Brit.J.industr.Med.,1950,7,65. [616639]

Brit.J.industr.Med.,1950,7,65.
CHRONIC INTOXICATION BYETHYLENE GLYCOL
VAPOUR*
BY
F.M.TROISI
Bologna, Italy
(RECEIVED FORPUBLICAT[ON JANUARY 16,1950)
Theindustrial useofsolventscontinues toincrease
andleadstonewobservations inthetechnical and
thepathological fieldswhichcallfortheexamination
ofnewproblems ofindustrial hygiene. Inthis
paperattention isdrawntotoxicmanifestations of
occupational originrecently observed andreferable
tothesolventethylene glycol.Thiscompound has
inrecentyearsfoundmorenumerous andmore
extensive industrial applications andevidence ofits
toxicityhasbeenobtained bothinhumantoxicology
andbyexperiment.
Ethylene Glycol
Ethylene glycol(CH2OH-CH2OH) isacolourless,
odourless, somewhat viscous, sweetish liquidwhich
boilsat197-20C.,andsolidifies at-123°C.Its
specificgravity is1-1176at15°C.;itsvapour
tensionis009mm.Hganditismiscible inall
proportions withwaterandwithalcohol. Itisnot
inflammable. Itsformula placesitbetween the
monohydric ethylalcoholandthetrihydric alcohol,
glycerol, andincertainwaysitresembles boththese
substances. Itisthefirstandsimplest oftheglycol
seriesandisextensively usedasasolventsubstitute
forglycerol.
Theprincipal industrial applications ofethylene
glycolareasanelectrolyte forelectrolytic con-
densers; acomponent inskinlotionsinwhichitis
physically mixedwithvariouspowders; ananti-
freezeagent; asolventfordyes;andavehiclein
pharmaceutical preparations andfoodextracts.
Ithasbeenshownthatethylene glycolisrapidly
absorbed fromthegastro-intestinal tractandfrom
subcutaneous tissues. Itisoxidized tosomeextent
inthebodytooxalicacid,whichincreases the
normalexcretion ofoxalates andproduces moreor
lessseriousrenallesions. Ithasanarcoticaction,
slighthowever, incomparison withthatpossessed
bymonohydric alcohol. Toxiceffectsarisingfrom
theinhalation ofitsvapours arenotpossible at
'Translated intoEnglish.by Maurice W.Goldblatt.normal temperatures because ofitslowvolatility,
andnosucheffectshaveinfactbeenreported.
Itisthusthemoreimportant fromtheindustrial
medical pointofviewthattoxiceffectshavenow
beenobserved amongindustrial workers whowere
exposed totheinhalation ofvapours produced by
submitting ethylene glycoltohightemperatures.
ReviewoftheLiterature
Anexamination ofthepathological andtoxi-
cological literature especially ofrecent yearsreveals
various casesofintoxication following oralingestion
ofethylene glycolandofprotracted inhalation of
thevapours ofdifferent glycols. These casesshow
thetoxicaction onthekidneys aswellasacharac-
teristictoxiceffect onthecentral nervous system
andontheblood-forming organs. Itwillbeof
interest toreviewthesecasesforcomparison with
thetoxicmanifestations Ihaveobserved.
Hansen (1930)described twocasesofsevere
intoxication intwoyoung menfollowing accidental
ingestion ofaconsiderable quantity ofethylene
glycol. Thisresulted frommistaking anethylene
glycolanti-freeze preparation foranalcoholic
liquor. Thetwomenacoupleofhoursafterthe
ingestion showed severesignsofpoisoning including
stupor, somnolence, coma, complete bilateral
paralysis oftheabducent nerveaccompanied by
mydriasis andunreactive pupils. Death waspre-
ventedprobably asaresultofthedecapsulation of
onekidney inwhichhemorrhagic nephritis was
found.
Browning (1937)citestwocasesoffatalpoisoning
brought aboutbythesameaccidental causeandin
which toxicsymptoms consisted ofvomiting,
cyanosis, andverysevereprostration, death super-
veningbyrespiratory paralysis withconvulsions.
Inthe1944annual reportoftheChiefInspector
ofFactories, Merewether mentions aworkman,
39yearsofage,whodied21.1hoursafterhaving
accidentally drunk140gm.ofethylene glycolmixed
with asmallquantity ofanti-corrosive. The
65 B

BRITISH JOURNAL OFINDUSTRIAL MEDICINE
symptoms inthiscaseresembled aseverealcoholic
intoxication. Inthereportoftheprevious year
twocasesofpoisoning arerecorded asduetothe
samesortofaccident. Asimilaraccident in1946
brought aboutafatalintoxication fromethylene
glycolinanItalianboy,thecauseofdeathbeing
toxicnephritis.
AmongworkersinEnglishfactories whohadbeen
incontactwithethylene glycolnodefinitesymptoms
ofintoxication werefound,andonlytwoofthem
complained; one,engaged ontheworkfortwo
years,complained ofslightconjunctival irritation
andrhinitis, andtheother,afterninemonths,
complained oflossofappetite andslightmental
torpor(Browning, 1937).
Widman (1946)reported sixcasesofacuteoccupa-
tionalpoisoning leadingtodeathwithsevererenal
lesionsfromthirtyhourstosixdaysafterthe
absorption ofethylene glycol. Twoofthecases
showed acuteanemiawithcomplete anuria,andat
thenecropsy severetubularlesionswerefoundand
numerous crystalsofcalcium oxalate, especially in
therenalcortex.
Opsahl(1948)published apaperrecording the
masspoisoning of67peoplebrought aboutbyan
anti-freeze solution consisting ofmethylalcohol
(10percent.)andofethylene glycol(90percent.).
Intwocasesthepoisoning wasfatal;inoneitled
tocomplete blindness andinanotheritledtosevere
disturbances invision. Theremaining casesre-
covered.
Hagemann andChiffelle (1948)investigated three
menwhohaddrunkaliquidcontaining 40percent.
ofethylene glycolanddeveloped afatalsyndrome
ofcoma,acidosis, hypertension, andconvulsions.
Theyalsofoundmarkedleucoeytosis, albuminuria,
microscopic hematuria, raisedN.P.N.intheblood,
changes intheC.S.F.and,anatomically, haemor-
rhagesinthelungs,kidneys,brain,andmyocardium,
andfattyinfiltration oftheliverandchangesinthe
brainandmeninges indicative ofatoxicmeningo-
encephalitis.
Zehrer(1948)described threecasesofpoisoning
(onefatal)whichresultedfromingestion ofethylene
glycolsoldasglycerol. Presenting symptoms were
malaise, nausea, vertigo, pallor, coldsweats,
paraesthesia oftheextremities, fluttering pulse,
somnolence, andthenprofound comawithabolition
ofreflexes. Onawakening, thesurvivors showed
retrograde amnesia andlateralnystagmus. There
wasnoanuriabutonlysignsofinvolvement ofthe
centralnervous system.
Muchlaboratory workonanimals(oral,sub-
cutaneous, intramuscular, intravenous, andintra-
peritoneal administration) haspointed toadepres-
santactionofethylene glycolonthecentralnervoussystem(Hanzlik andothers,1931;vonOettingen and
Jirouch, 1931); aselective toxiceffectonthe
kidneys, withseverelesionsandmarkedoxaluria of
renalorigin,anddisturbance oflipoidmetabolism,
attributed todysfunction oftheliverandkidneys
(Mauro, 1939).
Severalderivatives ofethylene glycol,withthe
characters ofethersoresters,haveinrecentyears
acquired considerable importance asindustrial
solvents. Inhalation ofthevapours ofthese
derivatives hasgivenrisetotoxiceffects. Donley
(1936)reported acaseoftoxicencephalopathy ina
womanengaged inironingshirtcollarstreatedwith
asolvent designed torenderthemstiff.This
solventcontained 3percent.ofmethylcellosolve
(OHCH2-CH20-CH3) whichvolatilized duringthe
hotironing. Besides thecerebral symptoms the
womanpresented ananxmia withlymphocytosis
(R.B.C.3,500,000; Hb85percent.;lymphocytes
46percent.).Greenburg andothers(1938)gives
clearertoxicpictures in19youngwomenwhohad
beenengaged inthesamekindofworkbutinwhich
thesolventusedcontained 33percent.methylcello-
solve.Ofthese,twobecameillwiththeacuteform
ofaplasticanemiawithtremorsandmarkedpsychic
depression; oneshowedpolyneuritis withneuro-
logicalsequele, whilsttheremaining 16casesall
showed abnormal bloodpictures. Among these
lasttherewerefourwithabnormal reflexes and
tremors ofthehands,andfourwithboththese
symptoms inmoremarkeddegreeaswellassigns
ofsomnolence andlassitude. Thebloodpictures
indicated formsofmacrocytic anemia withreduc-
tionofplatelets andtheappearance ofyoung
granulocytes.
Severepoisoning hasalsobeenproduced bythe
inhalation ofthevapourofdiethylene dioxide or
dioxan,thecyclicetherofethylene glycol.Barber
(1934)reported fivefatalcasesofanacuteformof
intoxication lastingfivetoeightdaysinworkerswho
hadbeenexposedfor15daystohighconcentrations
ofdioxanvapour. Duringthisperiodtheworkmen
experienced paininthenoseandeyes,migrainous
headache, somnolence, vertigo,lossofappetite and
nauseaandfinallypresented asyndrome character-
izedbygravegastricsymptoms, enlarged liver
without jaundice, anuria, anduraemic coma.
Necropsy offouroutofthefivecasesgaveevidence
ofhaemorrhagic nephritis andhepaticnecrosis.
Itisseen,therefore, thatthetoxicactionofthe
glycolsisdirectedparticularly tothenervous system
andtheblood-forming organsinthecaseofthe
inhalation ofvapours, whilstwhenadministered by
mouthorbyparenteral routestheactionismore
directed tothekidneys. ThethreecasesofZehrer
inwhichethylene glycolwasingested areexcep-66

ETHYLENE GLYCOL VAPOUR INTOXICATION
tionalinasmuch asthetoxicological pictureincluded
signsofdefiniteinvolvement ofthecentralnervous
system.
Observations inanElectrolytic Condenser Factory
Myobservations presented onthetoxiceffectsof
theinhalation ofethylene glycolvapourweremade
onwomenworkers engaged inadepartment ofa
factorywhereelectrolytic condensers weremade.
Thesecondensers areconstructed fromanouter
caseofaluminium, inwhichiscontained acylindrical
element formed byapositive armature anda
negative madefromaluminium ribbon, separated
byapaperribbonimpregnated withtheelectro-
lyticmixtureandrolledtogether. Onephaseofthe
workinvolved spreading amixture of40percent.
ethylene glycol,55percent.boricacid,and5per
cent.ammonia, constituting theelectrolyte ofthe
condenser, onastripofpaperplacedonanother
stripofaluminium, whereby itwasabsorbed bythe
paper. Thisoperation wascarriedoutbyhandwith
paintbrushesbyabout40womenseatedatlong
tables. Themixture wascontained inreceptacles
placedatsuchadistance fromtheworkers, inthe
middleofthetables,thatitwasreadilyreached by
theoutstretched hand.Thesereceptacles were
maintained, byelectricheaters, at1050C.,this
temperature beingnecessary tokeepthemixture
fluid:atroomtemperature themixture solidifies.
Theworkwasdoneinaspacious largeroom
amplyprovided withopenings, fairlywelllighted
andventilated, buttheworkwomen werenevertheless
exposed tothevapours ofethylene glycolwhich
theyconstantly inhaled. Whilstatordinary tem-
peratures ethylene glycolgivesoffpractically no
vapour,inthisworktheevolution ofvapours was
continuous andalwayswithininhaling distance of
thewomen,thereceptacles containing thehotfluid
beingquiteclosetothemduringthespreading
operation. Forthepurposes ofthisprocessitwas
necessary thattheethylene glycolshouldbeofthe
highestpurity.
Allthewomen wereyoungandthemajority of
themhadbeenalreadyengaged ontheworkfora
coupleofyears.
Forsometimeseveralofthesewomen, with
greaterorlessfrequency, hadbeensubjecttoattacks
oflossofconsciousness without havingeversus-
pectedtheirworkasthecauseofthem,butattribu-
tingthemtosomecommon nervous disturbance.
Itwasfoundthatwhilstthewomenwereintenton
theirworkoneorotherofthemwithout warning
wouldsuddenly emitacryasifapreytosuddenand
quicklypassingagitation andwouldpassintoa
stateofprofound sleep.Takenatoncetothe
workssurgerythelossofconsciousness wasseentolastforonly5or10minutes andwasfollowed by
rapidawakening without amnesia andwithsucha
quickreturntonormality thatthepatients demanded
toreturntotheirwork.Theperiodofsleepappeared
tobecalmandtranquil andwasnotfollowed
byanyreturnofanyparticular symptoms. These
attacksincreased infrequency duringthesummer
andrecurred asaruleafterafewhoursofcon-
tinuous work,about11o'clock inthemorning
shiftandinthefirsthourorsointheafternoon
afterlunch.Thesetwofactswereevidently con-
nectedwiththepossibility ofalargeabsorption of
thevapourofethylene glycol.
Ofthe38womenengaged inthiswork,ninewere
subjecttoattackswhichrecurred ratherfrequently,
andontheaverage twoorthreetimesaweek,but
inafewcasesalmosteveryday.Theselatteron
clinicalexamination showed signsofwell-defined
nystagmus. Fiveofthesewomen(thosewhomost
frequently developed theattacks) weresubjected to
thethermal testofBarany without provoking
abnormal reactive movements andvertigo, andon
hematological examination theyshowed absolute
lymphocytosis ineverycase.
Examination oftheurineinthewholegroup
showed noabnormality. Itwasnotpossible to
carryoutexaminations ofthebloodandurineofall
the38womenemployed inthedepartment, sothat
theremaining 29women, neverhavinghadthe
attacks described, wereexamined clinically as
ambulatory subjects: itwasthusfoundthatfive
ofthemshowednystagmus butnoothersigns.
InTableItherelevantdataaregivenonthenystag-
musobserved andonthehiematological findings.
Cases1to9hadattacksofunconsciousness. Cases
10to14hadnoattacksofunconsciousness.
Ofthenineworkers havingattacksofuncon-
sciousness, onlytwo,whoexperienced themrather
frequently, wereremoved fromthedepartment and
transferred toalternative work.Inthenewwork
theattacks nolongeroccurred. Theremaining
sevenwomenelectedtostayatthejobbecausethey
weretoldthatithadbeendecided toinstalaplant
whichwouldmechanize andenclosetheprocessand
byinternaldraughting ofthevapours oftheethylene
glycolpermitofitsrecovery. Sincetheinstallation
ofthisplanttherehasbeennochangeinthestate
ofhealthofthewomenemployed, excluding the
twotransferred, andtherehavebeennofurther
attacksofunconsciousness ornystagmus. Onthe
otherhand,beforethemechanization oftheprocess,
whenitwasstillcarried outbyhand,andupto
eightmonthsfromthefirstexamination, therewere
stillattacksofunconsciousness andnystagmus could
stillbeverifiedamongthewomenremaining inthe
department.67

BRITISH JOURNAL OFINDUSTRIAL MEDICINE
TABLEI
BloodFindings
IDifferential Count
Period HoorIWBCintheR.B:C. HoorWBCNameAgeWo (m- Index(thous- Nystagmus(Yar)ions) ands) .
00 0.
B.S.2424-34 901-04 5-54400505BilateralN.V.223.399851-06 5-75000480Bilateral
M.P.26 114-24 840.99 4-86211333LeftlateralF.V.237393821-02 4-85431411Bilateral rotatoryE.B.262409810.99 454411504Bilateral
A.S.19 11 Bloodnotexamined Infrequent attacks ofmod-erateamplitudeI.P.221E.B.272/12 ,,F.N.245/12A.T.241 ,,,,,, Attacks ofanticlockwiserotatory nystagmus onlateraldeviation ofrighteye
E.B.211 ,,.,,, Frequent attacksofbilateralnystagmus
I.M.232 ,,,,,, Bilateral nystagmus
A.A.265 ,.,,,, Infrequent attacks ofmod-erateamplitudeG.M.341 ,,,,,, Rotatory nystagmus onlateraldeviation ofrighteye
Discussion
Thefollowing factsindicate theaetiological
significance oftheinhalation ofthevapours of
ethyleneglycolinproducing toxiceffects. (1)Cessa-
tionoftheattacksafterenclosure anddraughting of
theprocess; (2)cessation oftheattacksamongthe
twoworkers transferred toalternative work;
(3)absence ofsuchattacksamongworkers inother
partsofthesamefactorywherewomenareemployed
andwherevapours andfumesareevolved. (The
factorystrength consists ofabout1,500women,
mostlyyoung.) Thesefactsnegative anysuggestion
thattheattackswereofahysterical nature. There
wasnoindication ofanykindthateitherammonia,
(5percent.ofthemixture) orboricacid(55percent.
ofthemixture) couldhavehadanything todowith
thetoxiceffectsobserved.
Thenystagmus couldnotbereferred tostrain
causedbythevisualapparatus because theexcellent
environmental lighting wasbydirectsunlight and
theworkdidnotinvolve anyfatigueoftheeye
muscles, thevisualexcursion inthespreading opera-
tionbeinglimitedtonomorethan50cm.
Thetypeofnystagmus metwith,although inmost
caseshorizontal andsuggesting thepossibilitv ofaperipheral lesionofthevestibular apparatus, was
intwocasesunequivocally rotatory incharacter.
Thisfactledustothemoreprobable viewthatthe
lesionwasnuclearfor,although rotatory nystagmus
occursinlesionsofbothsemicircular canalsand
caseshavebeendescribed inlesionsofonlyone
canal,itisdifficult toimagine atoxicagentselectively
attacking oneorbothsemicircular canals. The
latterhypothesis isindeedinvalidated bythe
accompanying periodic attacksofunconsciousness
whichmustbeaconsequence oftoxiceffectsonthe
brain,andbythefactthatnystagmus occurred,
unaccompanied byabnormalities ofreactive move-
mentsorbyvertigo, infiveworkers, whoweremost
subject toattacks, afterexcitation bymeansof
Barany's thermal test.Theseconsiderations could
leadustointerpret suchcasesofnystagmus asof
supranuclear originandwithout participation of
thevestibular nuclei. Thereis,ofcourse, no
question inthesecasesofeithercongenital or
hysterical nystagmus.
Theabsolute lymphocytosis foundinallthefive
casesinwhichbloodcountsweremade(TableI)
reveals aquitedistinct pathological actionon
hmematopoiesis, eventakingintoaccount thenormal68

ETHYLENE GLYCOL VAPOUR INTOXICATION
variations intherelativeproportions oflympho-
cytesinthebloodandalsoofthefactthatbad
technique couldgiverisetovariations ofthis
magnitude.
Thereferences quotedfromtheliterature reinforce
theconclusions wehavegivenastotheaetiology of
thetoxiceffects. Theseallpointtotheinhalation
ofthevapourofethylene glycolascausingperiodic
lossofconsciousness, nystagmus, andlympho-
cytosis. Thelimitedcharacter oftheeffectspro-
ducedwasaconsequence ofthelimitedextentof
possible absorption byinhalation ofthevapourof
thissubstance.
Whilstlossofconsciousness andnystagmus went
together inmanycases,thefactthatsomecases
showednystagmus butnoattacksofunconscious-
nessmayperhaps beexplained bysomegreater
resistance tothetoxicactioninsomeindividuals.
Thisleadstothehypothesis thatnystagmus maybe
regarded asanearlysignandprecursor ofmore
severeintoxication inviewofthefactthatthe
majority ofauthorsregardthenuclearandsupra-
nuclearcentrestobemoresensitive andmorelikely
toreacttotoxicinfluences.
Nystagmus wasalsopresent inthethreecases
reported byZehrer(1948). Nystagmus ofatype
similartothatdescribed inthepresentpaperfigures
inreportsonpoisoning byphenyl-hydroxylamine,
anaromatic amineeasilyabsorbed through the
skinandproducing cyanosis, depression ofthe
centralnervous system,spasms,trismus, nystagmus,
anddisturbances oftherespiration andcirculation
(vonOettingen andSayers,1931,quotedbyLanza
andGoldberg, 1939).
Itisrecommended thatsystematic examination
fornystagnus shouldbepractised forworkers in
contactwithglycolsorothersolvents ofthefatty
orthearomatic series.Summary
Inanelectrolytic condenser factory, 38women
wereengaged inspreading onpaperandaluminium
stripsamixture of40percent.ethylene glycol,
55percent.boricacidand5percent.ammonia,
maintained at1050C.Therewascontinuous
evolution ofthevapourofethylene glycoltowhich
thewomenwereexposed bythemethodofoperation.
Innineofthesewomentherewerefrequent attacks
oflossofconsciousness andnystagmus wasalso
observed. Infiveoftheseabsolute lymphocytosis
wasfoundbybloodexamination.
Afurtherfivecasesofnystagmus butwithout
attacksofunconsciousness werediscovered among
theremaining workers.
Theattacks completely disappeared whenthe
processwasoperated inanenclosed plantpermitting
ofrecovery oftheethylene glycol,thepersonnel
remaining unchanged. Removal oftwoseverecases
tootherworkalsoledtocomplete cessation of
attacks.
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