Brogan & Partners

Neurotoxic Effects of Gasoline and Gasoline Constituents

Author(s): Thomas M. Burbacher
Source: Environmental Health Perspectives, Vol. 101, Supplement 6: Health Effects of Gasoline
(Dec., 1993), pp. 133-141
Published by: Brogan & Partners
Stable URL: http://www.jstor.org/stable/4640367 .
Accessed: 18/06/2014 12:17

Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at .
http://www.jstor.org/page/info/about/policies/terms.jsp

.
JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of
content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms
of scholarship. For more information about JSTOR, please contact support@jstor.org.

The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating
with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives.

http://www.jstor.org

This content downloaded from 185.44.78.143 on Wed, 18 Jun 2014 12:17:31 PM

All use subject to JSTOR Terms and Conditions
 EnvironmentalHealth PerspectivesSupplements
101(Suppl.6):133-141(1993)

Neurotoxic Effects of Gasoline and Gasoline

Constituents
by Thomas M. Burbacher

This overviewwas developedas part of a symposiumon noncancerend points of gasoline and key gasoline
components.The specific components included are methyl tertiary butyl ether, ethyl tertiary butyl ether,
tertiary amyl methyl ether, butadiene, benzene, xylene, toluene, methyl alcohol, and ethyl alcohol. The
overviewfocuses on neurotoxiceffects relatedto chronic low-levelexposures.A few general conclusions and
recommendationscan be made based on the results of the studies to date. a) All the compoundsreviewedare
neuroactiveand,as such, shouldbe examinedfor their neurotoxicity.b) For most of the compounds,there is a
substantial marginof safety betweenthe currentpermissibleexposurelevelsand levelsthat wouldbe expected
to cause overtsigns of neurotoxicityin humans.This is not the case for xylene,toluene,andmethanol,however,
where neurologic effects are observedat or below the current Threshold Limit Value. c) For most of the
compounds,the relationshipbetween chronic low-levelexposure and subtle neurotoxic effects has not been
studied.Studies thereforeshouldfocus on examiningthe dose-responserelationshipbetweenchroniclow-level
exposure and subtle changes in central nervoussystem function.

Introduction Occupationalexposureto gasolinehas been associated

with numeroussigns of neurotoxicity.Significanteffects
This overviewwas developedas part of a symposiumon onintellectualcapacity,psychomotorandvisuomotorfunc-
noncancerendpointsof gasolineandkey gasolineconstit- tion, immediateand delayedmemory,and an increased
uents. The specificconstituentsincludedin the overview proportionatemortalityratio (PMR) due to mental and
are methyltertiarybutylether,ethyl tertiarybutylether, psychoneuroticconditionshavebeenreportedfor gasoline
tertiary amyl methyl ether, butadiene,benzene,xylene, servicestationworkers(2,3).Symptomssuchas headache,
toluene,methylalcohol,and ethyl alcohol.The overviewis fatigue, loss of memory,and giddiness have also been
notmeantto serveas anexhaustivereviewof the literature reported (4). Neurologicaleffects (dizziness,headache)
for all compounds.Instead, certain examplesof the neu- havebeen reportedin laboratorystudies of humanvolun-
rotoxiceffectsreportedfor eachcompoundare includedin teers exposed to gasoline vapor. These effects were
the contextof a discussionof a dose-responseanalysisor observedat a concentrationof 2600 ppm but not at con-
calculation of a no-observable-adverse-effect level centrationsof 1000ppmand below(5,6).
(NOAEL)forhumanneurotoxiceffectsdueto chroniclow- In animals,acute exposureof dogs to high concentra-
leveloccupationalor environmentalexposure.Finally,the tions of gasoline have been associated with neurologic
overviewdoes not includestudies of chemicalmixtures effects at 10,000 ppm and death at 25,000 ppm (7). A
other than gasoline. The focus for this overviewis on preliminarystudyof rats exposedto 1500ppmgasolinefor
specifickey componentsof gasoline. 6 hr/day,5 days/weekfor up to 18 monthsdemonstrated
moreextensiveaxonaldystrophyand degenerationin the
Gasoline distal gracile tract of the spinal cord as well as abnor-
The effects associatedwith the intentionaluse of gas- malities of anteriorhorncells (8).Chronicexposure,6 hr/
oline as an intoxicant(gasoline sniffing) are commonly dayfor5 days/weekfor 90 days,of rats andmonkeysto 400
and 1500 ppm gasoline, however,did not produce
neurologicin nature and includeataxia, tremor,and an ppm
acuteor subacuteencephalopathic syndrome[see Forten-
overt neurotoxicityor changesin visualevokedresponses
(9). In anotherstudy,rats andmice exposedto 50, 275, or
berry for a review(1)].
1500ppmgasolinefor 6 hr/day,5 days/weekfor up to 113
weeks also failedto showsigns of overtneurotoxicity(10).
Departmentof EnvironmentalHealth,Schoolof PublicHealth and A study of the effects of exposureto unleadedgasolineon
CommunityMedicine,ChildDevelopment andMentalRetardationCen- the hypothalamo-pituitary-thyroid-adrenal systemin rats
ter,RegionalPrimateResearchCenter,Universityof Washington,Seat- has indicated a increase in serum cortico-
tle, WA98195. significant
Thismanuscriptwas presentedat the InternationalSymposiumonthe sterone and adrenal catecholaminesand a decrease in
HealthEffects of Gasolineheld5-8 November1991in Miami,FL. hypothalamicnoradrenaline. These effectswere observed

This content downloaded from 185.44.78.143 on Wed, 18 Jun 2014 12:17:31 PM

All use subject to JSTOR Terms and Conditions
134 M. BURBACHER
T.
only after 60 days of exposureto > 600 ppm unleaded
gasolinein air for 8 hr/day,5 days/week.Effects were not
observedafter 1, 3, 7, 14, or 30 days of exposure(11).
A summaryof the neurotoxiceffects reportedfor gas-
oline is shown in Table 1. Thus far, studies of human
exposuresto gasolinehaveprovidedlittle data regarding
the actuallevelof gasolineexposure.Althoughsomeexpo-
suredataareavailableforthe studiesusinganimalmodels,
the smallnumberof studiesandthe use of differentdosing
schedules and neurotoxic end points make a dose-
responseanalysisforthe variousendpointsreportedvery
difficult.At this time, sufficientdata are not availableto
support calculating a no-observed-adverse-effectlevel
(NOAEL)for the neurotoxiceffects of chroniclow-level
gasolineexposure.
MethylTertiaryButylEther
Therehavebeenno reportsconcerningthe toxic(includ-
ing neurotoxic)effects of methyl tertiary butyl ether
(MTBE)in humansdueto occupationalexposure.The use
of MTBEas a therapeuticagent for dissolvinggallstones
(12)has providedinformationregardingthe side effectsin
humansof MTBE administeredby infusion.These stud-
ies, however,do not providedatarelevantto the evaluation
of MTBEneurotoxicity.
Studies in animalshavenot providedevidenceof overt
neurotoxicitydueto MTBEexposureat airconcentrations
from 100 ppm to 3000 ppm MTBE (13-15).In addition,
gross teratogeniceffects were not observedin rats and
mice at air concentrationsfrom 250 ppm to 2500 ppm EthylTertiary
MTBE(16-18).A decreasein offspringviability,however,
has been reportedat air concentrationsof 1000ppm and ary butyl ether (ETBE) couldnot be found.ETBE, like
2500 ppm(19).
Moresubtle neurotoxiceffects due to MTBEexposure date,productionof ETBE is verylow;however,production
havebeenreportedin twostudiessponsoredby the Methyl is
TertiaryButyl Ether TaskForce (20,21).The effects of a
single 6-hrexposureto MTBEandexposurefor 13days,6
hr/daywere examined.Both studiesused rats and MTBE
air concentrationsof 8000,4000, 800, and 0 ppm.Several Tertiary
neurobehavioral effectswerereportedat all levelsof expo-
surein bothstudies.Themost consistenteffectsrelatedto
Table1. Summaryof the neurotoxiceffects of gasoline.
Humans
Chronicgasolinesniffing
Ataxia,tremor,encephalopathic syndrome
Occupational exposure
Headache,fatigue,memoryloss, psychomotorandvisuomotordys-
function
Laboratorystudies
Headache,dizzinessat air concentrations above2600ppm
Animals
Acuteexposure
Tremorsandconvulsionsat airconcentrations above580ppm,severe
neurologicsigns at 10,000ppm,deathat 25,000ppm
Chronicexposure
No overt signs of neurotoxicityat air concentrationsof 1500ppm,
in
degeneration spinal cordand anterior horn cells at 1500ppm, increase
increasein serumcorticosteroneandadrenalcatecholamines and Studies of humans or animals focusing on TAMEneu-
decreasein hypothalamic noradrenaline at 650 ppm
This content downloaded from 185.44.78.143 on Wed, 18 Jun 2014 12:17:31 PM
All use subject to JSTOR Terms and Conditions
Table2. Summaryof the neurotoxic effects of
methyl tertiary butyl ether in animals.
Acuteexposure
Reductionin activityat 8000ppm,increasein activityat 4000and800
ppm
Chronicexposure
No overtneurotoxicity from100ppmto 3000ppm,
at airconcentrations
no overt teratogeniceffects from 250 to 2500 ppm, decreased
offspringviabilityat 1000and2500ppm,reductionin activityat 8000
ppm,increasein activityat 4000and800 ppm
MTBEexposurewerethose on activity.At higherlevelsof
exposure(8000ppm),a reductionin overallactivity,or a
sedationeffect,was observed.At the lowerconcentrations
tested (4000and 800 ppm),an increasein overallactivity
was observed.The authors stated that the increase in
overall activity observed at the lower MTBE air con-
centrationstested (4000 and 800 ppm) "mayreflect an
exposure-relatedstimulanteffect"(20).
A summary of the neurotoxic effects reported for
MTBEis shownin Table2. Todate,studiesof occupational
exposuresof workersto MTBE have not been reported.
The two MTBETaskForce studiesusing rats do provide
some dose-responsedata for MTBE effects in adultani-
mals. These studies do not report a NOAELof exposure
for MTBE.Centralnervoussystem stimulanteffectswere
observedat the lowest dose studied.
ButylEther
Reportsconcerningthe neurotoxiceffectsof ethylterti-
MTBE, can be used as a gasoline antiknockadditive.To
likelyto increasebecauseETBE has severaladvantages
overMTBEfor use in reformulatedgasoline(22).
AmylMethylEther
Onlyone reportconcerningthe toxiceffects of tertiary
amylmethylether(TAME)couldbe found(23).This study
examinedthe effectsof 125,500,or1000mL/kg/dayTAME
administeredto rats by gavage 7 days/weekfor 29 days.
Generalobservationsfor overtsigns of neurotoxicitywere
includedthroughoutthe dosingperiod.The results of the
observationsdidnotindicatethe presenceof overtsigns of
neurotoxicity.Only a few of the observationswere not
listed as "withinnormallimits."Fourof the animalsin the
1000mL/kg/daydosage groupdiedduringthe study.Two
deaths were relatedto dosingaccidents,andthe othertwo
were related to exposureto TAME.
Few conclusionscanbe drawnregardingthe neurotoxic
effectsof TAMEfromthe single studyavailableforreview.
In rats, oral doses of 1000 mL/kg/dayTAMEincreased
mortality.Eight doses of 500 and 125mL/kg/daydid not
mortalityor cause overt signs of neurotoxicity.
rotoxicityhavenot been reported.
 GASOLINENEUROTOXICITY
Butadiene
Neurotoxiceffects in humansdue to exposureto buta-
diene have not been reportedto date. Studies using ani-
mals, however,havereportedspecies-specificteratogenic
effects due to butadieneexposure(24,25).In mice, expo-
sure to 1,3-butadienefor 6 hr/dayon gestationdays 6-15
has been related to a decrease in maternal, fetal, and
placentalweights and an increasein the incidenceof fetal
variations.Reducedfetalweightsformaleswere observed
at the lowestexposureconcentration (40 ppm).Theremain-
ing effectswere observedat 200 and 1000ppmconcentra-
tions.In rats,reducedmaternalbodyweights at 1000ppm
butadienewere the only effects observed. No signs of
maternal neurotoxicitywere observed in either study.
Possible offspringneurotoxiceffects were not examined.
Differencesin the pharmacokinetics of butadienehave
been reportedfor rats and mice (26). These differences
resultin an accumulation of epoxybutene,a primaryreac-
tive intermediateof butadiene,in mice but not in rats. A
reported increased susceptibilityof mice to butadiene
carcinogenesishas been relatedto these differences(26).
The species-specificteratogenic effects reviewedabove
may also be relatedto these pharmacokinetic differences.
LikeTAME,very few conclusionscanbe drawnregard-
ing the potentialneurotoxicityof butadienefromthe stud-
ies avilableto date.Air concentrationsof butadieneas low
as 40 ppmhavebeenassociatedwithreducedfetalweights
for mice.Air concentrationsas high as 1000ppmwere not
associated with overt fetal effects for rats. Studies
focusingon the neurotoxiceffectsof butadieneforhumans
or animalshavenot been reported.
Benzene
The primary effects associatedwith chronicbenzene
exposurein humansand animalsare anemiaand leuko-
penia (27). Neurotoxiceffects in humansdue to benzene
exposurehavenot been reported.
In animals,overt neurotoxiceffects, usually signs of
narcosis,havebeen reportedat air concentrationsof ben-
zene above 4000 ppm. Benzene exposures above 10,000
ppm may result in death (28). Maternalinhalationexpo-
sure to 100-2200ppmbenzenefor6 hr/dayfromday6 to 15
of gestationdid not result in overt neurotoxicityin adult
rats, althoughmaternaland fetal weight effects and fetal
skeletal effects were observed (29). Subtle neurobehavioral
effects in animals due to benzene exposure have been
reported. Consistent and significant changes in mouse
milk-licking responses have been reported after approx-
imately 1 week of inhalation exposure to benzene at 300
ppm (27). Effects on adult rat motor activity and a
decreased response to d-amphetamine challenge have
been associated with neonatal exposure to benzene via SC
injection at 550 mg/kg (30). Benzene neurochemical
effects, in animals, have also been reported. Increases in
the level of catecholamines in various regions of the mouse
brain have been reported after exposure to benzene in
drinking water at 8 mg/kg/day (31).
This content downloaded from 185.44.78.143 on Wed, 18 Jun 2014 12:17:31 PM
All use subject to JSTOR Terms and Conditions
135
Table3. Summaryof the neurotoxiceffects of benzene in animals.
Acuteexposure
Narcosisat air concentrationsabove4000 ppm,deathat 10,000ppm
Chronicexposure
No overt neurotoxicityat air concentrationsbetween100 and 2200
ppm,increasein milk-lickingbehaviorat 300ppm,increasein motor
activityand decreasein responseto d-amphetamine at 550 mg/kg
IP, increasein catecholaminesat 8 mg/kg/dayin drinkingwater
IP, intraperitoneal.
A summaryof the neurotoxiceffects reportedfor ben-
zene is shownin Table3. The earliestindicatorsof effects
dueto benzeneexposurein humansandanimalsis anemia
and leukopenia.Although importantneurotoxiceffects
have been associatedwith benzeneexposurein animals,
these effects are observedat exposurelevels well above
those associatedwith hematologicchanges.
Xylene
The neurologiceffects due to short-termexposureto
xylene have been reported from laboratorystudies of
humanvolunteers.The results of these studies indicated
that the odorthresholdfor xyleneis approximately1 ppm
(32).Brief exposureto approximately70 ppm xylene did
not affectreactiontime or short-termmemory(33).Inha-
lation exposure at 90 ppm, however,caused deleterious
effects on reactiontime, manualdexterity,body balance,
and EEG (34).Short-termexposureto xylene at 300 ppm
has been associatedwith a decrementin performanceon
reaction time, memory span, and critical flicker fusion
tests (35).Exposureat 100-400ppmalso causedan impair-
mentof bodybalanceandincreasedreactiontime(36),and
eye irritationoccurredat 460 ppm(32).
In animals,repeatedexposuresto air concentrationsof
xylenein the range of 200-2000ppmhavebeenassociated
with effectsonbehaviorand/orbrainchemistry.Exposure
to xylene for 4 hr/dayfor 3 consecutivedays at 1600ppm
increasedmotoractivityin rats (37).Changesin dopamine
and noradrenalinelevels and turnoverin variousregions
of the rat brainhavebeen observedafter xyleneexposure
for 6 hr/day for 3 consecutivedays at 2000 ppm (38).
Changesin neurotransmitters havealsobeenreportedafter
a 30-dayexposurefrom200 to 800 ppm (39).The earliest
neurochemicaleffect of xylene, a decreasein brain glu-
tathione,occurredafter 5 days of exposureat 50 ppm(40).
A summaryof the neurotoxiceffectsreportedforxylene
is shownin Table4. The results of studies of humansand
animalsindicatexylene neurotoxiceffects belowthe cur-
rent TLVlevelof 100ppm.The results wouldpredictthat
occupationalexposureat the TLVwouldadverselyaffect
humanperformance.Thelong-termeffectsfromrepeated
exposuresto xylene remainuncertain.
Table4. Summaryof the neurotoxiceffects of xylene.
Humans
Acuteexposure
Reducedreactiontime,manualdexterity,disruptionof bodybalance
and EBG at air concentrations above90 ppm
Animals
Chronicexposure
Increasein motoractivityat 1600ppm,changesin neurotransmitters
between200and2000ppm,increasein brainglutathione at 50 ppm
136 T. M. BURBACHER
Methanol
The deliberateingestionof methanolhas beenrelatedto
severaltoxiceffects.The symptomsassociatedwith meth-
anol intoxicationinclude headache, dizziness, nausea,
vomiting,severe abdominalpain, and periodicbreathing.
Coma and death from respiratoryfailure can occur in
severe cases. Several visual symptoms have also been
reported after methanol intoxication. These include
blurredvision, alteredvisual fields, and total blindness.
These symptomsare observed as a result of metabolic
acidosis,whichdevelopsas a result of an accumulationof
formic acid. Autopsiesfrom lethal poisoningshave indi-
cated degenerativechanges in the basal ganglia. Sur-
vivors of severe poisonings sometimes display motor
distubancessimilarto Parkinsonism(41,42).
Prolongedoccupationalexposureto methanolhas also
been associatedwith severaltoxiceffects (43).Significant
increases in the prevalenceof blurredvision,headaches,
dizziness,nausea, and skin problemswere observedfor
teacher'saidesexposedto duplicatingfluidsof 99%methyl
alcohol.Air concentrationsof methyl alcohol near the
duplicatingmachines were well above the permissible
exposurelimit time-weightedaverageof 200 ppm.Meth-
anol air concentrations as high as 3080 ppm were
observed.A recent study using humanvolunteersexam-
ined the effects of exposureto methanolvaporat 192ppm
for 75 min (44).Severaltests were administeredto the 12
subjectsbefore,during,and after the exposure.Although
performanceon most tests was normal,a slight impair-
ment on a memory and concentrationtest and minor
changes in brainwave patterns in response to light and
soundwere detected.The results from these tests were
withinthe range observedfor the subjectswithoutmeth-
anol exposure.The significanceof the changes observed
duringmethanolexposure,therefore,awaitfurtherinves-
tigation.
In animals,metabolicacidosisand oculartoxicityhave
been observedin nonhumanprimatesand folate-deficient
rats afterhigh-dosemethanolexposure(45-48).Studiesof
nonhumanprimates have indicated that the minimum
lethal oral dose for methanolis approximately3 g/kg. A
dose of 2 mg/kg has been associatedwith metabolicacid-
osis and ocular toxicity.Several neurotoxiceffects have
also been reportedat lowerlevelsof methanolexposurein
nonfolate-deficient rats. Rats exposedto 3 g/kg methanol
exhibiteda disruptionin thermoregulation dueto an inhib-
itory action of methanol on heat productionpathways
(49,50).Altered auditoryresponses,which require tem-
poralresolution,have also been reportedafter methanol
exposureof rats at 0.25-3 g/kg (51).Studies of prenatal
exposureto methanolin rats havereportedeffectson fetal
developmentandpostnatalbehavior(52,53).Rats exposed
to methanolvia inhalationat 26,000 ppm exhibited an
increase in maternal toxicity (unsteady gait) and fetal
malformations. Fetal malformations werealso observedat
13,000ppmexposure,althoughthe increasewas not signif-
icant (52). Effects on newborn nesting behaviorwere
observedin rat offspringat maternalexposureof2.5 g/kg/
day. These effects were observedwithout any signs of
This content downloaded from 185.44.78.143 on Wed, 18 Jun 2014 12:17:31 PM
All use subject to JSTOR Terms and Conditions
Table5. Summaryof the neurotoxiceffects of methanol.
Humans
Methanolingestion
Headache,dizziness,visual symptoms,motordisturbances,meta-
bolicacidosis,degenerativechangesin basal ganglia
Occupationalexposure
Blurredvision,headache,dizzinessat air concentrationsbetween
300 and3000ppm
Animals
Acuteexposure
Metabolicacidosis,oculartoxicityin nonhumanprimates(2 mg/kg)
and folatedeficientrats (3g/kg)
Chronicexposure
Disruptionof thermoregulation in normalrats at a dose of 3 g/kg,
alteredauditoryresponsebetween0.25 and 3 g/kg, changes in
neurotransmittersat 3 g/kg, disruptionof newbornnesting
behaviorat 2.5 g/kg/daymaternalexposure,unsteadygait at air
concentration of 26,000ppm
overttoxicityin the mothersor the offspring(53).Finally,
studies of rats have also indicatedeffects of methanolon
brain chemistry(54-56). Changes in levels of dopamine,
norepinephrine,epinephrine,serotonin, and 5-hydroxy
indole acetic acid in various brain regions have been
reportedafter a single IP injectionof methanolat 3 g/kg.
A summaryof the neurotoxiceffects reportedfor meth-
anolis shownin Table5. The recent study by Cooket al.
(44) providespreliminaryevidenceof methanoleffects on
concentration,memory,and brain-wavepatterns at an
exposure concentrationof 192 ppm, which is below the
currentTLVformethanol(200ppm).Studiesusing animal
modelsprovideresults for a narrowrange of high doses
and do not providesufficientdatato determinea NOAEL
of chroniclow-levelexposureto methanol.
Toluene
The primary CNS effects associated with chronic
tolueneabuse are ataxiaand tremor,with cerebellarand
cerebralatrophypresentin severecases (57).Short-term
exposureto tolueneat aboutthe curentTLV(100-150ppm)
affects performanceon a number of tasks. Volunteers
exposed to toluene for 7 hr experiencedalterationsin
temperatureand noise perception,an increasein feelings
of intoxication,lower scores on vigilance tests, altered
short-termmemory,and poorermanualdexterityperfor-
mance.These effectswere not observedat 75 ppm(58,59).
These effects are similarto those reportedin studies of
occupationalexposureto toluene(60-63); effects on neu-
ropsychologicalfunctioningare usuallyobserved.
Short-termexposureto toluenein animalshas alsobeen
associated with several behavioraleffects. In rodents,
alterationsin response rates, locomotion,and avoidance
learninghavebeen observed(64).The effects on operant
responserates are dose dependent.Exposuresat approx-
imately1000ppm have been shownto increase response
rates,whereas exposuresat approximately 2000 ppmand
above decrease rates (65). Effects on locomotoractivity
are also dose dependent.An increasein activityhas been
reportedafter exposureat 5000 ppm,whereas a biphasic
response(increasethen decrease)was observedat higher
exposureconcentrations[10,000ppmand15,000ppm(66).]
 GASOLINENEUROTOXICITY
A decrease in shock avoidance responses has been
reportedafter exposureto tolueneabove1000ppm.Expo-
sure at 500 ppmand belowdid not affectresponding(67).
In monkeys,short-term exposure to toluene has been
shown to increase response time and decrease perfor-
manceon a cognitivetask at 2000 ppm.Exposureto 100,
200, or 500 ppm,however,didnot affectperformance(68).
The effects observedin the studies above appear tran-
sient.Responsetypicallyreturnsto normalsoonafter the
exposurehas ended.
Severalbiochemicaleffects havebeen reportedin stud-
ies of animalsafter short-termtolueneexposure.These
studies typically used a design that includes a single
exposureto tolueneor repeatedexposuresovera few days
beforethe sacrificeof the animal(immediatelyfollowing
the last exposure).The neurochemicaleffects of toluene
after a single IP injectionto rats at 200,400,or 600mg/kg
includea significantdose-dependentincreasein 5-hydrox-
ytryptamine (5-HT), a significant dose-dependent
increase in noradrenaline (NA) and 3-methoxy-4-
hydroxyphenyl-glycol(MHPG),and a significant dose-
dependent decrease in 5-hydroxyindoleaceticacid (5-
HIAA) in various regions of the brain (69). The neu-
rochemicaleffectsof short-terminhaledtolueneat 80,500,
1500,or 3000 ppmincludeda significantreductionin the
affinityin striatal [3H]spiperone-binding sites andin cor-
tical [3H]5-HT-binding sites at 3000 ppm, a decrease in
dopamine(DA)levelsin the marginalzone of the nucleus
caudatusand anteriorpart of the nucleusaccumbens,a
decrease in DA turnoverin the marginalzone and the
medialandcentralpart of the anteriornucleuscaudatusat
80 ppm,anda dose-dependenteffect,from80 to 1500ppm,
on P-adrenergicreceptors(70,71).
Studies of chronictoluene exposure in animals have
reported numerousbehavioraland biochemicaleffects.
These studiestypicallyuse a designthatincludesrepeated
exposuresto tolueneovera periodfrom 1 week to several
months.The behavioralassessments usually take place
duringtolueneexposure.Somestudies,however,examine
the nature of the behavioraleffects by testing subjects
after the exposurehas ended.Typically,biochemicalstud-
ies are conductedimmediatelyafter the last exposureor
after the last behavioralassessment.Chronicexposureto
high concentrationsof inhaledtoluenein rodentsto simu-
late humantolueneabuseis associatedwith alterationsin
visual, auditory,somatosensory,and peripheral nerve
evokedpotentials,locomotoractivity,andmotorcoordina-
tion (72-75). A transient decrease in total sleep and an
increase in locomotorand drinking activity have been
reportedduring2 weeks of tolueneexposurevia IP injec-
tion at 200 mg/kg/day.Neurochemicalchangeswere also
observed.Levels of 5-HT and 5-HIAAwere significantly
decreased,but MHPG,DOPACand HVAconcentrations
were significantlyincreased.Effectswere not observedat
100mg/kg/day(76).Chronicexposure(4 weeks) of rats to
toluenevia inhalationhas also been associatedwith neu-
rochemicalchanges in various regions of the brain. A
significantdecreasein amino-aciddecarboxylase(AAD)at
250 ppm and 1000 ppm, glutamic acid decarboxylase
(GAD)at 50 ppm,and receptorbindingof glutamateand
This content downloaded from 185.44.78.143 on Wed, 18 Jun 2014 12:17:31 PM
All use subject to JSTOR Terms and Conditions
137
GABAbindingat all levelsof exposurehavebeenreported.
In addition,a significantincrease was observedin glu-
tamine synthetase activity (GLN-S) at 1000 ppm and
receptorbindingof glutamateand GABAbindingat 50
and 1000ppm (77).
Developmentalexposureto toluenehas been associated
with severalbehavioraleffectsin exposedoffspring.Fluid
consumption,maternaland infantmortality,weight gain,
eye and ear opening, and startle and surface-righting
responseswere not affectedby tolueneexposure.Activity
in the open-fieldand rotorodperformance,however,were
alteredby tolueneand nearly all of the exposedanimals
were observedto havesplayedhindlimbs(78).
A summary of the neurotoxic effects reported for
tolueneis shown in Table6. The data regardingtoluene
neurotoxiceffectsindicatethatthe currentTLVof 100ppm
provideslittle or no marginof safety. In humans,short-
term exposureto tolueneat aboutthe TLValterspercep-
tionandlowersperformanceonmotorandcognitivetasks.
These effects are similarto those reportedin studies of
occupationalexposureto toluene.In animalmodels,short-
term exposure to toluene below the TLV decreases
dopaminelevels and turnoverin the brainand selectively
increases the number and decreases the affinity of
P-adrenergic receptors. Developmental exposure to
toluenealters activityand motorcoordination.
Ethanol
In humans,some of the neurotoxiceffects associated
with long-term alcohol abuse include anterogradeand
retrograde amnesia, dementia,ataxia, dysarthria, and
peripheral-nervedisorders. Wernicke'ssyndrome and
Korsakoffssyndromeare associatedwith chronicalcohol
abuse primarilydue to an alcohol-induced thiaminedefi-
ciency. Histologic features of these syndromesinclude
microscopiclesions in the thalamus,hypothalamus,mes-
encephalon,andbrainstemas well as cerebellarandcorti-
cal lesions (79-82).
The few studiesof ethanoleffectsafter inhalationexpo-
sure haveindicatedthat, in humans,the initialsymptoms
Table6. Summaryof the neurotoxiceffects of toluene.
Humans
Toluenesniffing
Ataxia,tremor,cerebellarandcerebralatrophy
Occupational or short-termexposure
Reducedmanualdexterityandvigilancescores,short-termmemory
loss, disruptionin perceptionat air concentrations
above100ppm
Animals
Short-termexposure
Dose-dependentchangesin responserates at air concentrations of
1000ppmandabove,increasein activityat 5000ppm,decreasein
activityat 15,000ppm,decreasein shockavoidanceresponsesat
1000ppmbutnotat 500ppm,decreasedperformanceoncognitive
task at 2000 ppm but not at 500 ppm and below,changes in
neurotransmitters at 80 ppmandabove
Chronicexposure
Transientdecrease in sleep, increase in activity and drinking,
changes in neurotransmittersat 200 mg/kg/dayIP, changesin
neurotransmitters at air concentrations
above50 ppm,increased
activityand motorincoordination after developmental
exposure
138 T M. BURBACHER
of ethanolexposureare coughing,eye and nose irritation,
which appearat a concentrationof approximately5,000-
10,000 ppm. At about 15,000 ppm, these symptoms
increase, and continuous lachrymationand coughing
occur. Concentrationsof 20,000 ppm and above were
judgedas intolerable(83).In rodents,constantexposureto
air concentrationsof ethanolfrom7,500ppmto 15,000ppm
for4-10 daysproducessigns of alcoholintoxication,depen-
dency,andwithdrawal.Pregnantrats exposedto air con-
centrationsof ethanolat 16,000ppmor 20,000ppmexhibit
signs of intoxicationandreducedweightgain.Twenty-day-
oldfetuses of damsexposedat the 20,000ppmconcentra-
tion exhibited a significantincrease in visceral and/or
skeletal malformations.Rats exposed to 10,000 ppm
showedno maternalor fetal effects (84-87).
The developmental deficitsassociatedwith fetal alcohol
syndrome (FAS) and fetal alcoholeffects(FAE),as well as
"socialdrinking"duringpregnancy,havebeenthe topicof
numerouspublications.FAS and FAE infants display
increasedirritability,tremulousness,and reducedweight
gain.Olderchildrendisplayincreasedsocialandemotional
problemsand intellectualimpairmentthat may continue
into adulthood.Offspringof social-drinkingwomendis-
playlowerbirthweights,abnormalstate regulation,lower
scores on infantdevelopmentaltests, growthretardation,
increased restlessness, short attentionspan, and motor
dysfunction.The pattern of alcohol consumptionmost
related to the effects observed in offspring of social
drinkers is more than two drinks/dayduring midpreg-
nancyandbingedrinking(morethanfivedrinks/occasion)
in the monthsjust beforepregnancyrecognition(88-91).
Severalanimalmodelshavebeen developedto replicate
the behavioralfindingsreportedfor humans(92).In addi-
tion, studies using animalmodels have investigatedthe
neuroanatomicaland neurochemicaleffects of prenatal
alcoholexposure.Most of the studies concerningthe neu-
rochemicaleffectshavefocusedon the GABAergicsystem
(93,94).The results of these studies, however,have not
provideda consistentpatternof effects.Theinconsistency
may be due to a biphasic dose-dependentresponse of
GABAto ethanol. Results indicate that glutamineand
GABAincreaseat low-levelexposure(2 g/kg ethanol)but
decreaseat higherexposureconcentrations(3 and8 g/kg)
(94).Not all studiesonthe neurochemical effectsof alcohol
have focused on the GABAergicsystem. Rats intubated
with 4 g/kg ethanolevery12 hr for 11-15days exhibiteda
significant reduction in the binding of mesolimbic
dopaminereceptors(20%).Thebindingof serotoninrecep-
tors was significantlyincreasedin the striatum(63%)and
brainstem(32%)and was significantlydecreasedin the
hippocampus(20%).The bindingof acetylcholinerecep-
tors was also significantlyincreasedin the striatum(7%)
andsignificantlydecreasedin the cerebralcortex(5%)(95).
Finally,recentresults from studies of nonhumanprimate
infantsexposedto weeklydoses of ethanolhaveprovided
some data regarding prenatal alcohol effects. Micro-
phthalmia,retinal ganglioncell loss, and alteredstriatal
dopamineconcentrations havebeen reportedthus far (96).
A summaryof the neurotoxiceffects reportedfor eth-
anol is shown in Table 7. Thus far, the most sensitive
This content downloaded from 185.44.78.143 on Wed, 18 Jun 2014 12:17:31 PM
All use subject to JSTOR Terms and Conditions
Table7. Summaryof the neurotoxic effects of ethanol.
Humans
Alcoholism
Ataxia,dysarthria,dementia,amnesia,peripheral-nerve disorders,
cerebellarandcorticallesions
Developmental exposure
Fetal alcoholeffectsobservedat exposureto > 1 oz absolutealcohol/
day
Animals
Chronicexposure
Alcoholintoxication,dependenceand withdrawalat air concentra-
tions from 7500 ppm to 15,000ppm, intoxicationand reduced
weightgainat maternalexposureof 16,000ppmbut not at 10,000
ppm, changes in neurochemistryat doses from 2 to 8 g/kg,
microphthalmia, retinalganglioncell loss, altereddopaminecon-
centrationsafter maternal"binge"drinking
indexes of alcohol exposure effects are those observed
aftermaternalalcoholintakeduringpregnancy.Offspring
effects on behaviorhave been reported at blood alcohol
concentrationsassociated with the intake of > 1 oz of
absolutealcoholper day.
Discussion
Determining the neurotoxic effects associated with
chroniclow-leveloccupationalor environmentalexposures
requires dose-response data for several neurotoxicend
points from well-designedstudies. Data may come from
studiesof occupationalexposureof workers,studiesusing
animal models and, for some compounds,studies from
controlledexposuresin the laboratory.The studiesshould
includeseveralexposurelevels and proceduresfor deter-
mininga NOAEL.Studies of occupationalexposureand
effects shouldincludea completeworkhistory,neurologi-
cal examination,and neuropsychologicaltest battery of
the workers,measuresof workplace(andotherpotential)
exposures,and proceduresfor estimatinginternal dose.
Thestudiesshouldincludean appropriatecontrolgroupas
well as sufficientexposed workers for a dose-response
analysis. Studies using animal models should focus on
subtle neurotoxiceffects after chroniclow-levelexposure
and includeproceduresfor assessing the effects of expo-
sureonbehavior,neuroanatomy, andneurochemistry. Pro-
ceduresfor examiningthe transientor permanentnature
of the effects shouldbe used. Studies of both adults and
developing animals should be performed because the
effects from developmentalexposures may be different
fromthose observedin adultanimals.
This report provides an overviewof studies that are
availableforthe evaluationof the neurotoxiceffectsassoci-
ated with chroniclow-levelexposureto gasoline and cer-
tain gasoline constituents.In general, the occupational
studies of these compoundsdo not even meet the first
criterion discussed above because most do not include
measuresof workplaceexposures.Fortoluene,xylene,and
methanol,studies of controlledlaboratoryexposuresindi-
cate neurologiceffects near or below the current TLV.
Althoughthese effects may be transient,they can influ-
ence workplacesafety. In addition,the long-termconse-
quencesof these effects havenot been studied.
 GASOLINENEUROTOXICITY
Little dose-response data are availablefrom studies
using animalmodels.Manyof the studies examinedonly
one dose level. Results from other studies sometimes
provideddatafordetermininga NOAEL butonlyforsigns
of overt neurotoxicity.In general,data for determininga
NOAELfor moresubtleneurotoxiceffects (e.g., learning
andmemory)are not available.Finally,exceptfor ethanol,
noneof the compoundshas been studiedextensivelyusing
a developmentalapproach.
A few generalconclusionsand recommendations can be
madebased on the results of the studies to date. a) All of
the compoundsreviewedare neuroactiveand, as such,
shouldbe examinedfor their neurotoxicity.b) For most of
the compounds,there is a substantialmargin of safety
betweenthe currentpermissibleexposurelevelsandlevels
that wouldbe expectedto cause overt signs of neurotox-
icityin humans.Thisis notthe case forxylene,toluene,and
methanol,however,whereneurologiceffects are observed
at orbelowthe currentTLV.c) Formost of the compounds,
the relationshipbetween chroniclow-levelexposureand
subtle neurotoxiceffects has not been studied. Studies,
therefore,shouldfocus on examiningthe dose-response
relationshipbetweenchroniclow-levelexposureandsubtle
changes in central nervoussystem function.d) Limited
dataare availableconcerningthe neurotoxiceffectsassoci-
ated with exposureto MTBE, ETBE, and TAME.The
extensive use of MTBE in gasoline is a relativelynew
development.The use of ETBE and TAMEremainslow
but is expectedto rise. Additionalstudies of these com-
poundsshouldbe prioritizedbecausethey seem to repre-
sent the future for reformulatedgasoline. e) Except for
ethanol,few studiesare availableconcerningthe potential
developmentalneurotoxicityof the compounds.Further
studies shouldbe developedfocusingon this issue. These
studies shouldfollowthe guidelinesrecentlypublishedby
the EPA for testing potential developmentalneurotoxic
compounds.
The authorthanksJacquelineSmith,Peter Spencer,andHughTilson
for their commentson the draft reportthat formedthe basis for this
review.The authoralso thanks the staff of the AmericanPetroleum
Institute for their help in obtainingthe articles for this review.This
reviewwas developedundercontractto the EnvironmentalProtection
Agency.
REFERENCES
1. Fortenberry,J. D. GasolineSniffing.Am.J. Med.79:740-744(1985).
2. Kumar,P.,Gupta,B. N., Pandya,R. P.,and Clerk,S. H. Behavioral
studiesin petrolpumpworkers.Int.Arch.Occup.Environ.Health.61:
35-38 (1988).
3. Schwartz,E. Proportionatemortalityratio analysis of automobile
mechanicsand gasolineservicestationworkersin New Hampshire.
Am.J. Ind. Med.12:91-99 (1987).
4. Pandya,K.P.,Rao,G.S.,Dhasmana,A.,andZaidi,S. H. Occupational
exposureof petrol pumpworkers.Ann. Occup.Hyg. 18: 363-364
(1975).
5. Davis, A., Schafer, L. J., and Bell, Z. G. The effects on human
volunteers of exposure to air containing gasoline vapor. Arch.
Environ.Health1: 92-98 (1960).
6. Drinker,P.,Yaglou,C.P.,andWarren,M.F. Thethreshholdtoxicityof
gasolinevapor.J. Ind. Hyg. Toxicol.25: 225-232(1979).
This content downloaded from 185.44.78.143 on Wed, 18 Jun 2014 12:17:31 PM
All use subject to JSTOR Terms and Conditions
139
7. Haggard,H. W. The anestheticand convulsanteffects of gasoline
vapor.J. Pharmacol.Exp.Ther.16:401-404(1921).
8. Spencer,P.S. Experimentalevaluationof selectedpetrochemicals for
subchronicneurotoxicproperties.Adv.Mod.Environ.Toxicol.6: 199-
214 (1984).
9. Kuna,R. A., and Ulrich,C. E. Subchronicinhalationtoxicityof two
motorfuels.J. Am. Coll.Toxicol.3: 217-230(1984).
10.MacFarland,H. N. Chronicgasolinetoxicity.In: Proceedingsof the
Toxicology of Petroleum Hydrocarbons. American Petroleum
Institute,Washington,DC, 1982,pp.78-86.
11.Vyskocil,A., Tusl, M., Obrsal,J., and Zaydlar,K. A. Subchronic
inhalationstudywithunleadedpetrolin rats.J. Appl.Toxicol.8: 239-
242 (1988).
12.Allen,M.J., Borody,T.J., Bugliosi,T. F.,May,G. R., LaRusso,N. F.,
and Thistle,J. L. Rapiddissolutionof gallstonesby methyltertiary
butylether.N. Engl. J. Med.312:217-220(1985).
13.API. A 9-Day InhalationStudy of MTBEin the Rat. API Project
Report No. 32-30235,AmericanPetroleumInstitute,Washington,
DC, 1984.
14.Greenough,R. J.,McDonald,P.,Robinson,P.,Cowie,J. R.,Maule,W.,
Macnaughtan,F., and Rushton,A. Methyl TertiaryButyl Ether
(DRIVERON)Three Month InhalationToxicityin Rats. Project
ReportNo. 1596,InvereskResearchInternational, Edinburgh,1980.
15. Robinson,M.,Bruner,R. H., andOlson,G. R. Fourteen-andninety-
day oraltoxicitystudies of methyltertiarybutylether in Sprague-
Dawleyrats.J. Am.Coll.Toxicol.9: 525-540(1990).
16.API. An InhalationTeratologyStudyin Rats with MethylTertiary
Butyl Ether (MTBE).API ProjectReportNo. 32-30236,American
PetroleumInstitute,Washington,DC, 1984.
17.API. An InhalationTeratologyStudyin Micewith MethylTertiary
Butyl Ether (MTBE).API ProjectReportNo. 32-30237,American
PetroleumInstitute,Washington,DC, 1984.
18. Conaway,C. C., Schroeder,R. E., and Snyder,N. R. Teratology
evaluationof methyltertiarybutyletherin rats andmice.J. Toxicol.
Environ.Health16:797-809(1985).
19.Biles,R. W.,Schroeder,R. E., andHoldsworth,C. E. Methyltertiary
butyletherinhalationin rats:a singlegenerationreproduction study.
Toxicol.Ind. Health3: 519-534(1987).
20. Gill, M. W. Methyl TertiaryButyl Ether Single ExposureVapor
InhalationNeurotoxicityStudyin Rats. ProjectReportNo. 52-533,
BushyRunResearchCenter,Export,PA,1989.
21. Dodd,D. E.,andKintigh,W.J.MethylTertiaryButylEther(MTBE):
Repeated(13-Week)VaporInhalationStudyin Ratswith Neurotox-
icity Evaluation.ProjectReportNo. 52,707,Bushy Run Research
Center,Export,PA, 1989.
22. Unzelman,G.H. U.S.CleanAirAct expandsrolefor oxygenates.Oil
GasJ. (April15):44-48 (1991).
23. ExxonBiomedicalSciences,Inc.TeriaryAmylMethylEther:28-Day
Subchronic OralToxicityin the Rat.FinalReport,ProjectNo.237470,
ToxicologyLaboratory, ExxonBiomedicalSciences,Inc.,NewJersey,
1989.
24. Hackett,P.L.,Sikov,M.R.,Mast,T.J.,Brown,M.G.,Buschbom,R. L.,
Clark,M.L.,Decker,J. R.,Evanoff,J. J.,Rommerwin, R. L.,Rowe,S.
E., andWesterberg,R. B. InhalationDevelopmental Toxicology Stud-
ies: TeratologyStudy of 1,3-Butadienein Mice.ProjectReportNo.
6412,PacificNorthwestLaboratory, Richland,WA,1987.
25. Hackett,P.L.,Sikov,M.R.,Mast,T.J.,Brown,M.G.,Buschbom,R. L.,
Clark,M. L., Decker,J. R.,Evanoff,J. J.,Rommerein, R. L., Rowe,S.
E., andWesterberg,R. B. InhalationDevelopmental Toxicology Stud-
ies of 1,3-Butadienein the Rat. Project Report No. 6414, Pacific
NorthwestLaboratory,Richland,WA,1987.
26. Rreiling,R., Laib, R. J., Filser, J. G., and Bolt, H. M. Inhalation
pharmacokineticsof 1,2-epoxybutene-3 reveal species differences
betweenratsandmicesensitiveto butadiene-induced carcinogenesis.
Arch.of Toxicol.61: 7-11 (1987).
27.Dempster,A. M., Evans, H. L., and Snyder,C. A. The temporal
relationshipbetweenbehavioralandhematological effectsof inhaled
benzene.Toxicol.Appl.Pharmacol.76: 195-203(1984).
28. Laskin,S.,andGoldstein,B. D. Benzenetoxicity:a criticalevaluation.
J. Toxicol.Environ.Health(suppl.)2:1-148 (1977).
29. Green,J. D.,Leong,R. J.,andLaskin,S. Inhaledbenzenefetotoxicity
in rats. Toxicol.Appl.Pharmacol.46: 9-18 (1978).
30. Tilson,H. A.,Squibb,R. E., Meyer,O.A.,andSparber,S. B. Postnatal
140 T. M. BURBACHER
exposureto benzenealters the neurobehavioral functioningof rats
when tested during adulthood.Neurobehav.Toxicol.2(2): 101-106
(1980).
31. Hsieh,G. C., Parker,R. D., and Sharma,R. P. Subclinicaleffects of
groundwatercontaminents.II. Alterationof regionalbrain mono-
amineneurotransmittersby benzenein CD-1mice.Arch. Environ.
Contam.Toxicol.17:799-805(1988).
32. Carpenter,C.P.,Kinkead,E. R.,Geary,D. L.,Sullivan,L. J.,andXing,
J. M. Petroleumhydrocarbontoxicitystudies.V.Animalandhuman
responsesto vaporsof mixedxylenes.Toxicol.Appl.Pharmacol.33:
543-558(1975).
33. Olson,B. A., Gamberale,F., and Iregren,A. Coexposureto toluene
andp-xylenein man:centralnervousfunctions.Br. J. Ind. Med.42:
117-122(1985).
34. Savolainen,X., Riihimaki,V., Seppalainen,A. M., and Linnoil,M.
Effectsof short-termm-xyleneexposureandphysicalexerciseonthe
centralnervoussystem.Int. Arch.Occup.Environ.Health45: 105-
121 (1980).
35. Gamberale,F.,Annwall,G.,and Hultengren,M. Exposureto xylene
andethylbenzeneIII. Effectson centralnervousfunctions.Scand.J.
WorkEnviron.Health4: 204-211(1978).
36. Riihimaki,V., and Savolainen,X. Human exposure to m-xylene
kineticsandacuteeffectsonthe centralnervoussystem.Ann.Occup.
Hyg. 23:411-422(1980).
37.Bushnell,P. J. Behavioraleffectsof acutep-xyleneinhalationin rats:
autoshaping,motor activity, and reversal learning. Neurotoxicol.
Teratol.10:569-577(1988).
38.Andersson,X.,Fuxe,X.,Nilsen,O.G.,Toftg,R.,andGustafsson,J. A.
Productionof discretechangesin dopamineandnoradrenaline levels
andturnoverin variousparts of the rat brainfollowingexposureto
xylene, ortho-,meta-, and para-xylene,and ethylbenzene.Toxicol.
Appl.Pharmacol.60: 535-548(1981).
39. Honma,T., Sudo, A., Miyagawa,M., Sato, M., and Hasegawa,H.
Significantchangesin the amountsof neurotransmitter andrelated
substancesin rat braininducedby subacuteexposureto lowlevelsof
tolueneandxylene.Ind. Health21: 143-151(1983).
40. Savolainen, X.,andPfaffli,P.Dose-dependent neurochemical changes
duringshort-terminhalationexposureto m-xylene.Arch.Toxicol.45:
117-122(1980).
41. HealthEffects Institute.AutomotiveMethanolVaporsand Human
Health:An Evaluationof ExistingScientificInformationandIssues
for FutureResearch.Reportof the HealthEffects InstituteHealth
ResearchCommittee,May1987.
42. Jacobsen,D., and McMartin,K. E. Methanoland ethyleneglycol
poisonings:mechanismof toxicity,clinical course, diagnosis and
treatment.Med.Toxicol.1: 309-334(1986).
43.. Frederick,L. J.,Schulte,P.A., andApol,A. Investigationandcontrol
of occupationalhazardsassociatedwiththe use of spiritduplicators.
Am. Ind. Hyg. Assoc.J. 45: 51-55 (1984).
44. Cook,M. R.,Bergman,F. J.,Cohen,H. D.,GerkovichM.M.,Graham
C., Harris,R. X., and Siemann,L. G. Effects of MethanolVaporon
HumanNeurobehavioral Measures.ResearchReportNo. 42, Health
Effects Institute,Cambridge,MA,August,1991.
45. Martin-Amat,G., Tephly,T. R., McMartin,X. E., Makar,A. B.,
Hayreh,M. S.,Baumbach,G.,andCancilla,P. Methylalcoholpoison-
ing II. Developmentof a modelfor oculartoxicityin methylalcohol
poisoningusingthe rhesusmonkey.Arch.Ophthalmol. 95:1847-1850
(1977).
46. McMartin,K. E., Martin-Amat,G.,Makar,A. B., and Tephly,T. R.
MethanolpoisoningV. Roleof formatemetabolismin the monkey.J.
Pharmacol.Exper.Ther.201:564-572(1977).
47.Makar,A. B., and Tephly,T. R. Methanolpoisoningin the folate-
deficientrat. Nature261:715 (1976).
48. Makar,A. B., andTephly,T. R. MethanolpoisoningVI: Roleof folic
acid in the productionof methanolpoisoningin the rat. J. Toxicol.
Environ.Health2:1201-1209(1977).
49. Mohler,F. S., and Gordon,C. J. Effects of methanolon autonomic
thermoregulation of rats at differentambienttemperatures.Toxicol.
Lett. 52: 153-162(1990).
50. Mohler,F. S.,andGordon,C.J. Thermoregulatory effectsof methanol
in Fischer and Long Evans rats. Neurotoxicol.Teratol.12: 41-45
(1990).
51.Wecker,J. R.,andIson,J. R.Acuteexposureto methylorethylalcohol
This content downloaded from 185.44.78.143 on Wed, 18 Jun 2014 12:17:31 PM
All use subject to JSTOR Terms and Conditions
altersauditoryfunctionin rats.Toxicol.Appl.Pharmacol.74:258-266
(1984).
52. Nelson,B. K.,Brightwell,W.S., Mackenzie,D. R., Khan,A., Burg,J.
R.,Weigel,W.W.,and Goad,P. T.Teratologicalassessmentof meth-
anol and ethanolat high inhalationlevels in rats. Fundam.Appl.
Toxicol.5: 727-736(1985).
53. Infurna,R.,andWeiss,B. Neonatalbehaviortoxicityin rats following
prenatalexposureto methanol.Teratology33: 259-265(1986).
54. Jeganathan,P. S., and Namasivayam,A. Methanolinducedbiogenic
aminechangesin discreteareas of rat brain.Ind. J. Physiol.Phar-
macol.32: 1-10 (1988).
55. Jeganathan,P. S., and Namasivayam, A. Brainbiogenicaminelevels
after methanoladministration:possible mechanismof action on
centralmonoaminergic neuronsin discreteareas of brainin Wistar
rat. Ind. J. Physiol.Pharmacol.33: 151-156(1989).
56. Jeganathan,P. S., and Namasivayam,A. Methanolinducedmono-
aminechangesin hypothalamus and striatumof albinorats.Alcohol
6: 451-454 (1989).
57.Smith,M.S. Theneurological seguelaeto tolueneinhalation.J. R. Nav.
Med.Serv.76:69-74 (1990).
58. Baelum,J.,Lundqvist,G.R.,Molhave,L.,andAndersen,N. T.Human
response to varying concentrationsof toluene. Int. Arch. Occup.
Environ.Health62: 65-71 (1990).
59. Echeverria,D., Fine, L., Langolf,G., Schork,A., and Sampaio,C.
Acuteneurobehavioural effects of toluene.Br. J. Ind. Med.46: 483-
495 (1989).
60.Antti-Poika,M., Juntunen,J., Matikainen,E., Suoranta,H., Hann-
inen, H., Seppalainen,A. M.,and Liira,J. Occupational exposureto
toluene:neurotoxiceffectswith specialemphasison drinkinghabits.
Int. Arch.Occup.Environ.Health56: 31-40 (1985).
61. Foo, S. C., Jeyaratnam,J., and Koh, D. Chronicneurobehavioral
effects of toluene.Br. J. Ind. Med.47: 480-484 (1990).
62. Juntunen,J.,Matikainen, E.,Antti-Poika,M.,Suoranta,H.,andValle,
M. Nervoussystem effects of long-termoccupationalexposureto
toluene.ActaNeurol.Scand.72: 512-517 (1985).
63. Merck,H. I., Winkel,P.,andGyntelberg,F. Healtheffectsof toluene
exposure.Dan. Med.Bull.35: 196-200(1988).
64. Benignus,V. A. Neurobehavioral effects of toluene:a review.Neu-
robehav.Toxicol.Teratol.3: 407-416 (1982).
65. Glowa,J. R. Some effects of sub-acute exposure to toluene on
schedule-controlled behavior.Neurobehav. Toxicol.Teratol.3:463-465
(1981).
66. Himnan,D. J. Biphasic dose-responserelationshipfor effects of
tolueneinhalationon locomotoractivity.Pharmacol.Biochem.Behav.
26: 65-69 (1987).
67.Rishi, R., Harabuchi,I., Ikeda,S., Yokota,H., and Miyake,H. Neu-
robehavioral effectsandpharmacokinetics of toluenein rats andtheir
relevanceto man.Br. J. Ind. Med.45: 396-408 (1988).
68. Taylor,J. D.,andEvans,H. L. Effectof tolueneinhalationonbehavior
andexpiredcarbondioxidein macaquemonkeys.Toxicol.Appl.Phar-
macol.80:487-495(1985).
69.Arito,H., Tsuruta,H., and Nakagaki,R. Acuteeffects of tolueneon
circadianrhythmsof sleep-wakefulness andbrainmonoamine metab-
olismin rats.Toxicology33:291-301 (1984).
70. Fuxe,R.,Andersson,R., Nilsen,O.G.,Toftgard,R., Eneroth,P.,and
Gustafsson,J.A.Tolueneandtelencephalicdopamine: selectivereduc-
tion of amineturnoverin discreteDA nerveterminalsystems of the
anteriorcaudatenucleusby low concentrationsof toluene.Toxicol.
Lett. 12:115-123(1982).
71. Fuxe, R., Martire,M., Von Euler, G., Agnati, L. F., Hansson,T.,
Andersson,R., Gustafsson,J. A., and Harfstrand,A. Effects of
subacutetreatmentwith tolueneon cerebrocortical alpha-andbeta-
adrenergicreceptorsin the rat. Evidencefor an increasednumber
and a reducedaffinity of beta-adrenergicreceptors.Acta Physiol.
Scand.130:307-311(1987).
72. Dyer,R. S.,Muller,R. E., Janssen,R.,Barton,C. N.,Boyes,W.R.,and
Benignus,V.A. Neurophysiological effectsof 30-daychronicexposure
to toluenein rats. Neurobehav. Toxicol.Teratol.6: 363-368(1984).
73. Himnan,D. J. Toleranceandreversetoleranceto tolueneinhalation:
effects on open-fieldbehavior.Pharmacol.Biochem.Behav.21: 625-
631 (1984).
74. Mattsson,J. L., Gorzinski,S. J., Albee, R. R., and Zimmer,M. A.
Evokedpotentialchangesfrom13 weeks of simulatedtolueneabuse
 GASOLINENEUROTOXICITY
in rats. Pharmacol.Biochem.Behav.36: 683-689(1990).
75. Pryor,G. T. A toluene-induced motorsyndromein rats resembling
that seen in somehumansolventabusers.Neurotoxicol. Teratol.13:
387-400(1991).
76.Arito,H.,Tsuruta,H.,Nakagaki,R.,andTanaka,S. Partialinsomnia,
hyperactivityandhyperdipsiainducedby repeatedadministration of
toluenein rats:theirrelationto brainmonoamine metabolism.Toxicol-
ogy 37: 99-110 (1985).
77.Bjornaes,S., and Naalsund,L. U. Biochemicalchangesin different
brainareas after tolueneinhalation.Toxicology49: 367-374 (1988).
78. Rostas,J., and Hotchin,J. Behavioraleffects of low-levelperinatal
exposureto toluenein mice.Neurotoxicol. Teratol.3: 467-469(1981).
79. Charness,M. E., Simon,R. P.,andGreenberg,D. A. Ethanolandthe
nervoussystem.N. Engl. J. Med.321:442-454(1989).
80. Freund,G. Chroniccentralnervoussystem toxicityof alcohol.Ann.
Rev.Pharmacol.13:217-227(1973).
81. Pratt, 0. E., Rooprai,H. K., Shaw,G. K., and Thomson,A. D. The
genesis of alcoholicbraintissue injury.Alcohol25: 217-230 (1990).
82. Shoemaker, W.J. The neurotoxicityof alcohols.Neurobehav.Toxicol.
Teratol.3: 431-436(1981).
83. Lester,D., and Greengerg,L. A. The inhalationof ethyl alcoholby
man.Q.J. StudiesAlcohol12:167-178(1951).
84. Ferko,A. P.,andBobyock,E. Inductionof physicaldependencein rats
by ethanol inhalationwithout the use of pyrazole.Tocicol.Appl.
Pharmacol.40: 269-276(1977).
85. Goldstein,D.B ., andPal,N. Aleoholdependeneeproducedin miceby
inhalationof ethanol:gradingthe withdrawalreaction.Science172:
288-290(1971).
86. Nelson,B. K.,Brightwell,W.S.,MacKenzie,D. R.,Rhan,A.,Burg,J.
R.,Weigel,W.W.,and Goad,P. T. Teratological assessmentof meth-
This content downloaded from 185.44.78.143 on Wed, 18 Jun 2014 12:17:31 PM
All use subject to JSTOR Terms and Conditions
141
anol and ethanolat high inhalationlevels in rats. Fundam.Appl.
Toxicol.5: 727-736(1985).
87. Rogers,J.,Weiner,S. G.,andBloom,F, E. Long-termethanoladmin-
istrationmethodsforrats:advantagesofinhalationoverintubationor
liquiddiets.Behav.Neur.Biol.27:466-486 (1979).
88. Conry,J. Neuropsychological deficitsin fetal alcoholsyndromeand
fetal alcoholeffects.AlcoholClin.Exp.Res. 14:650-655(1990).
89. Nanson,J. L.,andHiscock,M.Attentiondeficitsin childrenexposed
to alcoholprenatally.AlcoholClin.Exp.Res. 14:656-661(1990).
90. Streissguth,A. P.,Barr,H. M.,andSampson,P.D. Moderateprenatal
alcoholexposure:effects on child IQ and learningproblemsat 71/2
years.AlcoholClin.Exp. Res. 14:662-669(1990).
91. West, J. R., Goodlett,C. R., and Brandt,J. P. New approachesto
research on the long-termconsequencesof prenatalexposureto
alcohol.AlcoholClin.Exp. Res. 14:684-689(1990).
92. Riley, E. P. The long-termbehavioraleffects of prenatal alcohol
exposurein rats.AlcoholClin.Exp. Res. 14:670-673(1990).
93. Hunt, W. A. The effect of ethanol on GABAergictransmission.
Neurosci.Behav.Rev.7: 87-95 (1983).
94. Systinsky,I. A, Guzikov,B. M.,Gomanko,M. V.,Eremin,V. R., and
Konovalova, N. N. The gamma-aminobutyric acid(GABA)systemin
brainduringacuteandchronicethanolintoxication. J. Neurochem.
25:
43-48 (1975).
95. Muller,P., Britton,R. S., and Seeman,P. The effects of long-term
ethanolonbrainreceptorsfordopamine,acetylcholine,serotoninand
noradrenaline. Eur.J. Pharmacol.65:31-37 (1980).
96. Clarren,S. K.,Astley,S.J.,Bowden,D.M.,Lai,H.,Milam,A. H.,Rudeen,
P. R., and Shoemaker, W. J. Neuroanatomic and neurochemical abnor-
malitiesin nonhumanprimateinfants exposedto weekly doses of
ethanolduringgestation.AlcoholClin.Exp.Res. 14:674-683(1990).