges pesurc. wIksi rx|mrtl to biglier rnmmtraonu*. ily The only finding suggesting a specific toxic action of vinyl chloride is die increase in liver wrighl on exposure to 3ft for 19 slays and to 2ft over 92 data The increase in liver weight is not only highly significant statistically liut is also substantial, amounting to a 30ft increase over die controls. It is unfortunate that no information is available at to wlirtlicr this inerrase is reversed on dis continuing the cx|wirr. Tlte increase in ' liver weight may lie inn-iprru-tl as indiraiiag die *tme token, Imt nveilookrd liy tlic nullum, tlic iuervased lisstr: body weight ratio m female rats at 100 and 200 |i)xn is with R)ual reason artefact bemuse no sta tistically significant increasr nrrurml at 300 |>pm, A|i|iafendy. also, s|ircics differences are of ini|iortancc in die reactivity to vinyl chloride, male guinea pigt suffering a significant di'crcoic in tlieir Kvvrtbody weight ratio when exposed to 100 |i)int for six umntlis. alterations in water, dcctrulyirs ami |nnicin There an- six |Hiwitile rranhinatinn* of the content of die lisrr paitnchvma, hut that pnwmre or ilsnse of |uilinlngy and in- such changes pierage the des-rluptm-tit of ctcaw-s, decreases uud no cliangc in Uvrr actual histologic lesiont is not cciluin in weight. Ike one cumhinaliun not observed 20550009- BFG03948 1 274 1X3 by Toflrlwi, rl <t lustnpalliolngiral 40 time* time ued by ToHtrhon, rl of. II changr >w<uinl with a ilenraar in fiver any wlianee h to Ixr placed in a iWvfffn weight. Obviously, if five of the six pmlih trlatinmitip, lailmlogy nf some nxeislreahlr combinations bit bem efitmed in a irb- degree should hate been fhund in our n. Indy nnaU ample, no canal cannertiim prrimratx Vet naljr titoe]iltological alina- can be said to tx between time two lions of die character already describes! and pictured were teen, which, in our knowledge and capctfence, are of no pathological signi . Changes in the liver:body weight ratio ficance. Whctiwr tiic explanation residro in , may wet! have some toxic ugnificancc, but a dilTcrrace between the rat tlraina used by i they are unaccompanied by histnpatho- us and by Toritebon ft oL or ebcwhrre a. bgSeai alterations, increased fat content or trot known, but without additional data it serum transaminase changes it is impeoiltle ' is impnaabic to reaohx tlie contradiction. m conclude diat taken alone tley signify much. Reference to Table VII wit Stow On the bask of the present data, and the that the liver: body weight ratios of the rats seeming immtpmtanc. of the liver ssrighl used as control animals in die b'.l exposure clianga seen by Torkehon ft oand withwen significantly higher tiisn tlx experi out further evidence, a change of die pres mental animals in the 2% ex|xwr.re. This ent threshold limit value o( SCO fpm emit illustrates wrll tlx; fact that tlx ugh control unwarranted. animals are used, unknown and non-specific changes in the environment, time of the sear, Summary temperature, diet, etc., may 'lie responsible for changes in organ: body weigh1 ratio with out at the same time producing pathological alterations in the organ. From S-minute cxjiosnre* of V.;mau sulrjects to concrntrstion* of vinyl *. loride rang ing from 04 to 2.0%, it it estimated tluit a prolonged exposure m a level of (tore dian Similar consideration* apply to die de crease in spleen weight: lure, nut only was pathology not observed, hut th.-re was no difference in the merpholcsirai cluiractrr at 'cither die 2% or i^c iesvl between die experimental and contml groups. 0.6% k necessary to predt.ee raininituu tnajmiw of intoxication. Ka.t nt|K>srd fur up u tux Invn to higher cmitemrations ex hibited moderate intoxication zi.5%, lust tlseir righting reflex at 7'e and tlie romral reflex at 10i. Respiratory failure occurred at li%. If the exposure to lO'i was long Unlike the interstitial and tubular changes continued (lire B-liotir daily exposures), in kidneys of rat* exposed to 200 pjun of mortality increased; dead) was apjiarently vinyl rhluride rrportsxl by Ten kelson, rl iJ,, caused by a pnetrmonir process, but it was was the lack of any patlmictgy in one animals . impossible to decide whether dii* teas tlie exposed to 2% and and the fact tliat result of a primary action or secondary to dm tlx; only mor|ilx>loi(ical alivration in wliirh a anetbesia. significant diflcirnce between control and experimental animals oerurrrd (kidney at 2%) indicated tliat the control animals svrre further front "ntmnar*. Ilreamr it k imicasonable to attach tnxir significance to clsangr* associauxl with a rsnitrui air ex posure, it is our Ix'lit-f dial tlx- uxHyilx-k'gical allrratiutis w liasr- nlwmsl sluxihl ixit be intrrpielcd as nitiiiifmatiixM of (uiluil- *or. Rats exposed eight hours daily tn 5% ter 19 days or to 2r/i over 92 days did not show any lung involvement. These levels Iasi no eflects upon growth rate, hetnegtobhs, licnia- toem or prothrombin time. At. both ran- rentratinus three were iiureasr* in lie liver: laxly strigltl ratii> ami iliTmm iu tlu- uliiu* cells; at 2% Urn S|ilrru: laxly weight nttiu dmriunl aud at lla-rr was an increase in red rr!h. The rmsrtuliaiam* In wliirli tlx- rat- wtxr No piM la inx*ismv|iir rliatnps nv Subjrvlrd in lla>r r\|iei inx-iits *nr at kxiw banal iu any ihsm* tliat was rewrvlairel will* Z0556010 BFG03949 t { lututlritl Ujjprne Journal 373 thr in lint formed Hnwnti ft the ItlnrxL 'Hie inrrasr in livrrlujy weight mum were wwuinl with iwir<iliul>Qial allftatinfh in llir Gut iiu li a|i|iraird tn have an patlwtlngiral significance, while no meaningful morphological alterations were evident in citiier kidneys or spleens. Became, m Uie Ionsterm npc!,>,ref< * was impossible to attach any toxic significance *10 the changi-t tinted or to observe any liistopathology, and because otlirr aqtccts of the animab' reactions, such as growth rate, were unitnpairrd, die presently arccptct! tlircshold Emit value ot 300 ppm for vinyl chloride, onc-fortirth of the concentration tested lirrr, teems to offer an adequate margin at safety for human exposure. Acknowledgment ft b a pleasiirr tn acknowledge the tech nical assistance uf Malcolm Xiraduin, Frederick A. Putt and Miss Lillcinnr Wall- mark. , RtfwsacH _____ ... __ ____ (or reus |imn nff*moa< ritrify cal NfoMf P*f*rk U. i fWW* .b fMvirr, 414.,C (Men. 0. U IfOrf. i Meewowit, L, .V U. >"*. II................. II. n JoImImm 1mm* mi V>M ChWaAo m Uliwuff .Wmofc. Ammt. iW. Kyf. 4mm. J. 21: |(M. Ndll. _ S> Tmmmr. T. I., f. Ovik. m4 V. I. IUmi Tte InMf I Vmyl Qilieidr UtWlniwI lif IUmwI A(mMmMT}f. f4it TU |UH. |d4t6M1JM. k Iwr. $md. N|f. 4 Wnm. llT fw Ja.r (mmnI CwMWoimi--Hy Urn IIrnN UA.Im-- 4mm Ja4 0H. ' 4mm. $. 17: l?i CI4S61. _ 1 rm, F. i. W. I*. Veot. m4 C. F W m Aim JlMfewieer W (mMi Kn M V iwoi ml Vm Xm *> Miriel fliWM Ct'imwMw* V. Viml AbI* r JVomlaA /4/JJ 4S: 1X1 (Am*. tU). x v. Sources and Use of Toxicological Information The New York University .tfcdical Center in cooperation with the American Industrial Hygiene Aemriat*'n will present a course on Soared and Vtt of Toxleolepesi Iniormatifn. Die course will be given October 14-18, 1963, at the Onekista Conference Center, Sterling Forest. Tuxedo. New York. The course is designed to acquaint those eoneerned with advanced methods of securing and mUTpre'.inj pertinent toxicological information. Application and principles will be stressed rather titan tictaib of rx|x-rimcntal toxicology. The design of thr course ciituinatct the need for speriaiixed scirntirtc back ground so that all administrative and technical persons having responsibilities for use of toxirolovical information can hmrftt. Curst lecturers who are spe cialists in sclcrit-d (it-lds will suppiriiirnt the stall nf N.Y.U. Institute of Induv trial Msslicinr for pirsenution nf llir suljjrcl material. Arras ui he covered are: biological principles involved, sonrrrs uf uaxintkigiral information, applicatiem tn in-plant problems, Federal regulations, and requireturnu uf various agenciesInqttirics and registrations should lie directed u> New York University Medical Center, Institute of Industrial Medicine. 5.V) First Avenue. New York 16, New York. Yin* registration fix* is $130 with a tlc|*wit of $33 nstuitui. AcennuuntUtiom (double occupancy) at tlssr Onrluuu Conferencr Center for the evening (dinner! October 13 tlmnieh lunrh Oetolier IH are available at $21 per day including mcab (payable tn the Center un departure). * 20558011 BFG03950