Document zdmLE8Ma623yX944138pXYZan

! vV, . _ 7l V>-4***-*,, ~V-~. *.>^'VT-' ~. . ..:>.-;- ., V* ' -w . *. -- *.*-y' -*' ,f.Try~. . l j- ;; sols Effects of Single and Repeated Exposures of Humans and Rats to Vinyl Chloride tightly Co., :th rc>.-.diance nrd for small- .err cn- .i Mtiall .) mph. rsperi .i ro of ;V WitS .,i only, uid he irt ichs. under ^ that tv- .* .. kcaf- nl.jrcte lies of r-i the t>) val* ! diK't. .;hnnjd from .\y.vi. a \ c the D. LESTER, Ph.IV L. A. GREENBERG, Ph.D. * and \V\ ROBERT ADAMS, M.D.t Laboratory of Applied Biadynnmicr, YgU i:n rcrtity and Department of Pathology, School of Medicine, Yale University, New flaz en, Connecticut y Rats exponcd righf hour* dally to vinyl chloride at concentrations of 27c for ; three months td 57r for 19 days exhibited changes la liver and spiccn weight | and in red and white cell counts. Except in the case of liver, fmur alterations did ' not accompany these changes. The alterations In liver morphology were within / the norma! range and were not pathologic in character. Because other facets of l the animals' response, such as rate of growth, serum transaminase and hemoglobin, ' were unchanged, it is suggested that the present threshold limit value of 0.05% need not be lowered. 'a lafroJuction T'KS TOXICITY of vinyl chloride has beer, reviewed recently.1*3'* Because the threshold limit value of 500 ppm is based limited data4 using vinyl chloride less pure 'tan that now obtainable3 the cfTccts of flfutc exposure in man and rats and long ,rnn exposure in rats was investigated by us in 1939 and is described here. Our data dn not support the conclusion of Torkelson, ' cf.1 that the threshold limit value should be reduced ten-fold; indeed their data indi te a need for further studies prior to any ^vision of the threshold limit value. together svith a trace of air and carbon dioxide. Taolz I Analysis of Vinyl Chloride Monomer Acetylene Aldehyde Sulfur Thrmal Nm. Vol, Wtcr Qninr Avtiy 2.2 ppm ao 1.9 ppm 0.0 r.o 60 ppm 11 row 170 ppm Sa'.W 99+r* Methods Experimental Malaria! The vinyl chloride monomer M as supplied the Perkins Plant of Solway Process Divi.r,, Allied Chemical Corporation, in four 1 "l lb. cylinders with the characteristics 'kawn it: Table I, presumably differing ma nually from the vinyl chloride used by lotkchon, rl at.3 only in the presence of ''> ppm ai the inhibitor, phenol Gas rhrovato-mphy of the liquid phase indicated the presence of more than 99% vinyl chloride, t Ihp Twenty-third Annual hfrrtins of the '"/ftfjn 1.`J'UlrijI Hygiene A**''option, Washington. D. ` Mtf. isi Ilia w.*rt; *j$ >upf>orif<i in part hr a ff-orrh grant frmn '*'*1 Clt'ctira! ("?rj>or.itinn and in part by l . 5 l\iblw Srrvim firyni C-2W8. 'I'r-fw: adtireu: ItiovhemiUry anri Phvvot'Mrv, Krthw it.H,La,b\"opvr.a* toJrryo,eyRustr*-TH< Slate: t'ms**;ty, Nr*'1 ofStyf,.JSf, Public Health Server Sctiiof Rrsr.nrb Desired concentrations were obtained by metering air and vinyl chloride through flowmeters calibrated for these gases and pass ing the appropriate flow* through a 2-liter mixing chamber. The concentration was also continuously monirored by a thermal conductivity meter calibrated for vinyl chlo ride versus air. The desired concentration of vinyl chloride was maintained svith less than 5% deviation. The total gas (loss' was about 50 liters per minute (Ipm) in all but one of the experiments. Five experiments were conducted: (1) a five-minute exposure of human beings to concentrations of vinyl chloride ranging from 0.0 u> 2.0%.; (21 an exposure of rats (Sher man strain rats from Rockland Farm, New City. N. Y.) for as long as ttso hours with conrcntrations up to 15%; and (3, 4, and 5) . ,< -f t!idaxtTi(if Hygirnr journal 267 were <K*f' 'Ml* .* ol >1 irft h*u : '-r^r to putting on the mask; no suggestions J anY ^nd were made. The responses of ? v subjects are ynrjinarizccl in Tabic II. * ' s apparent that the maximum conccntra; *' causing no effect in any subject lies bc; ' 'ni 0.8 anci 1.2^r. From the responses it i ; evident that vinyl chloride causes clear^ ;i intoxicating symptoms which can serw ' a`lvquatc warning signs of its presence. thesia for two hours; on removal to air, there was an uneventful and prompt rccovery. Experiment 3 Some notion of the distinctive and specific pathology that might be caused by vinyl chloride was our object in exposing rats to a concentration of 10%. lyjit r.111*' r,.i x'Ut, ^b 11v |!m* /,, ( Tadi.e IT Thirty-six rats, equally divided as to sex, Nrsnonsr* of Human Subjects to Varying Concentrations of Vinyl Chloride were divided randomly into an experimental and a control group; the 18 experimental . <>ni J Jtrtftome rats were exposed to the gas in a 1100-liter steel chamber. The concentration was initial d'^rrfpre* reported fry Subject* I, 2. <. 5 and v I v S"Vff- w*tKltN tltrry**. ly raised rapidly to the desired level by ad ' N* (i:ir.-r.-,,c^ by all suMert*. * * Sn */j/Tr.vw? irpr>rtetf by iubjrrn |, 2, 4, 5 mitting vinyl chloride without admixture ; . , ```il *i Jvibirrt 3: heady''. ' X di/Trrrtvrc* rr|>ortr<i lv Subjrct* 1. 3. 4 and /*. with air until the effluent from the chamber Sulttrri J "iwirr, X'lnrwluf dirj'y i fntdtib' of attained the desired level as noted on the : r'l*mrr. Subject 6, reefing, swimming head. "jmt , Mr tfriiifirf n". thermal conductivity meter. A fan within ; - N rfur i reported by Subjrct 5. Alt other* report i.-wiiM** / iAlotir.ttiftn with <Ji?z*iirs. fight* the chamber, connected by a flexihie cable `t 7 hrnd^c'ncM. some n.iusf.3. duffing of vu.nl *nu auHi* !*? ftr<: ihnu* *yinpt<MTu disappeared rapidly upon to an electric motor outside of the chamber f lertninatsnn of the exposure. 1 AM huKj-'ch reported intrrcir.vins rfftcti. Subject f (thus avoiding the hazard of an explosion), : fntortmg a SratLtrhe that persisted for 30 minute*. mixed the vinyl chloride with the air with n*i|.(wit< *ppr.v(ti earlier in the rxpmure hae Af ).('> nd the *ympon> were more intrude in the- chamber. Thereatter, the effluent ' Ilian at 1.6'*. from the 2-liter mixing vessel was admitted . . f ' <!" rin;ni; ') to the chamber; to conserve gas, the through put of this highest concentration was 20 : j logain further insight into the intoxical- 1pm. . t -\' effects of vinyl chloride rats were ex The experimental rats were exposed daily 's *^tl lo varying concentrations of vinyl- from 0830 to 1630 hours while the control t ride for periods up to two horn's. The animals were exposed from 0000 to 0300 ,|:iint gas from the mixing chamber, at hours. At this concentration, as already `'(li-sired ronccntration, was passed through noted, rats lose consciousness, regaining it f ill-liter a'i-glass exposure chamber con- five to ten minutes after removal to air. 'asnir two rats. At a 5% concentration in- After two consecutive 8-hour exposures, how . " ui.iiion is moderate but the righting re- ever, the appearance of the animals sug ? 'a is Inst: intoxication is more intense at gested that there would be no surv ivors if diis hut tire righting reflex is still present. concentration were maintained for the con i 1 -is irflrx is lost at a concentration of 7%; templated 15-day period: consequently, be 5 "sni-a! reflex disappears at a concernrn- ginning with the third exposure, the con 10',,. On removal from the chamber, centration was reduced to 8%. The test / ' animals return to the pre-exposure state was interrupted for one day after the sev ; iiliy. One animal was sacrificed alter ox- enth daily exposure because of a mechanical vin' to the I0% concentration and slinucd breakdown. Of the group exposed in this si-ihlc gross pathology. Exposure to a fashion, three female rats died, after the sec * titration of 15% resulted in deep anes- ond, fifth and fourteenth exposures: the two within fiie minutes. Effusion of fluid animals that died earliest were replaced with 1 i the mouth preceded respiratory failure substitutes for the remaining exposure pe ; ' rat after 42 minutes; autopsy revealed riod; eight female rafs were thus alive at 'h *H.t and congestion of the lungs. The sec- the end of the fifteenth exposure. Female r.u was maintained under this deep aiics- rats exposed 10 and 15 times were autopsied SPI-02609 .-:'vvV :.4 969 j t'liutirial Hygienr. Journal ey* fvtir.it io 269 c; as *rna. iihin vL*cn thr Hin ts in 7MI0 sccrt "tui tion. wril rrll* fin;ir.m mu* .\TlT ion* jiort .lion vfl> inns vcrr to!i-s ar* v ..I t^rl .al.*t-*fi '/ii ustrativc of the class descriptions in Table ' There were no significant differences - t the scoring of the groups, although there i ' a class "5" and no class "3" in the rats i `*t*ti at the termination of the exposure, | ' `liras there were no livers in class "5" r'..in(T the control animals. There were no : u*s ,-5" livers among the experimental rats two weeks after the exposure; the 5 ' were evenly divided between scores ^ ' 3 and 4. i Kirlney slides from the experimental ani: were not graded differently than from > controls but all spleen slides from cx- `imental animals received the highest ! differing significantly from the con- spleens, although some controls also `soil such high scores, t ' i ' t-riment 4 , Hiesc preliminary tests seemed in indicate "'t vinyl chloride was an anesthetic gas r,1|h might also act as a lung irritant. In j "!,t to assess this feature of its action, to flight significant pathological features and i avoid the potentiality of damage arising ' in anesthesia alone, five female and five ; rats, matched with controls, were ex` for eight hours daily to five per cent vinyl chloride in air for 19 consecutive days. The experimental animals Were placed with in the chamber at 0830 ar.d removed at 1630 and the control animals from 0000 to 0800 hours. To prevent contamination of food or water, both groups of animals were placed within the chamber in empty cages: hence experimental and control animals were de prived of food and water for eight hours daily. The requisite concentration of the vinyl chloride was attained initially as in Ex periment 3, but the chamber was ventilated at 50 1pm. Although the body weight of the experi mental rats decreased initially, this trend was reversed by the fourth exposure, the rate of growth thereafter being no different than the controls. The drop in weight at the start and the subsequent resumption of growth was paralleled by an apparent increasing tol erance to the gas as the exposures continued. At the start, the intoxication of the rats was marked, instability of the hind legs being a prominent feature of the exposure. With each exposure, however, there was an obvious diminution of these symptoms, so that by the fifth or sixth cx|>ourc, it was not possible to distinguish any evident symptoms of neu rological deficit. Hemoglobin determinations during the cx- t I i i SPI-02611 . /PC-' V .5 t < '"'"trie! Hygiene Journal i was several weeks old anti probably chamber to 2.0fc vinyl chloride for eight ^u-Uted to the exposure. Both experi- hours per day (0830 to 1630) on Monday t **v.l and control animals had parasitic through Friday for a period of three month'. . .Uftr `is's- No d-i-fT--cr-c-n-c-e-s .in.. _arplp-e-a-r-a-n-ce. The control animals were exposed to 0.0'r Cnsr. consistency or degree of congestion of the test gas, that is. to a flow of 50 1pm noted between the livers of the two of air, in the same chamber as the experi "in. The other organs and tissues were mental group for eight hours per day on normal limits in their gross appear- the same days of the week. No food or water j r. with no difTerenccs between experi- was present in the cages during either ex j tiMl and control groups. posure. Ali rats svrre weighed at approxi | '`'th the exception of the pleural adhe- mately weekly intervals; hemoglobin deter s '>in one animal, the microscopic appear- minations, from tail blood, were made at ' "f all the organs and tissues was nor- monthly intervals. In neither body weight '> ' Tlir gross observation of parasitic liver nor in hemoglobin values were there any sig t in all animals was confirmed micro-. nificant differences between the control and i * '-i- ally. Liver sections from all animals experimental groups. o! tin* ! stained for fat, but none revealed evi- stltf'-* -.1 of increased fat nor were there any `in- r'-l ' '''I'-iirrs in intracellular fat between the During the course of the exposure, there were five deaths; of these, four occurred in the control group. No data from these ani ' fable i rate i.-anth i 1 vi-ups. i 1 `nssifiration of the liver slides for the ; wtph'ih'giral designations of Table IT I <sl diircrenees between the control and mals are included in any of the tables. On the 89th day blood was withdrawn from the control animals under anesthesia as previously described (Experiment 4); these U ***' who h i.> i.v! Is- . , Ml- t.iib ,li-lot*v (*.I|Hli*l "riinrnt.il groups. The mean score of the 'i,.i,,| group was 2.93 and that of the A ;*ninrntal group was 4.56, with only one { "-"I animal being graded "4-' and no ; ">'iiriii*ntal animal being graded less than ' '$' The differences between the tncans ` *iS thus highly significant, yielding a "p" j o' *" than 0.001. animals were then killed with ether and autopsied. A similar procedure was followed on the 92nd day for the experimental ani mals. The livers and spleens of all animals were weighed prior to fixation in formalin. The mean values of the tissue: body weight ratios are shown in Table VII. The dif ferences in the means were in all instances ..It lb** (lillcrcnccs in kidney or spleen slides significant, the liveri larger and the spleens ; '''ii experimental and control animals smaller in the experimental as compared with * -- noted. the control animals. No significant differ ences between the groups ap;reared in the '1'iifiit 5 j '`urv human exposure to vinyl chloride unlikely at concentrations of the gas , h ttuMter than the concentration causing , 1 "f intoxication, that is, at 1.2 to l.fi^r. I 's'i: term exposure of rats was conducted ' ' "'innitration of 2.0Cr. : Si's rats, each weighing about 75 grams. -iwaiid randomly into two groups of . If imI.a am| |5 females and placed in eight cages. In the week, before the ex- j {*"<' was started, the rats were observed, i s^jW'l twice and blood withdrawn for values for hematocrit and prothrombin. The scrum transaminase was not determined. Monocytes and eosinophils showed no dif ferences between the groups: values for the other blood rirments are shown in Table VI. The external appearance of all animals was normal. Parasitic liver cysts were pres ent in all animals. There were no differ ences in appearance, color, consistency or degree of congestion between the livers of tlu- two groups. Ali Other organs ami tis sues were similatly normal, no differences between the groups being apparent. `. \f>xl"liin determination. The experimen- All the organs and tissues examined histo ' 4>l ininiah were exposed in the 1100-liter logically were within normal limits, no path- v> ` SPI-02613  .** . - >A-' X*- r*-/* ; v ? ;rv ;',;^-Si > .fl-.^^i.t-fev'. -' ;, i .*. -June, ISS3 . ,. a rn:-feristic 7^! 3 -i -X ? huhmrial l/ye.i >ic Journal "tiusijs in the 2 Co exposure. It must be ent- 273 view of the wide range that the liver: body inis cp.ii j ; d again that the growth of the rats weight ratio may encompass -Table VII). stionab!'- j `hiring the 5r/<, exposure support the observa- Rather this increase may signify a non-spc- c ccrtaisl* i ,M'ti of the rat's behavior which indicated eilie response to metabolic derangements oc ..-ribcd wii! j tli.it there was a rapid development of toler- casioned by mild and moderate intoxication . of the gao ; tno- in the intoxicatin'; clTcrts of this con- for daily 8-hour periods. From the data ob n from tin1 : i ''er.ti.uion. tained here, it is not certain that histopatho- wtis an ''J'* ^ - in rats ai- ; The pres- - Neither the 2r/c- nor the 5r/c concentrations 1 iiiv:! changes in tiic prothrombin time, logicai change would have occurred had ex posures been carried out for longer times. > the pos- { A lung tis- | ,,vcvcr, ihc. caused by . j -.ere Cfi>* j .;y dcprrl- . j unewnat 1'}' t regular o'- ' | '"la.itocrit or hemoglobin values. At both the 2(e and the 5% concentrations, the "liiie cell count was lowered significantly, although still well within the normal range. I he increase in red cells, although signifit-tntiy elevated in the i>r/r exposure, was not torrdated with changes in the hemoglobin content. The increase in concentration of In the paper by Torkclson et al., histopatho'ogicai chances in the liver and in creased liver: body weight ratios are re ported in male rats exposed to 500 ppm vinyl chloride for 4.5 months. That there is no causal relation between the reported histopathology and the increases in liver;bodyweight ratio is evident from the extensive tin- vinyl chloride is associated with a greater data gathered by these investigators. Female . 'T s describe:: l i-ill in the white cells and a greater (anti rats exposed to 500 ppm vinyl chloride for xposed fur _ f significant) increase in the red cells at the 4.5 months showed no statistically significant "c of vinyl although l < iff level. Although lymphocytes and ncu'"phils arc increased, only the change at increase in liver weight but arc reported to have histopathological changes in the liver. r.n ancstb*'- J h.-iy !\W , ; wings agivr found I'' - j '!" 2% concentration unlike the previous "11 changes, reaches the statistically signifi*Jtit level. It is difficult to know if these changes have any toxic, significance, since no Female rats exposed to lower concentrations (100 and 200 ppm', for six months had sig nificantly increased liver:bodv weight ratios but no pathology. On the other hand, rab sf;d for "0 i 'i'snc changes were seen upon microscopic bits of both sexes exhibited liver pathology 1 VCi'pt tll-3! I 'vamination that would account or he as without showing any increase in liver weight vs result ...J athoiosev s* ' } m rc>:f sociated with a drop in the white cells or an increase in red cells. The decrease in spleen: body weight ratio is in a direction opposite to after rxposurc for six months to a conccnnalion of 200 ppm. The authors correctly point out that organ:body weight ratios may could seen; ' 1'iat usually associated with a severe drop well hr ar:r,'actual, illustrating the point hv ...ms fount! . j hi white cells; although the white cell count the significant decrease in kidney weight well ar> : 'btl not suffer a severe drop, the decrease was found in frmnlc rats exposed to 50 ppm for some so- ; "ilntantial at the termination of the cx- six months: such rats exhibited no changes There "'3s J i'lsurc. when cx|iosed to higher concentrations. By ; 5 Co level j I'hc only finding suggesting a specific the same token, but overlooked by die . upon the ; action of vinyl chloride is the increase authors, the increased liver:body weight .i ; J hiMiib. a liver weight on exposure to 5Co for 19 '' iv c a,ul i,, 2ff over 92 days. The increase ratio in fn-.-.alc rats at 100 and 200 ppm is with equal reason artefact because no sta sensitive 1 ;l- hver weight is not only highly significant tistically significant increase occurred at 500 in a roll- j iJtisiically hut is also substantial, amounting ppm. Apparently, also, species differences are woduris :< ; a increase over the controls. It is of importance in the reactivity to vinyl lie- sharp '"ifi'itimate that no information is available chloride, male guinea pigs suffering a signi . -et iincfiMl " to whether this increase is reversed on dis- ficant decrease in their liver: body weight ..-. iswre wa * "iiiiniiing the exposure. The increase in ratio when exposed to 100 ppm for six ilie 1,;- ' !ivi-i weight may be interpreted as indic ating months. - it ni'e l*e- ' dictations in water, electrolytes and protein There arc six possible combinations of the ,ii rats of `"titect of the liver parenchyma, but that presence or absence of pathology and in <-f growth i ,?h changes presage the development of creases, decreases and no change in liver tween (hr - iv.iial histologic lesions is not certain in weight. The one combination not observed SPI-02615 I'iriuitrinl Hy^;nir Journal 275 !.".c changes in the fnruwd elements of the ; Wood. The increases in liver:body weight ` ra:;os were associated with morphological alterations in the liver which appeared to ,.-ive no lithological significance, while no meaningful motphologica! alterations were evident in either kidneys or spleens. Ilcrause, in the long term exposures, it was :..;iossib!e to attach any toxic significance the changes noted or to observe any his; topathology, and because other aspects of the v.tn-.a!.,' reactions, such as growth rate, were unimpaired, the presently accepted threshold .> Itmit value of 500 ppm for vinyl chloride, anc-forticth of the concentration tested here. ' seems to offer an adequate margin of safety | fur human exposure. Acknowledgment It is a pleasure to acknowledge the tech nical assistance o: Malcolm Nicholson, Frederick A. Putt and Miss Liiiemor Wallmark. References I. \o> OfTTivC'v. W. F.; Trt H*l*gen*!e4 Pttrtiusl Daniffi. L`. S. Pi.Site Knith Vrvt.-. I*ublifa:fn 4 i 4. Covtmmco: Printing OfT*t"r. D. C 2- M*si*e!M*rrr.r.. K., A. M. Fixmfa, H. Cmhxttk, and II Dt\ttnvt: Acme Jnhalatinn Toxicity f Vinv| ('hlnrid* K* l^homory- Amrr.aLt. Amtr. Ind. it\g. J. 2h 3*4 (Oci. 15*),. 3. To*KfJ-ov. T. R.. F. Oviv, and V. K. R<nit: The Toxicity ot Vtn>l Chlorice .v Determined by Repeated F.xpciure n* Laboratory AnT.:*1!. Aner. /W. //>?. A.'imf. J. 334 (Oc:. 4. S*vrn. If. F., J.t Inar-wcd Communication--Hy. (licue Sfandxr<! f*r Dnilv Inhalation. .4mr. /ai. h'yg. As-*. J IT: (IMF*.'. 5. hm, F. A.. H\ I*. Yant, and C. P. Acute Rr*por* f Guinea Pirn to A`atier ? Sotne New Com- mnetal Orcanic CompounH*. V Vi.-.vl Chloride. Tuh* he Health Rep9't (U.Sj 4J; 1563 (A*. 1930). { Sources and Use of Toxicological Information The New York University Medical Center in cooperation with the American Industrial Hygiene Association will present a course on Sources and Use o[ Toxifningical Information. The course will be given October 1-i-iS, 1963, at the Onchiota Conference Center, Sterling Forest, Tuxedo, New York. The course is designed to acquaint those concerned with advanced methods of securing and interpreting pertinent toxicological information. Application and principles will be stressed rather than details of experimental toxicology. The design of the course eliminates the need for specialized scientific back ground so that all administrative and technical persons having responsibilities for use of toxicological information can benefit. Guest lecturers who arc spe cialists in selected fields will supplement the staff of N.Y.U. Institute of Indus trial Medicine for presentation of the subject material. Areas to he covered arc: biological principles involved, sources of toxicological information, appli cations to in-plant problems. Federal regulations, and lequircmcnts of various agencies. Inquiries and registrations should he directed to New York University Medical Center. Institute of Industrial Medicine. 550 First Avenue. New York 16, New York. The registration fee is $150 with a deposit of $25 required. Ac commodations (double occupancy' at the Onchiota Conference Center for the evening (dinner) October 13 through lunch October 18 are available at $21 per day including meals (payable to the Center on departure'. SPI-02617