Document Xz5ZEQo9JVV5G5MZ2gvOODkJK
1
Effects of Single and Repealed Exposures* of Humans and Rats to Vinyl Chloride
Dl LESTER, rfcO),* L. A. CREEXBERC. PhJ>.,* and W. ROBERT ADAMS, XLIXt
1 -1 *--j Applied Ri*dyn*mUt.
(/mmd Dcpmrlmnt /
Altditmt, l`if Uaircruty, AW //, Cmmmcttual
Sekaat /
0 Bait npstral debt Boon datly la viayi chloride at caactalntiaaa at 2% far
lAm atanitu aa4 3" far 1? Aar* cakibiirA (banco in Eset mf micro weicht of in ref and while cril minis. Faiipt in ike caac af liver, ibwt aUrratiana did Ml accompany Unt chsnstw The ahcratiniw in D*cr maiphatagy a vithia 'the annual ranee and were aat pslbalesic in character. Became wthcr faetts af the animals' tnpaiut. tacit at .ut af pawk, tcrun* Iramamiaate IH1 ' casoglobin, rare unchanged, it it msecm.-* that the procst threshold litmt mine af KBil need aat he lotnd.
Introduction
together with a trace of air and carbon
dioxide.
THE TOXJCITY of vinyl cKaride hat been reviewed recently.UM Because tlie
Ttu t
threshold limit value of 500 ppm it luted
Analysis of Vinyl Chloride Mon- mcr
on limited data* using vinyl chloride lets pure
than that now obtainable* the effects of acute exposure in man and rats and long term exposure in rats vvai iaveitijp.ted by us in 1959 and it described here. Our data do not support the conclusion of Turkclion. cl at* that the threshold limit value should
IlM S*U1mt
Nm. VO.
IVaMt Cmb*
Amt
Oft
SW M OJ
to rvr
.11 S-"
HO r.w
t9*
n+%
be reduced ten-fold; indeed their data indi- -
cate a need for funiter studies prior to any Methods revision of the threshold limit value.
Experimental
Malarial
The vinyl chloride monomer was supplied by tire Perkin* Plant of Solway Process Di vision. Allied Chemical Corporation, in four 100 lb. cylinders with the characteristics shown hi TaMr I, presumably differing ma terially from the vinyl chloride uvd by Torkelsnn, cl a/.1 only itt the presence of 00 |>pin of tin- inhibitor, pln-nol. Cat chro matography of die liquid pli.lv indicated the presence of more titan 9f)^c vinyl chloride,
Nrtratnl r| tlnv Toraiyrimtl Aaausl Mrtimt ! the
.WrwiR ImIumiwI
A.'^i.iti*n, lh>f mm, D-
c., f*.?.
Tbs*
was aanaffiril am (**rt K* icwiuflt ff*wi |mm
,\H4 ( kaNasaal ('m|Miamw lad iat
by (I. (. 1`nhliC
llrabh Swisr (da' 1 . "IB.
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l*(t>
alnfy. bmr<**lb bMt`
bnwa abb, \rw Irrwt.
Saw
1lDftpii ml t> S. I'mlsi* |t.allIt kf*M W*at kW*Hb
riw^, x. n<j7.
Desired eoneentrationt svere obtained by metering air and vinyl chloride through flow meters calibrated for these gases and pass ing dtc appropriate flows through a 2-litcr mixing cliambcr. The coneemration was also continuously monitored by a thermal conductivity inrtcr calibrated for vinyl chlo ride versus air. The desired concentration of vinyl chloride was maintained with less Ilian rjr/e deviation. Tlie total gas flow was alxmt 50 liters per minute (1pm) in all hut one of the experiments.
Five experiments were conducted: (11 a fivc-tiiimitc ex(K>siirc of human Iicings to niiicfiilraiirmt of vinyl chloride ranging from 0.0 to 2.0',1 ; (2) an cvfsnurc of rats (Slierman stiain ratv fioin UihU.wuI Farm, New
City, N. V.) for at_Jong as two Imurs with ctMimUraiions up to Ib'/c; and (3, 4, and S)
365
266 Uey-Jnne. 1963
exposures of nil to concentrations of B to slides of tie Ih-rr, spleen, and kidney wire
10% lor 15 days, 5% ;w |g cnwouKt examined and classilietl, then recoded and
day* and 2% for 92 dl)\
re-examined; in this manner "a rnrasutc id
the consistence and reliability of die paslml-
htlb(inl
ogist's technique was obtained. Tim enn-
. The experimental and control- animals were killed by etlier inhalation alter expos ure* to 2, 5 and 8 to 107i tiny) chloride mere completed. Each animal wot autopsied according to standard practire. In addition
sistcncy was nearly Jierfrct in the case of Gvcr slides, and only slightly less so for qtlern and kidney. The results of these examina tions are reported in the appropriate follow, big sections.
to the gras examination ol all animals, all Results
(he liven, kidncyi and epicene nt examined microscopical!)- and enmc animah received
Experiment l
a com)>ietc niicTOscojnc examination, llrart,
llccause the main objective was the deter
lung, Ever, spleen, urinary bladder, testa, mination of the effect of long term rx|tosnrc
prostate, ovary, brain, tpinal cad, pituitary, to vinyl chloride, die maximum conrmtm-
tibia, pancreas, ttnmarh, email and brge tioli of the gas to which humans might
intestine, adrenals, kidneys, uterus, fallopian conceivably be exposed without any imme
tubes, tliytmts, thyroid, parathyroid, eye, knee diate scute effects was determined; this con
joint, bone marrow, skeletal muscle, salivary centration then became the basis for deter
glands and skin were removed from each mining the concentration used during the
animal and preserved in 107r buffer xl for 92-day exposure of rats.
malin. All tissues svere examined grossly
Three men (26, 35, 50 yean; 86, 78, 73
both at autopsy and after formalin cixation. Kg.) and three women (25, -40, 55 years;
Following fixation, representative samples of 64, 52, 61 Kg.) svere exposed twice each
SlD tissues wore proecssrd according stand day, separated by a 6-hour interval, for
ard histological procedure and suincJ with litres successive data to six different con
hematoxylin and eosin; separate specimens centrations of vinyl chloride: 0.0, 0.4, Oil,
of liver were stained for fat with the Flam 1.2, 1.S and 2.07c. The concentrations were
ing Rti technique. The animals receiving presented in a different order to each sul>-
such a complete examination of die tissues jeet to nuke it possible to factor out any
listed included two males and one female rat pouiblc adaptation to either dir gas or dir
that had been exposed 15 times and one experimrntal situation; the 0.07c concentra
female rat exposed ten times to the 8 to tion was included so that some asu-ssnintt
10^6 level; eight experimental and nine of suggestibility could lie made.
control animals surviving the 5% exjxnurc;
Until its conclusion, tlir subjects were told
and 20 randomly selected ran. equally di neither the effects to rxjicct from tlte rx|tns-
vided as to experimental and control croup* urc nor the puqiosr of the rxjieriincnt; nnr
and 10 sex, exposed to 27c vinyl ctduiidc.
was information vouchsafed at to llic con
The marked increase* in liver weight ac centrations dial were used at any time, llie
companying the exjxtsnrcs to 2% and 57e subjects each ul in a rliair separated from
of die ps the decrease in splrrn weight in die gas . mixing rqtiipm*-ni by a srrcrti, a
tile 27* expsottre ami the rc)>ortcd kidney simple plastic breathing mask affixrtl nsi-r
chaagcs in exftenure to 500 jijsin' led us tn the face, covering the tiumlli and m--**. The
examine these ftartieular tis-ucs with a hliml rate of air or air-gas mixture |ia--sxl thiouch
technique, thus excluding tlu- o]K-ration of the uusk was uiffirient (511 Ipm) U jm-vriu
any bias or |>rrjndire from the judgment*. any dilution rffi-rts frnm the atnuiqiheri-. AU slides, imlmling duplit .no. wete ran After five minute- uf Inrallting the mivltnr.
domly immltcrixt mi dial it was iill|mssib|r tlis- i-x(Mtsurr was let mutant! ami tin- Milto diuirtgmslt, w iilwKit tlte e**le. whit It hail jixts isvie u4.nl to t in,,1 sti r iltt-ir f,-*ltit"'
) been cx|avimrmal and w-lm h tnnlnil. IIic at this lime Ut the time immetliait-ly
I I
T
n*
I I
l
lo/iutlr'al Hj-giene Journal
267
prior to putting on the mail:; no wggcstions thesia for two liours; on removal to air,
of any kind were made. The rct|>oma if Utrre was an uneventful and profnpt item-
die subjects arc summarized in Table II. ery.
It is apparent that the maximum eonccntra* thus causing no effect in any subject lies be* Experiment 3
tween 0-8 and l-27e- From the response* it is evident that vinyl chloride causes, clear* cut intoxicating symptoms which can serve as adequate warning signs of iu presence.
Some notion of the distinctive and specific patltology that might be caused by vinyl chloride was our object in exposing rats to a concentration of 107*.
Tails II JLesfaonscs at Human Subjects to Varying
-Cenctturaiions ot Vinyl Chloride
Thirty-six rats, equally divided as to sex, were divided randomly into an experimental and a control group; the IS experimental
hr Cm
rats were exjmsed to die gas in a 1100-Iitrr
K# dillnntn wwhi4 W kbjtin i. 2, 4 i
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u mrn4 6. Setbjm is
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Tfcm i^wfi>an iMntrd nlt i* ib% xwwwn
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mh' mm* mw
Am m IS'Uu
steel diamber. The concentration was initial ly raised rapidly to tlte desired level by ad mitting vinyl chloride without admixture with air until tlic effluent from the chamber attained the desired level as noted on the thrmul conductivity meter. A fan within tlic 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 from the 2-Iiter mixing vessel was admitted,
Experiment 2
to the chamber; to conserve sat, the dirmrghput of this highest concentration was 20
To gain further insight into the intoxicat- 1pm.
mg eflccts of vin>'t chloride rats were ox-
The experimental rats were cxpnscd daily
posed to varying concentrations of vinyl from 0030 to 1630 hours while die control
cldoridc for periods up to two hours. The rOIuent gn* from tlte mixing chainher, at the desired concentration, was |Qvxl ttirough
animals were exposed from 0000 to 0000 hours. At this concentration, as already noted,, mts lose consctnusnrss, regaining it
a 10-litcr all-gl-uv ex|>os>irc chamber con five to ten minutes after removal to air. taining two rats At a 57? ranerntmiinn in After two consecutive 6-hnitr exposures, how
toxication is uiodrratc lmt the righting re ever, tlic appearance of the animals sug flet h tost; intoxication is more interne at gested that there would be no survivors if this
65b but tlte righting reflex is still present concentration were maintained for the con This reflex is lost at a concentration of lr,'o; templated 13-day |>s-riod; consequently, be
the corneal reflex disupjxars at a concentra ginning with tlic third exposure, the con tion of 107?. On removal from llte chamber, centration was reduced to f!7. Tlte test the animals return to the pre-exposure state was interrupted for one day after die sev rapidly. One animal seas sacrificed after ex enth daily ex;insure because of a ntccltanical posure to tlte 107c eoneemration xml sltotved breakdown. Of tlic group rx|Msi-d in this no visible gross |iatltlogy. Ex|unurc to a fashion, direr frtitalr rats died, after die sec concentration of 1.17/- resulltxl in drrp anrs- ond. fifth ami fouileerith rx|msurrs; llte two iltcsia svithin five minutes. F.fTttsion uf fluid animals that dietl earliml were rrjilaced with from tlic'month |ntvitltil rrspiralory failure sulrviitoies fur the reuumung exposure Jiem one rat after I if miimiev: xuin|ny revt-nlid rind; right female rats wmc thus alive at nlraia ami nmgestioii of-thr lungs. The sec tlir rml uf tlw fifternth i-s|uvsurc. Female
) ond rat was uiaintaiiu-d mitler this derp anes ratsrxpuwd 10 and 13 lima were autojisied
f
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At the trrmtnation of the exposure; the re* mining six rats were tuiopwd IS days liter, 6 of liiese rats having been exposed IS tines and the sixth rat 13 times. The mortality was greater among the male rats: only two males survived IS exposures, the remaining males, and their rcplaeouents, surviving only an average of eight .'xposures. The two male rats exposed IS ernes were autopsicsl at the termination of the -xposure.
There was no weight gain in the initial days of the exposure to this cone-notation, at* though after the ninth day seme resumption of growth seemed to occur, possibly an in dication of the development of tolerance to the effects of the gas as the rxrtsurr con tinued. Upon termination of the exposure, growth resumed promptly at the same rate
as the control animals. Both at the 16th and at the 30th days, there appeared to be no differences in liver: body weight ratios between rxjsrrintrmal and control rats, al though too few livers were weighed at the termination of the experiment to nuke mean ingful comparisons of this ratio.
The external opjicarancr, coat and tail, of all the animals was within normal limits. About a third of the animals iiad parasitic Kvcr cysts. No dilTrrcnrrs in appearaner, color, condstmry or dtguT of congestion were observed brtmrti tin- livvrs of rx|xrimcntal and control animals. Tlir lungs of tlirre cx|v"r>ncnuil animals sarrir>red initnetliairly upon itioiiwi of tin- cx|<nsurc 1usd nuim-roos focal fibrinous plmral exudalrs overlaying tuulular villim-bumn |rmcliynial lesions which had the appearance of regions of arnlr iH-rriui/ing fwal pnn* monia. Of tin- six rx|-rmimt:il animals SAcrificrtl two wi-els after the rSfKwurr, the lungs of twu revralesi a few adliermt Muons
pleural adhesions which were interpreted as representing regions of healed pneumonia. All other organs and tissues were, within normal limits, with no differences between
experimental and control animals.
Tire experimental animals sacrificed at die termination of tire exposure receives a com plete histologic examination. The lesions in the lungs of tlic three animals m this group showing gross pleural pathology were seen to be due to acute focal necrotizing ]srcumonia in varying stages of organization. Some pulmonary edema was present as well as diffuse infiltrates of mononuclear cells in the alveolar irptae. Some areas of meta plasia were present in and near the regions of pneumonia and were interpreted as secon dary to the pneumonia.
Tire parasitic fiver cysts seen grossly were
confirmed microscopically. The liver sections
stained for fat revealed individual variation
of some degree but no significant deviation
from normal. The coded slidrs of die livers
were
arrortting to the drveriptions
in Table III while kidney and spleen were
judged according to the criteria in Tables IV and V; Figures 1, 2, 3, 4, and 5 arc
T&au V OiMuftrMMi of Mflrphitbtpr dun^n in Spleen
(3m
PrifTini--
I A*** tiaw MIwIpx, WiiW kr P* nnntiwi. K*L*sarr
Wumpp ltmdrye\ grawMmJ rgmaW-kaMM pmal Wtft
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, saluarn 4 gvsiwMwf teaseis Ipm llam talaati
grripl^iA hwnWstm,
3 CrswmJ rrMet. t^**^*4*a*4r mm* *> m pram
pAramt )*p|ilas>mt pwmraaip fuaimmia. 4 Warrwal anatlat *4 kwHslaPM. br|i>T)lMS tJ
iMMiaal rrmea* [c*^oa>a Ibja anlanir pi [wnphrut
3 3 rtww, M WWysav 111
-- naaMtaUrh *mmd gmmat rrmaaa* taaipaiag
aW Wmitw
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4 (tar iMvsstwmm.
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fltuitrative of the class descriptions in Table vinyl chloride in air for 19 consceativc days.
III. There were no significant differences The experimental animals sverr p aced svith-
in the scoring of the grou|ts, 'although there iu die diamber at 0330 and remos-ed at 1G30
svas a class "5" and no claw "3" in the rats and die control animals from 0000 to OMOO
kilted at the termination of ths exposure, Imon. To prevent rnntaminatior. of food
whereas there were no livers in eiass "5" or water, both grou|H of animals s.rrc placed
among die control animals. There were no within the rhamber in empty cages; lienee
class **5" livers among the experimental raw experimental and roiurol animals svere de
killed two tvrt-ks after the ex|>osure; die prived of food and water for eight hours
slides were evenly divided between scores daily. The rec|uisite concentration of die
of 3 and 4.
vinyl chloride svas attained initially as in Ex
Kidney slides from the experimental ani periment 3, but the chamber was ventilated
mals were not graded differently titan from at 50 1pm.
the controls but all spleen slides from ex
Although die body weight of the experi
perimental animals received the highest mental rats decreased initially, this trend svas
score, differing significantly from the con reversed hy the fourth rx|>osure, die rate of
trol spleens, although some controls also growth tlirrcafter being no different than the
roerived such high scores.
controls. The drop in weight at the start
and die subsequent resumption of grosvth
Experiment 4
I
was jiaralleled hy an ap|iarmt increasing tol erance to the gas as the ex|mxnrr* continued.
These preliminary trsts smwsl to indiealr At the stait. thr intoxication of tlir rats svas
dial vinyl chlmidc svas an anesthetic gas innikixl. instability of rill- hind legs licing a
whirl) might also art as a lung irritant, in promitietii feature of (lie rs|smirr. With
Onlrr to asses* this feature of its anion, In earh rx|Ktsiin-, limvexs-r, iheie svas ait olivious
highlight significant I.illwil'-^ii`al fi-alnies and iliuiittuiHiti tif llii-v- symptoms, so tltnt hy dte
to avoiil die |arminlily of il.im.igi- arising fifih or sixth evjiosuir. it ss-as not jtnxsihlr
from anrsthesia alone, fivr fi-m.ih* ami live to di-tiuttui-h any t-s-iih-tit symptoms of nen
male rats, naul**d s-iili nmimli, woe ex- rol*-giral tlelieit.
V [SMil fur eight Imhu* daily to live per cent
Hemoglobin determiiutiims during the ex-
C v; CT
t if,
T
>s-
270 Mty-June, 1963
Taolx VI Formed Elements ( the Blood at Termination of Exposure to S and 2% Vinyl Chloride
ponirc period revealed no difference between experimental and control groups
On the twentieth day experimental and control animals were anesthetized' with di ethyl ether, blood was drawn by cardiac puncture and 1/9 volume of O.i.l/ sodium oxalate was added to the blood. The ani mals were then killed with an overdose of the anesthetic and auto|icd. Measurements of hemoglobin, prothrombin timt hemato crit, red cells, white cells, differential white cells and scrum transaminase were performed on the blood drawn. So urn transaminase, hematocrit values and prothrombin times were normal for both groups. Table VI lists the values for some of the formed de ments of the blond. Monocytes and cosines.
phik-ionned only a smalt proportion of the white cells; no differences betwetn control and experimental animals occurred. The red cells were somewhat elevated and the white cells lower in the experimental group. Table VII shows dial the liver: body weight ratio of the experimental animals was significantly elevated.
AH 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. The three fe male experimental animals and all the con trol animals had normal coats and tails. One male exjierimental animal had fibrous pleural adhesions on the left side: the fibrous nature of these adhrsiom suggested that thr
Tadix VII Liver and Spleen Wriffhu of Rats Exposed to Vinyl Chloride
Cwmmp
rill! C%)
CnN CnUW St-cW CwMri (WnI
Cmm
^pd*
* s 4 e|l |ft
1`ovtWid (no low *nis
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t:
tKtt
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ftf
14 14
rr
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fftt rr
4ft
u
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4ft
u it
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tr*
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LHmr
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StiM
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ft.Cft 4.1f ft.tft 4.14*
.3d J0 .If 4.M
ft 49 3ft
f.IRft MU u;
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ft It ft.ft* 4.t* l.t>
ft. 4ft ft.4ft ,r
ft.&
l.3
c u tl os o o
InJultriml Hygiene Journal
771
proem was nml wrx-Ls c*ld and [iroiubly dumber to 2X>' vinyl chloride fur eight
not related to tlic cxjxmire. floth cxjici l- Ik*its per day (01130 to IUT0) on Monday,
- menial and control animal* had ;iarasitic through Friday for a (irriud of three inontlo.
Cm cysts. Xo dilTcrmccs in appearance, `Flic control animals were exjxwtxl to 0.0%
color, consistency or drjne of congcstit*t of tlic tot gas, that is, to a (low of 50 Ipm
were noted between the liven.d the two of air, in tlic shin: dumber as the experi
(roup*. The other organs and times were mental group for eight hours per day on
within normal limit* in their gross appear- tlic same days of the week. Xo food or water
, anee, with no differences between expen- tot present in die cages during either ex
' menu] and control groups.
posure. All rats were weighed at approxi
With the exception of the pleural adhe sions in one aniinal, the microscopic appear ance of all die organs and tissues was nor mal. The gross observation of parrsitie liver cjrstes in all animals was confirmed micro scopically. Liver sections from all animals
mately weekly intervals; hemoglobin deter minations, from tail blood, were made at monthly intervals. In neither body weight nor in hemoglobin values were tltc.r any sig nificant differences betwent the centre! and experimental groups.
were stained for fat, but none revrated evi
1hiring the course of tlx- rx[tee tire, there
dence of increased fat nor were there any were five deaths; of time, four nrrurml in
differences in intracellular fat between the the control group. Xo data from tlicsc ani
' two groups.
mals are included in any nf the tables.
Classification of the liver slides for the
On the 89th day blood was widtdrawn
morphological designations of Table 'III from the control animals under anesthesia
shewed differences between the control and as previously described (Experiment 4); tlicsc
experimental groups. The mean score of the animals were then killed with ether and
control group was 2.93 and that of the autopsied. A similar procedure was followed
experimental group was 4-55y with only one on the 92nd day for the experimental ani
controi animal fccir.r graded "4" and no mals. The liven and spleens of all animals
experimental animal being graded less than 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 VII. The dif-
of less than 0.001.
ferencc* in the means were in all instances
No differences in kidney or spleen slides significant, the livers larger and the spleens
between experimental and control animals smaller in the experimental as compared with
, were noted.
.the control-animals. Xo significant differ,
s .
cnees hctwrrn the grmi|n appeared in the
Experiment 5
Because human exposure to vinyl chloride seems unlikely at concentrations of the gas much greater than the concentration causing signs of intoxication, that is, at 1.2 to 1.6%, die long term exposure of rats was conducted at a concentration of 2.0%.
Sixty rats, each weighing about 75 grams, were sejiaratcd randomly into two groups of * 15 males and 15 females and placed in eight separate cages. In the week before the ex posure was started, the rats were observed, weighed twice and blood withdrawn for
values for hematocrit and prothrombin. The scrum transaminase was not determined. Monocytes and rusiimpUils showed no dif. formers Itrtwcrn tlic groups; vtilucs for die oilier blood elements are shown in Table VI.
The external ap|tearanee of all animab was normal. Parasitic liver cysts were |>rcvent m all animals. There were no differ, enrrs in apjiearnnee, rnlor, consistency or degree of congestion lietw'evn tlic livers of the two groti|n. All other organs and tis sues were similarly normal, no differences between tlie groups being apparent.
hemoglobin determination. Hie expcrirneti*
All the otganv ami tissues evamiiw-d histo
tal animals were exposed in the 1100-liicr logically were wiiltip mutual limits, no path-
n
c
(= !
n G3 O O
T
'ft
)
V.-
273 JtrrrJunt. toes
ology being evident in either cxjicrinicntal tn produce some singular or characteristic
or control sninoli
patlielngy. It cannot be said dial this goal
The pinnitic IKrr ryjti irm grossly rt was achieved, the results being questionable
confirmed microscopically. I-K-rr lection* and uncertain. Lung lesions were certainly
stained for fat rtvralvd normal variation, hut present but these could not be ascribed widr
bo animals loti increased intracellular fat nor certainty to any irritant properties of die gas
were there cliffcrcncn between tlic experi since they might well have arisen from the
mental and control anitnah. Craded in long-continued anesthesia; there was an ap
accord with die mnqtlmliflf in Table III, parent regression of these lesions in rats al
the liver slide* revealed differences between lowed a 14-day recovery period. The pres
the group*. The mean score of the control ence of pneumonia certainly raises the pos
group was 1.58, that of the experimental sibility cl an acute toxic effect on lung tis
group 3.63. No Ever in die control group sue at these concentrations; however, die
scored more than 2 and none in the ex pneumonia could just as well be caused by
perimental group scored less titan 3; one Ew secondary infection during the severe cen
er scored 3. Because there was no overlap tral nervous system and respiratory depres
the differences between die means are high sion, an interpretation favored somewhat by
ly significant.
the diffuse lesions and L/ the irregular oc
There were no differences m scorr for the currence of the pneumonia.
spleens in the two groups, but the kidney The kidney and Ever changes described
slides of the experimental animals scored by Mastromatlco, at oL* in rats exposed for
. significantly less than their controls.
30 yninutes to 20, 30 and 40% + vinyl
chloride, were not observed here, -'though
Direunion
15 repeated S-liour exposures to an anesthe tic concentration is also a relative severe
The data from the prrscnl investigation stimulus. Tlic findings in the l'u y. agree
confirm die acute effects to be exported from with die relative lack ef effect frmxl by
various concentrations of vinyl chloride: Mastromatlco rt al. in rats expose*, for 30
concentrations below 1%, when ex|msttre minutes to 10% vinyl chloride, rxc.pt that
il limited to five minutes, cause mi ob continued exposure, for days, decs rsult in
servable intoxicating effects; five minutes, mortality. The relative lack ef pathology as
however, is shorter than die time necessary the result of 30 minute exposure at 10%
to reach an equilibrium level in the circula found by Mastromatlco et at would seem
tion; from behavioral observations in die to support the view that lung lesion: found
tat, it may be estimated that in five minutes after repeated exposures could well arise
some two-thirds of the equilibrium Irvcl is from the anesthesia and not from seme ac
reached; consequently a concentration of 0.6 tion peculiar to vinyl chloride. There was
to 0.7%, if long continued would not pro no indication at either the 2% or 5% level
duce intoxication. As the concentration rise* of any untoward or other effects upon the
above this level tlx- intensity of tlic intoxicat lung tissue.
ing signs increases until at a concentration of
As an overall measure of general hraltli,
7% tlic righting reflex is kwt; at 10% the body weight ami rate of growth are sensitive
corneal reflex di*ap|tran and at mnmitra- indicants. Rvm in die exposure to a con-
tions of Upi and abovr rrs|xratnry failure rmtratinn nf 5'}, whirls at first produces a
takrs plarc. Vinyl rhlortdc thus arts a* an markrtl and x*vrrr intoxication, tlx- sitarp
anethrtir gas, its dqitnum anion iurmtsiitg drop isi dir weight nf male rx|K-rinxntnl
with increasing rouriniiaiiuii of tlx- gas in animals imi at tlx- start of lltr rx|wwnrr was
tlic air Ixeallxxt. dir Iix iC|welding hu'i rav soon iT-wrwd mi dial liy tlx* mil nf llx- 111.
ing nniroingiral dclirii* ending in ilralli at tkty rx|xnun* lltm* was no difi*rrrtx*r lx-*
conrcutraixni* greater tli-m 15%. TJx- jmr- tvvni rxjHiiimutal .and rontml rats of
pose in px|x*ving rats to HHrtilraliixi* rain rithiT xx Ihxlv weight ami tale nf growth
ing anrstlx-via (II In 111%) was an attempt similarly dxneixl no dilfcivtH'cs lietween tlic
c
u
C.l
C5 o o
T
Mmantt llytirmr /*/
37)
gpm|* in tin* 2# n|i>uiir. It must he rm- virw- of thr wide range dial die lhrr: Irdjr
phasiml n^.iin tint tlic gmwih of tin: nits weight rutin may rmimtpavi ("faille V'tf),
during tlx* .Vi rxpnstu-r snpjiurl tin- i4nm li.llher llii> iuricWM* nety signify a rm-pr-
tint at tin: rat's In-luvior which imliralrtl rilir n-^imiw tn nn-tnladir do angru.cnls oc-
tint tltCTC wa a rapid drvcfc>|inicut at tnler- mamnl lir mild and imliTJlr nilnxicatinn
sncc to die intoxicating effects p[ this con for daily Odour jx-rinsh. firm die data ob
centration.
tained here, it is not certain diat histopatho-
Neither tiie 2# nor die 5# cenrtnttatiant logteal rltange would have occurred had ex caused changes in the prothrombin time, posures been earned out for longer times.
hematocrit or hemoglobin values. At both In the paper by TorkeCon rl f., htslo-
the 2{ and the 5% conceittrations, the |satliologieal elranges in die User and bs-
White cell count was lowered significantly, . treated livmliody weigiit ratios are re
although Mill well within tltr normal range. ported in male nits exposed ui 900 ppm
The increase in red cells, although signifi vinyl chloride for 4J month*. That shore is
cantly elevau-d in tlte j't cxixmrre, was not no rausal relation her. an dir reported his-
correlated with changes in the Ixinojlobin tofiatliolngy and the innrasrs ir liver:body
Content. The inerrase in cottcet tration of weight ratio is evident front die intensive
die vinyl chloride is associated with a greater data gathered by these investigator. Female
tsD in the white cells and a greater (and rats cs|imcd to DOC ppm vinyl ridwide for
significant) increase in the red cells at tlte 4j months showed no statistical) - significant
5% level Aldiough lymphocytes and neu increase in liver weight but are reported to
trophils are increased, only die change at base hisropatliological changes in die liver.
the 2f* concentration unlike the previous Female rats exposed to lower cr neennations
cell changes, reaches the statistically signifi (tOO and 200 ppm) for six mon\u had sig-
cant lpvel It is difficult to know if these nifirantlv increased liver-.body weight ratios
changes have any toxic significarce, since no but no patliology. On the odier hand, tab.
tissue changes were seen upon microscopic bits of both sexes exhibited fis-r.* pathology
examination that would account cr he as svithout showing any increase in ."ivtr weight
sociated with a drop in the whit* cells cr an after exposure for six months to a concen
increase in red ceils. The decrease in spleen: tration of 200 jipm. Tlic autiiort correctly
body weight ratio is in a direction opposite to (mint out lieu organ :hody weight ratios may
diat usually associated with a severe drop- well lie ancfartual. illustrating tlic point by
in white cells; although the white celt count thr significant firrrras:: in kidney weight
did not suffer a severe drop, the decrease was finind in female rats r-tpmi**i in 50 p|mi for
substantial at die termination of die ex six montlis; suc h rats rxhihilid no rtiangrs
posure.
wlwn rxposrd to higlier rom rtiiration*. lly
The only finding suggesting a specific toxic action of vtnv) chloride is tlic increase in liver weight on ex|xmirc to 55i for 19 days and to 2fa over 92 days. The increase in liver weight i not only highly significant statistically but is also substantial, amounting to a 30# increase over the controls. It is unfortunate dial no information is available as So wiiellier this increase is reversed on dis continuing the exposure. The incrente in ' fiver weight may Iv imerpirtvd as iiulirating
tlic tame token, hut met looked liy die million, die increased liver: tiody weight ratio iu female rats at 100 and 200 p|xn is with espial reason artefact b-.vausc no sta tistirully significant increase nmirmf at 500 P|mii. Ap|t.in-ntly. also, sjiecics differences are of im|x>rtancc in tlic reactivity to vinyl chloride, mate guinea pigs suffering a signi ficant dt-create in tlwir liver:body weight ratiu wlicti ex|xed tn 100 |i)im for six montlis.
alterations in water, electrolytes autl juntcin
Tluie art* six [Hiwiblc cninhinatirins of the
content of the livrr |iarcnrhyma, but dial presence or alwence of p-itiinlegy ami in
such changes jm-sage die development of ti cavs, decreases and no rlunge in liver
actual liisinlugie lesions is not cvilnin in weight. Tin; unc combination not observed
37* iftp/asr, /Pti.7
by Terlrlwn, rt eL S> !inU^ullioirr;iral 40 times those used by ToHtrkm, rt el. II
change associated with a limrair in fiver any reliance to le placed in a dnw-ciTrrt
weight. Obviously, if five of the six pranSjfe niationsliip, jatlmlogy of some runmlrsahlr
combinations hate brm olnerved in a irh- degree slimikl lave been found in ostr rs.
tivdjr snail sample, no rauxal connrrtkm perimeats. Vet only moqdiologiral alirta.
can be said to exist between dic*e two tions of die character already described and
measures.
pictured were seen, which, in our knowbslgr
Change* in the liver:body weight ratio . may well have mne toxic significance, but
if they are unaccompanied by histnpathologieal alterationi, increased fat contrat or tenon transaminase change* it i* impossilile to conclude dial taken alone they tonify much. Reference to Tabic VII will dtow
and experience. are of no pathological signi ficance. Wlicdtcr die explanation reside* in a difference between the rat strains used by us and by Torkclsnn rt eL or elsewhere w not known, but w-idiout additional data it is impocssUc to resolve die contradiction.
On die bans of the present data, and die
that the liver:body weight ratio* of the rat* seeming unimpnrtanc. -of the liver weight
tued as control animal* in die it'i. rxposurc diangcs seen by Torkehon cl el., and with
were significantly higlirr dan die experi out further evidence, a changr of die pres
mental animals in the 27i ex|xni:rc. Tin* ent threshold limit value of 500 ppm seems
illustrate* writ die fact that dir ugh control unwarranted.
animals are used, unknown and non-specific
change* in the environment, time of die tear, Summary
temperature, diet, etc., may i>e responsible for changes in organ: body weigh1 ratio with out at die same time producing pathological alterations in the organ.
From 5-minute exjiomrc* of *smsn sutw jerts to concentrations s>f vinyl *. loridc rang ing from 0.0 to 2.07c, it is estimated dial a prolonged exposure to a level of norc dtan
Similar consideration* apply to die de crease in iplecn weight: litre, nut only was pathology not observed, hut tli.-re was no difference in the morphological cluiractrr at
'either die 271 or 37c level between die experimental and contiol groujis.
0.6% is necessary to produce minimum jyasjjttmts of intoxication. Ra.s rxposrd fur up ta two hours to higher mnrrniraiitint ex hibited moderate intoxication at. 57c. lust dicir righting reflex at 7fe and the corneal reflex at 107c. Respiratory failure occurred
at 15%. If the exposure to 1071 was long
Unlike die interxlitial and tubular changes continued (two 8-hour daily exposures),
m kidneys of rats exposed to 300 ppm of morality increased; death was ap|iarently vinyl chloride reported by Tnltism, i t el., earned hy a pneumonic process, but it was was die lark of any patlmlogy in onr animals . imjioixible to decide whether diis was the
exposed to 27* and 371 and the fact diat tcsult of a primary action or secondary to the die only morpltulogical alteration in which a anethesia.
significant differvnee lietwven control and experimental aniitals oernrrrd (kidney at 2%) indicated dial die control animals were further from "normal*'. Ilrramc it is un reasonable to attach toxic significance to
etiangrs associated with a eouirol air ex posure, it is our belief tlwl die ii>ir|>lK.l<-giCal altcraliuii* W: liavr Mlsrnrtl should not far interpieu-tl as m.mift-\iatm of jiailiol.
Rats exposed eight hours daily to 5fi for 19 day* or to 27c over 92 day* did not show any lung involvement. Tlicsc levels lad no effects upon growth rate, hemoglobin. Itcniatocrit or prothrombin time. At. both con centrations time wise increase* in tin- liver: IxkIv wright ratio ami decreases in tin* white cells; at 2% die s|>leeti:lMxly weight ratio ilrm-auxl and at 57c lln'rr was an increase
CT-
in red rells.
Tlif rsntreiilnttwaiv l wliiefs Ilu- rat- were
No jiim n mienwis>t>ir elumgt-- wen*
subjected in ll*x C\j VI mums wen- at least found in any tissue tlat was rrarekilrd with
n
c
U u
H* O
T
f
/a/mlntl Itygi+ne Journal
273
thr efiangrx in tlx; formrd rlrnirnls nf the
Mond. "Il*r* iimno in livrr:l*)y ni*lil
ratio* rnr amciautl with nie>iJ<r^raJ allmtiMv in liar liver kliirli a|t|iran-d In
have on pallmlogiral sitpiifu-ancr, while no meaningful tuoritltologiral alteration* were
evident in citiicr kidney* or spleens. Because, m die Ion; term exposures, it was
impossible m attach any toxic significance 'to the changes nntrd or to observe any his* topothology, and because other asjicct* of die animals' reactions, such at growth rate, were unimpaired, die presently arccpted diresliold Emit value of 500 ppm for vinyl chloride, one-fortieth of the concentration tested here, seems to oiler an adequate margin nf safety for human exposure.
Acknowledgment
ft is a plrasurr in arknowhvjgr the tech
nical atwsumre uf MaUtrlm Xir'vJwm,
Frctlcrirk A. Putt and Mew Liltemnr Wail-
mark.
.
References
I. m OiWM--q. W. f.: Tnitr^ rnmd $*rrirr,
Tie IW>rmW U- S. rU< |*ttioR
OAr*. K,p| lW> D. CL. H*0>K
* L. X M. >!*. IL Cmnim,
II. iWett | tfUii i* 1*iriif ! \*UI
1
U(a!*!mw. *wj. 2.mht*U.na--.i,t*pi*t..?(rh*A*m*)--.. >b*4.
flm*. iW. v. a. im*i
Un.
tw
VmhI Qlfiilr m DrWftMM^ by CcynMl Fjrmm* f 1.1--iwy A>-->b. 4mv, JW. iivt*
/. L*: '04 | On.
4. iC F-- Ja.r (mumH C*> nil1 -Hy
tM ImwL** bo
a. Am** i4* Hn>
Ammr. /. /;. I?* msi. $ r*m, F. V. W. l\ Ya*t, aai C- P. W* ni An*
sj Cotiee FW* * Viieiee set jUsmo New C*--
wwil OtfW
V. Vmtl CUar-'-fe.
At NWlA
a'Jj .* t (Am|. Hi)*
Sources and Use of Toxicological Information
The New York University .tfcdical Center in cooperation with the American Industrial Hygiene Assoriat>~n will present a enursc on Sourcrx and Utt of Toxtcofegirai Inforntetinn. Pin course will be riven October 14-18, 1953, at the Onehiota Conference Center, Sterling Forest. Tuxedo. Sew- York.
The course is designed to acquaint those eoneerned with advanced methods of securing and interpreting pertinent toxicological information. Application and principles will be stressed rather titan detail* of cxf-riincma) toxicology. The design of the course eliminate! the netxl for specialized scientific back ground so that all administrative ami technical persons having responsibilities for use of toxicological information can licnrfit. fittest lecturers who arc spe cialist* in selected field* will suppirmroi the sialT nr N.Y.U. Institute of Indus trial Meilirinr for ptescmaiiun of the suijjtn l matt-rial. Areas ut lie ruvrred are: biological principle* involved, sotirers uf toxirulngiral information. appli cations to in-pbint problems, Federal regulations, and trquiretiK-nts uf various agencies.
Inquiries anti registration* should lx* dirertrtl In New York University Medical Center, Institute nf Imiustrial Metlifinr. 330 Kiru Aeintie. New York 16. New York. ITit- registration ftT is $130 with a ilc|xwit of $23 retpiited. Acranuttodation* (double oeeti(xancv) at the Oniltiota Clonfrrener Center for the evening (dinner! October 13 thmueli lurteh Ortolirr IB are available at $21 per day inrhuling meals (payable to the Cit-mrr un departure).
*
T
N
U
C.T 13
O
H*.
