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Ambient Water Quality Criteria
              Criteria and Standards Division
              Office of Water Planning and Standards
              U.S. Environmental Protection Agency
              Washington, D.C.

                       CRITERION DOCUMENT

                             TOLUENE                     ^^


                          Aquatic Life

     The data base for freshwater aquatic life  is  insufficient  to

allow use of the Guidelines.  The following  recommendation  is  in-

ferred from toxicity data for saltwater organisms.

     For toluene the criterion to protect freshwater  aquatic  life

as derived using procedures other than the Guidelines  is  2,300

ug/1 as a 24-hour average and the concentration  should  not  exceed

5,200 ug/1 at any time.

     For toluene the criterion to protect saltwater aquatic life

as derived using the Guidlines is 100 ug/1 as a  24-hour average

and the concentration should not exceed 230  ug/1 at any time.

                          Human Health

     For the protection of human health from the toxic  properties

of toluene ingested through water and through contaminated

aquatic organisms, the ambient water criterion  is  determined  to

be 12.4 mg/1.

     Toluene  is a clear,  colorless,  noncorrosive liquid
with a sweet, pungent, benzene-like  odor.   The production
of toluene  in the United  States  has  increased  steadily since
1940 when approximately 31 million gallons  were produced:
in 1970, production was 694 million  gallons.   Approximately
70 percent  of the toluene produced is converted to  benzene,
another 15  percent, is used to produce chemicals,  and  the
remainder is used as a solvent for paints and  as  a  gasoline
additive (Dep. Health Edu. Welfare,  1973).
     Toluene is produced  primarily from petroleum or  petro-
chemical processes (96 percent), and on a small  scale from
metallurgical coke manufacturing (Kirk and  Othmer,  1963).
Approximately 70 percent  of the  toluene produced  is converted
to benzene, another 15 percent is used as a feedstock,  15
percent is  used for the production of other chemicals and
the balance is used directly as  a component of gasoline
or as a solvent for paints and coatings.  The  total annual
discharge of toluene to the environment by  industry is esti-
mated at 691,800 metric tons; 99.3 percent  (686,960 kkg)
is in the form of atmospheric emissions and 0.7 percent
(4,840 kkg)  as a constitutent in wastewater.
     Toluene, also referred to as toluol, methylbenzene,
methacide,  and phenylmethane, is an aromatic hydrocarbon
which is both volatile and flammable (Occup. Safety Health
Admin., 1975).  The molecular structure is distinguished
from that of benzene by the substitution of a methyl  group
for one hydrogen atom.
                             \  A-l

     Toluene has the molecular formula CyHg, a molecular

weight of 92.13g, a boiling point of 110.625°C, a freezing

point of -94.9°C (Stecher, 1968), a density of 0.86694 at

20°C, a vapor pressure of 30 mm Hg at 26.03°C, and a refrac-

tive index of 1.4893 at 24°C  (Kirk and Othmer, 1963).  Toluene

is only slightly soluble in water, 534.8 +4.9 mg/1 in freshwater

and 379.3 + 2.8 mg/1 in seawater  (Sutton and Calder, 1975).

It is miscible with alcohol, chloroform, ether, acetone,

glacial acetic acid, carbon disulfide and other organic

solvents  (Shell and Ettre, 1971).

     The nucleus of toluene, like that of benzene, undergoes

substitution reactions.  Substitution occurs almost exclusively

in the orthro  (2) and para  (4) positions and occurs faster

with toluene than with benzene  (Bradsher, 1971).  The presence

of a methyl group offers additional possibilities for reaction;

the most important is dealkylation to produce benzene (Kirk

and Othmer, 1963).  Hydrogenation of toluene takes place

readily to form methylcyclohexane  (Kirk and Othmer, 1963).

Toluene may be oxidized with air  in the presence of manganese

or cobalt naphthenates to form benzoic acid; controlled

chlorination of toluene yields benzol dichloride which may

be hydrolized to benzaldehyde  (Gait, 1967).  Most reactions,

however, require specialized conditions and are carried

out commercially.

     Freshwater aquatic studies indicate that toluene is

toxic to goldfish, Carassius auratus, fatheads, Pimephales

promelas, bluegill, Lepomis macrochirus, and guppies, Poecilia

reticulata.  Toxicity data for several species of freshwater

  algae  have  demonstrated that they are more resistant to

 toluene than fish.   Several marine studies indicate that

 toluene is toxic  to marine  bacteria (interfering with chemo-

 reception and  chemotaxis),  phytoplankton,  Artemia,  and

 marine  fish  (coho salmon, Oncorhynchus kisutch).

     The effect of  toluene  on the  chronic  exposure  of workers

 subjected to chronic exposure of toluene vapor  in numerous

 industrial plants has been  reported.   The  effects of  toluene

 inhalation include  decreased  phagocytic activity of leukocytes,

 depression of  the central nervous  system,  narcosis, addiction

 and even death at high levels.  Animal studies  have demon-

 strated similar effects.

     Toluene has  been reported to  cause tainting of fish

 flesh (Teal, 1959).  Yellow perch,  Perca flavescens,  were

 exposed to toluene  for seven  days  in water maintained at

 50°F.  Under these  conditions, the  taste threshold  for toluene

 as determined by  a  taste panel was  reported as  250  pg/1.

     Although toluene is a volatile compound and has  been

 shown to be  readily  transfered from water  surfaces  to the

 atmosphere under  ideal conditions  (Mackay  and Wolkoff, 1973),

 its transport and persistence under environmental conditions

 is not well known.   In the atmosphere, toluene  is subject

 to photochemical degradation  to benzaldehyde and  traces

of peroxybenzoyl nitrate.  It is known also that  toluene

can re-enter  the hydrosphere  in rain (Walker, 1976).

     Toluene  has been detected in municipal finished  water

supplies at levels ranging from 0.1 pg/1 to 11 pg/1.  The

toluene  metabolites benzaldehyde and benzoic acid, were also

found in finished water at concentrations up to  19 pg/1.



Bradsher, C.K. 1971.  McGraw-Hill encyclopedia of science

and technology.  McGraw-Hill Book Co., New York.

Department of Health Education, and Welfare. 1973.  National

Institute for Occupational Safety and Health criteria for

a recommended standard...Occupational exposure to toluene.

Gait, A.J. 1967.  Heavy  organic chemicals.  Pergamon Press

Ltd., Oxford.

Kirk, R.E., and D. Othmer. 1963.  Kirk-Othmer Encyclopedia

of Chemical Technology.  2nd ed. John Wiley and Sons, Inc.,

New York.

Mackay,  D., and A.W. Wolkoff. 1973.  Rate of evaporation

of low-solubility contaminants from water bodies to atmosphere,

Environ. Sci. Technol.  7: 611.

Occupational Safety and  Health Administration. 1975.  Occupa-

tional exposure to toluene.  Fed. Regis. 40 (194). Oct.


Shell, F.D., and L.S. Ettre. eds. 1971.  Encyclopedia of

Industrial Chemical Analysis.  Interscience Publishers,

John Wiley and Sons. Inc., New York.

Stecher, P.G. Ed., 1968.  The Merck Index. 8th ed.  Merck

and Co. Inc., Rahway, N.J.

Button, C. , and J.A. Calder. 1975.  Solubility of alkylbenzenes

in distilled water and seawater at 25°C.  Jour=. Chem. Eng.

Data 20: 320.

Teal, J.L. 1959.  The control of waste through fish taste.

Presented at the Am. Chem. Soc. Natl. Meet.  (Personal communi-


Walker, P. 1976.  Air pollution assessment of toluene.

MTR-7215.  Mitre Corp. McLean, Va.


                       FRESHWATER ORGANISMS


     Acute  toxicity tests  have been conducted with toluene and a

variety  of  freshwater  fish and Daphnia magna; the latter appears

to be  significantly more resistant than the fish.  All but one of

the tests were  conducted under static  procedures with unmeasured


Acute  Toxicity

     The range  of  adjusted 96-hour LC50 values  for the goldfish,

fathead  minnow, guppy,  and bluegill is 6,940  to 32,400 ug/1

(Table 1).  When the geometric mean of these  values is divided by

the species sensitivity  factor (3.9),  the  Final Fish  Acute Value

of 5,200 ug/1  is obtained.  The use of this sensitivity factor

appears  to be appropriate  since the value  derived is  slightly

lower  than the  lowest LC50 value  and thus  is  likely to protect 95

percent  of the  species.
*The reader is referred to the Guidelines for Deriving Water

Quality Criteria for the Protection of Aquatic Life  [43  FR  21506-

(May 18, 1978) and 43 FR 29028 (July 5, 1978)] in order  to  better

understand the following discussion and recommendation.   The  fol-

lowing tables contain the appropriate data that were found  in  the

literature, and at the bottom of each table are the calculations

for deriving various measures of toxicity as described in the


     Daphnia magna  is  the  only  tested  invertebrate species and

the 48-hour EC50 for this  species  is 313,000  ug/1  (Table 2).   The

Final Invertebrate  Acute Value  based on  this  result is  13,000

y.g/1.  Since the comparable  value  for  fish  is lower (5,200 u.g/1),

it becomes the Final Acute Value.

Chronic Toxicity

     No test results have  been  reported  for the  chronic effects

of toluene on freshwater fish or  invertebrate species.

Plant Effects

     Two freshwater algae  have  been exposed to toluene  and the

results (Table 3) demonstrate that these  species are  relatively

insensitive compared to the  fish.  The lowest plant value,

245,000 ug/lf is based on  a  reduction  in  cell numbers of the

alga, Chlorella vulgaris  (Kauss and Hutchinson,  1975).


     No measured steady-state bioconcentration factor  (BCF)  is

available for toluene.  A  BCF can  be estimated using  the octanol-

water partition coefficient  of  540.  This coefficient  is used to

derive an estimated BCF of 70 for  aquatic organisms that contain

about eight percent lipids.  If it is  known that the  diet of  the

wildlife of concern contains a  significantly  different  lipid  con'

tent, an appropriate adjustment in the estimated BCF  should  be



     Wallen, et al. (1957) exposed mosquitofish  to toluene in th

presence of high concentrations of suspended  solids and calcu-

lated a 96-hour LC50 value of 1,180,000 ug/1  (Table 4).


                      Freshwater-Aquatic Life

 Summary of Available Data

      The concentrations below have been rounded to two signifi-

 cant figures.

      Final Fish Acute Value = 5,200 ug/1

      Final Invertebrate Acute Value = 13,000 ug/1

           Final Acute Value = 5,200 ug/1

      Final Fish Chronic Value = not available

      Final Invertebrate Chronic Value = not available

      Final Plant Value = 250,000 ug/1

      Residue Limited Toxicant Concentration = not available

           Final Chronic Value = 250,000 ug/1

           0.44  x Final Acute Value = 2,300 ug/1

      No  freshwater  criterion can be derived for toluene using the

Guidelines because  no Final Chronic Value  for either  fish or

 invertebrate species  or a  good  substitute  for.either  value is


      Data  for toluene and  saltwater organisms can  be  used to

estimate a  criterion.

      For toluene  and  saltwater  organisms 0.44 times the Final

Acute Value is  less  than the  Final  Chronic Value derived  from

results of  an embryo-larval  test  with  the  sheepshead  minnow.

Therefore,  a reasonable estimate  of  a  criterion for toluene  and

freshwater  organisms  would  be 0.44  times the  Final Acute  Value.

     The maximum  concentration of  toluene  is  the Final  Acute

Value of 5,200 ug/1 and the estimated  24-hour average concentra-

tion is 0.44 times the  Final Acute Value.   No important adverse

effects on freshwater aquatic  organisms  have  been reported to be

caused by concentrations  lower than 'the  24-hour  average  concen-


     CRITERION:   For toluene  the  criterion  to protect freshwater

aquatic life as derived using  procedures other than  the  Guide-

lines  is 2,300 ug/1 as a  24-hour  average and  the concentration

should not exceed 5,200 ug/1  at any  time.

              Table  1.   Freshwater fish acute values for toluene
                        Bioaseay  Teat      Time
          Ad lusted
LC50      LC&O
 ug/11    (uq/l>


Goldfish. FT
Carasslus auratus
Goldfish. S
Carassius auratus
Fathead minnow, S
Pimephales promelas
Fathead minnow, S
Pimephales promelas
Guppy. S
Poecilia reticulatus
Bluegill, S
Lepomis macrochirus
Bluegill. S
Lepomis macrochirus

M 96 22,800 22.800 Brenniman, et al. 1976
U 96 57,680 31.530 Pickering & Henderson,

U 96 34,270 18,740 Pickering & Henderson,

U 96 42,330 23.140 Pickering & Henderson.

U 96 59.300 32.400 Pickering & Henderson.

U 96 24.000 13.120 Pickering & Henderson.

U 96 12.700 6.940 U.S. EPA, 1978






*  S = static, FT = flow-through
** U = unmeasured, M = measured
   Geometric mean of adjusted  values = 20,380 Mg/1    29'280 = 5,200 pg/1
   Lowest value from a flow-through test with measured concentrations = 22,800 \>g/l

                         Table  2.   Freshwater  invertebrate  acute values  for toluene (U.S.  EPA,  1978)

                                                                            Adjusted •
                                    Bioaaaay  Test      Time      LC50      LC60
                                    flgfrhoj*   cone.**    jhre)      (ug/l>     
                             Table  3.  Freshwater plant effects for toluene
               Chlorella yulgaris


EC50 24-hr
cell numbers

96-hr EC50 for
chlorophyll a

96-hr EC50 for
cell numbers
Kauss & Hutchlnson, 1975
U.S. EPA. 1978
U.S. EPA. 1978
               Lowest plant value •> 245,000 Mg/1

                                 Table 4.  Other  freshwater data  for toluene  (Wallen,  et al.  1957)
Puratigq  Effect
              Gambusla affinis
 96 hrs   LC50 in turbid water  1,180,000

                        SALTWATER ORGANISMS


     Three fish species have  been acutely exposed to toluene as

have several species of shrimp  and  one  copepod  species.   Results

of these tests indicate a  range of  50 percent effect concen-

trations from 3,700 ug/1 for  the grass  shrimp to  between 277/000

and 485,000 ug/1 for the sheepshead minnow.  All  of  these tests

were conducted using static test procedures  although concen-

trations were measured  in  several tests.

Acute Toxicity

     Adjusted 96-hour LC50 values for the  striped bass  (Benville,

et al. 1977) and coho salmon  (Morrow, et  al. 1975) were  4,470  and

12,000 ug/1, respectively  (Table 5).  The  sheepshead minnow  (U.S.

EPA, 1978) appears to be much more  resistant to toluene  (Table

9).  The Final Fish Acute Value  derived from these data  is 2,000


     Potera (1975) conducted  a  variety of  24-hour exposures  with

the grass shrimp, Palaemonetes  pugio, using static procedures

with measured concentrations  (Table  6).  Temperature  (10  and

20°C), salinity (15 and 25°/00),  and life  stage (larvae  and

adults) were the variables considered.  The total range  of ad-

justed LC50 values for  the six  tests was 4,920 to 10,900  ug/1;

this small difference indicates  that the variables did not have  a

very great effect.  These data and  those for a copepod, mysid

shrimp, and bay shrimp  are  used  to derive the Final Invertebrate
Acute Value of 230 ug/1;  this  value also  becomes  the Final Acute
Chronic Toxicity
     A chronic value  of 2,166  ug/1 (Table 7)  has  been obtained
from an embryo-larval test  with  the sheepshead minnow in which
the observed  adverse  effect was  on hatching and survival (U.S.
EPA, 1978).
     The unadjusted 96-hour LC50 for the  sheepshead minnow in the
same study  (U.S.  EPA, 1978) is between 277,000 and 485,000 ug/1
and, when compared to the no observed effect concentration during
the embryo-larval test  of 2,800  ug/lr indicates that the latter
concentration is  less than  0.01  of the 96-hour LC50.  When the
chronic value for the sheepshead minnow is divided by the sensi-
tivity factor (6.7),  the Final Fish Chronic Value of 320 ug/1 is
obtained.   No chronic data  are available  for any  saltwater inver-
tebrate species and toluene.
Plant Effects
     Several  studies  have been conducted  with saltwater algae and
one has been  conducted  with kelp,  Macrocystis pyrifera (Table 8).
Effects on  growth, respiration,  and photosynthesis occurred at
toluene concentrations  from 8,000  to greater than 433,000 ug/1.
The results are quite variable since these extreme values are for
the same species, Skeletonema  costatum.
     No measured  steady-state  bioconcentration factor (BCF) is
available for  toluene.   A BCF  can  be estimated using the octanol-
water partition coefficient of 540.   This coefficient is used to

derive an estimated BCF of  70  for  aquatic  organisms that contain

about eight percent lipids.  If  it  is known  that  the  diet of the

wildlife of concern contains a significantly different  lipid con-

tent, an appropriate adjustment  in  the estimated  BCF  should  be



     Potera (1975) observed narcosis of grass shrimp  within  15

minutes during an exposure to  19,800 u.g/1  (Table  9).  The  results

of the sheepshead minnow acute test were discussed  earlier.


                     Saltwater-Aquatic Life

Summary of Available Data

     The concentrations  below have been rounded to two signifi-

cant figures.

     Final Fish  Acute  Value = 2,000 ug/1

     Final Invertebrate  Acute Value = 230 ug/1

          Final  Acute  Value = 230 ug/1

     Final Fish  Chronic  Value = 320 ug/1

     Final Invertebrate  Chronic Value = not available

     Final Plant Value = 8,000 ug/1

     Residue Limited  Toxicant Concentration = not available

           Final  Chronic  Value = 320 ug/1

           0.44 x Final Acute Value = 100 ug/1

     The  maximum concentration of toluene is the Final Acute

Value  of  230 ug/1 and the 24-hour average concentration is 0.44

times  the Final  Acute Value.  No important adverse effects on

saltwater aquatic organisms have been reported to be caused by

concentrations lower  than the 24-hour average concentration.

     CRITERION:   For  toluene the criterion to protect saltwater

aquatic  life as  derived  using the Guidelines is 100 ug/1 as a

24-hour  average  and the concentration should not exceed 230 ug/1

at any time.

                           Table. 5.   Marine fish acute values for toluene
Organism Method*
Coho salmon, S
Oncorhynchus kisutch
Striped bass, S
Horone saxatilis

Teat Time LC50 LC60
Cone.** ifirei juq/l| luq/U
U 96 10,000- 12.000***
M 96 6,300 4,470

Morrow, et al. 1975

Benville, et al. 1977

             *  S =» static
             ** U = unmeasured, M •» measured
             *** Adjusted geometric mean of LC50 range
                Geometric mean of adjusted  values = 7,324 pg/1
= 2,000 pg/1

              Table 6.  Marine invertebrate acute values  for  toluene
                        bioassay  Test

Time      LC50      LCbO

           mi/!)     (iKi/U     l-fetfcience
Copepod, S
Nitocra spinipes
Copepod, S
Nitocra spinipes
Mysid shrimp, S
Mysidopsis bahia
Bay shrimp, S
Crago franciscorum
Grass shrimp, S
Palaemonetes pugio
Grass shrimp (adult) , S
Palaemonetes pugio
Grass shrimp (adult), S
Palaemonetes pugio
Grass shrimp (adult), S
Palaemonetes pugio
Grass shrimp (adult) , S
Palaemonetes pugio
Grass shrimp (larva), S
Palaemonetes pugio
Crass shrimp (larva), S
Palaemonetes pugio

M 24 24,200 6.920 Potera, 1975
M 24 74,200 21,200 Potera. 1975
U 96 56,300 47.686 U.S. EPA. 1978
M 96 3,700 4.070 Benville. et al. 1977
U 96 9,500 8.050 Tatem. 1975
M 24 20,200 5,780 Potera. 1975
M 24 17.200 4.920 Potera. 1975
M 24 37,600 10,800 Potera, 1975
M 24 38,100 10,900 Potera, 1975
M 24 30.600 8.750 Potera. 1975
M 24 25,800 7.380 Potera. 1975
*  S = static

** U = unmeasured, M = measured

                                                        11  399
   Geometric mean of  adjusted values = 11,399  |jg/l     —49—  -  230  iig/1

                          Table  7.  Marine fish chronic values for  toluene  (U.S.  EPA.  1978)

                                                   Limits     Value
            Organism                     Test*      luq/H     (ug/lj

            Sheepshead minnow.           E-L    2,800-6,700   2,166
            Cyprinodon variegatus
            * E-L = embryo-larval

              Geometric mean of c

              Lowest chronic values <=> 2,166 ug/1
                                                   2   k
Geometric mean of chronic values - 2,166 i»g/l      }  %   •= 320 Mg/1

              Table   8.    Marine  plant effects for toluene
Macrocystis pyrifera
Amphidinium carteri
Chlorella sp.
Chlorella sp.
Cricosphaera carterae
00 Dunaliella tertiolecta
£ Alga ,
Skeletonema costatum
Skeletonema costatum
SUeletonema costatum

96-hr EG50 for
chlorophyll a
96-hr EC50 for
reduction in cell
100 , 000
Anonymous , 1964
Dunstan, et al.
Potera, 1975
Potera, 1975
Dunstan, et al.
Dunstan, et al.
Dunstan, et al.
U.S. EPA, 1978
U.S. EPA, 1978
Lowest marine plant value = 8,000,)ig/l

                              Table  9.  Other marine daCa for coluene
Grass shrimp,
Palacmonetes pugjp

Shcepshead minnow,
Cyprlnodon varlegatua
                                   Duration  Eti ect
                                    15 mins   Narcosis
                                    96  hrs    LC50

 ''19,800     Potera, 1975

>277.000     U.S. EPA, 1978



Anonymous.  1964.  An investigation of the effects of dis-

charged wastes on kelp.  Publ. No. 26: 58. Calif. State

Water Control Board.

Benville, P.E., Jr., et al.  1977.  The acute toxicity

of six monocyclic aromatic crude oil components to striped

bass  (Morone saxatilis) and bay shrimp (Crago franciscorum).

Calif. Fish Game.  63: 204.

Brenniman, G., et al.  1976.  A continous flow bioassay

method to evaluate the effects of outboard motor exhausts

and selected aromatic toxicants on fish.  Water. Res.  10:


Dunstan, W.M., et al.  1975.  Stimulation and inhibition

of phytoplankton growth by low molecular weight hydrocarbons.

Mar. Biol.  31: 305.

Kauss, P.B., and T.C. Hutchinson.  1975.  The effects of

water-soluble petroleum components on the growth of Chlorella

vulgar is Beijernck.  Environ. Pollut.  9: 157.

Morrow, J.E., et al.  1975.  Effects of some components

of crude oil on young coho salmon. Copeia  2: 326.


Pickering, Q.H., and C. Henderson.  1966.  Acute toxicity
of some important petrochemicals to fish.  Jour. Water Pollut,
Control Fed.  38: 1419.

Potera, F.T.  1975.  The effects of benzene, toluene and
ethylbenzene on several important members of the estuarine
ecosystem.  Ph.D. dissertation.  Lehigh University.

Tatem, H.E.  1975.  Toxicity and physiological effects of
oil and petroleum hydrocarbons on estuarine grass shrimp
Palaemonetes pugio.  Ph.D. dissertation.  Texas A.  and M.

U.S. EPA.  1978.  In-depth studies on health and environmental
impacts of selected water pollutants.  Contract No.  68-01-

Wallen, I.E., et al.  1957.  Toxicity to Gambusia affinis
of certain pure chemicals in turbid waters.  Sewage Ind.
Wastes.  29: 695.

 Mammalian Toxicology and Human Health Effects
 Ingestion from Water
      Toluene has recently been identified in both raw water
 and finished water supplies  of several communities in the
 United  States.   Levels of up to 11 jug/1 were found in November
 1974,  in  finished water from the New Orleans area (U.S.
 EPA,  1975a).   After the results of the study were publicized,
 a  nationwide survey,  the National Organics  Reconnaissance
 Survey  (NORS),  was undertaken to determine  the  concentration
 of  organic  chemicals  in drinking water.   Ten cities  across
 the country were  selected to represent the  major  types of
 raw water sources.  A total  of  72 compounds were  identified
 in  the  first  five  water supplies surveyed (Coleman,  et al.
 1976) .  Toluene was 1 of  18  compounds  occurring in more
 than one-half of  the  finished waters of  the  ten cities  (U.S.
 EPA, 1975b).  Six  of  the  ten water supplies  contained toluene.
 Levels  of 0.1 and  0.7 jug/1 were  measured  in  the two water
 supplies where quantitative  results were  available.  Benzalde-
 hyde, a toluene metabolite,  was  identified  in three water
 supplies.   Fifteen >ug/l of benzoic acid,  a second metabolite,
was found in another  city's  water.
     A second nationwide  survey of levels of organic chemi-
cals in the Nation's water supplies,  the National Organic
Monitoring Survey  (NOMS), was conducted in three phases
in 1976 (U.S. EPA, 1977).  In the first phase of this survey,
toluene was apparently not included in the analytical screen.

Toluene was, however, detected  in 1 of 111 community finished

water supplies during the second phase of the program.

In the third and most recent phase, toluene was  found  in

One raw water and three finished water supplies  of 11  communi-

ties surveyed.  A level of 19 jug/1 was measured  by gas chroma-

tography/mass spectrometry  (GC/MS) in one of these finished

waters, while 0.5 pg/1 was found in another.  Concentrations

of 0.1 and 0.5/ig/l of benzaldehyde were present in the

drinking water of two cities.

     Although little information is apparently available

concerning potential sources of organics in drinking water,

investigations of the phenomenon are underway  (U.S. EPA,

1975b).  Suspected sources include industrial effluents,

spills, discharges of oil and gasoline from boats, municipal

waste  treatment facilities, agricultural runoff,  and land-

fills.  Volatile hydrocarbons such as benzene and toluene

would  be expected to evaporate  rapidly into the  atmosphere

from bodies of water. Mackay and Wolkoff (1973)  calculated

the evaporative half-life for toluene in water to be 30.6

minutes at 25°C.  The half-life for benzene was  slightly

longer, 37.3 minutes, although  the vapor pressure of benzene

is about three times that of toluene.  This discrepancy

can be explained by the higher water solubility  of 1,780

mg/1 for benzene versus 515 mg/1 for toluene.  Mackay  and

Wolkoff (1973) point out that actual rates of evaporation

in the environment may be substantially reduced  from these

estimates, due to insufficient diffusion of organics in

water  to the air-water interface to replace those organics


being lost by evaporation.   Insufficient  diffusion can be

the result of inadequate mixing  of  the  water  and absorption/

solubilization of  the organic  on or  in  particulates and

sediments.  The half-life would  therefore be  expected to

be considerably shorter for  toluene  in  a  fast-flowing,  shallow

river than for that  in a deep  lake or the ocean.

Ingestion from Food

     Very little data on levels  of toluene  in  foods are

available.  Apparently this  is due in large part  to the

lack of concern for  toxicity of  the  chemical.  Ogata  and

Miyake  (1973) did  detect toluene  in  sea water  and  fish  after

an offensive odor  appeared in  fish caught from harbour  waters

in the proximity of  petroleum  and petrochemical plants  near

Mizushima, Japan.  Identification of toluene was confirmed

by gas chromatography, infrared  absorption spectrometry,

ultraviolet absorption spectrometry, and  mass  spectrometry.

The flesh of one representative  fish was  found to contain

5 ;ig/g toluene.  Ogata and Miyake (1973)  confirmed  that

toluene was readily  taken up into the muscle and liver of

eels kept in tanks containing water  to which either petroleum

industrial waste or  toluene and other aromatic hydrocarbons

were added.  In a  subsequent publication  (Ohmori, et  al.

1975) , the same group of investigators reported that  eel

liver  homogenate was inferior to that of  rats  in the  metabo-

lism of p-nitrotoluene and p-nitrobenzyl  alcohol, analogues

of toluene and benzyl alcohol.  The authors speculated that

this metabolic deficit might contribute to accumulation

of toluene in fish.

     Two of the major metabolites of toluene, benzaldehyde
and benzole acid, are found in substantial levels  in foods.
Benzaldehyde occurs as a natural constituent of bitter almond,
peach, and apricot kernel oils and is added intentionally
as a flavoring agent.  Benzoic acid is used as an  antimicro-
bial agent or food preservative  (Natl. Acad. Sci.  1972).
Benzoic acid appears to have a very large margin of safety
in animals and man  (World Health Organ.  1974).  It is rapidly
and effectively metabolized and  seems to have little potential
to produce tissue injury.  Estimated acceptable daily intake
in man is placed at 0 to 5 mg/kg, based largely upon an
observed no-effect level in rats of approximately  500 mg/kg.
     A bioconcentration factor  (BCF) relates the concentra-
tion of a chemical in water to the concentration in aquatic
organisms, but BCF's are not available for the edible portions
of all four major groups of aquatic organisms consumed in
the United States.  Since data indicate that the BCF for
lipid-soluble compounds is proportional to percent lipids,
BCF's can be adjusted to edible  portions using data on percent
lipids and the amounts of various species consumed by Ameri-
cans.  A recent survey on fish and shellfish consumption
in the United States  (Cordle, et al. 1978) found that the
per capita consumption is 18.7 g/day-  From the data on
the 19 major species identified  in the survey and  data on
the fat content of the edible portion of these species (Sidwell,
et al. 1974) , the relative consumption of the four major
groups and the weighted average percent lipids for each
group can be calculated:

                           Consumption       Weighted Average
        Group               (Percent)          Percent Lipids

Freshwater  fishes              12                   4.8

Saltwater fishes               61                   2.3

Saltwater molluscs              9                   1.2

Saltwater decapods             18                   1.2

Using the percentages  for  consumption and  lipids  for each

of these groups, the weighted  average percent lipids is

2.3 for consumed fish  and  shellfish.

     No measured steady-state  bioconcentration factor (BCF)

is available for toluene,  but  the equation  "Log BCF  = 0.76

Log P - 0.23" can be used  (Veith, et  al. Manuscript)  to

estimate the BCF for aquatic organisms that contain  about

eight percent lipids from  the  octanol-water partition coeffi-

cient (P). Based on an octanol-water  partition coefficient

of 540, the steady-state bioconcentration factor  for  toluene

is estimated to be 70.  An adjustment  factor  of 2.3/8.0 =

0.2875 can be used to adjust the estimated BCF from  the

8.0 percent lipids on which the equation is based to  the

2.3 percent lipids that is the weighted average for  consumed

fish and shellfish.  Thus, the weighted average bioconcentra-

tion factor for toluene and the edible portion of all  aquatic

organisms consumed by Americans is calculated to be  70 x

0.2875 = 20.

     Although toluene has been detected  in  the  atmosphere,
current levels are only a fraction of  the vapor concentra-
tions considered potentially harmful in  occupational  settings.
One of the first reports of atmospheric  toluene was by Williams
in 1965, who detected it in air  samples  in  Vancouver, Canada.
Grob and Grob  (1971) identified  108 hydrocarbons including
39 ppb toluene by gas chromatography in  the air of Zurich,
Switzerland.  They noted that the composition of their atmos-
phere bore a striking resemblance to that of gasoline.
Pilar and Graydon  (1973), upon analysis  of  air  samples taken
at different times of the day from areas of Toronto with
high and low traffic density, concluded  that the toluene
and benzene contamination in their city  was closely linked
with automotive transportation.  Altshuller, et al.  (1971)
also found that atmospheric levels of  toluene in Los  Angeles
were largely associated with motor vehicle  emissions.  Pilar
and Graydon  (1973) measured a maximum  level of  188 ppb tol-
uene in Toronto, and an average  level  of 30 ppb.  These
values are comparable to those seen several years before
in Los Angeles by Lonneman, et al.   (1968).  These investi-
gators reported a maximal concentration  of  129  ppb and an
average concentration of 37 ppb.  Toluene was the most abun-
dant aromatic hydrocarbon.  Its  concentration was more than
twice that of benzene or m-xylene, the next most abundant
aronatics.  Comparison of toluene:benzene ratios in the
atmosphere with those in auto exhausts revealed higher ratios
in the atmosphere  (Lonneman, et  al. 1968; Pilar and Graydon,
1973).  This finding suggests that a substantial amount
                              C-6                             ''(

of atmospheric toluene originates  from a  source  other  than

automotive emissions, possibly from solvent  losses.

     Solvents are used for a variety of purposes  including

chemical processing, metal degreasing, dry cleaning, as

thinners/vehicles in chemical products, and  as surface coat-

ings.  The majority of solvents which are produced eventually

evaporate into the atmosphere, either intentionally or unin-

tentionally  (Natl. Acad. Sci. 1976).  A relatively small

proportion enters water.  In data reviewed by the National

Academy of Sciences (1976) on estimated solvent usage in

the United States in 1968, toluene was the fifth most exten-

sively utilized solvent, ranking behind only petroleum naptha

(which contains toluene), tetrachloroethylene, ethanol,

and trichloroethylene.

     As with most other volatile hydrocarbon solvents, the

most significant inhalation exposures to toluene occur in

occupational and inhalant abuse settings.   Typical industrial

exposure environments and their associated exposure levels

are reviewed by the National Institute for Occupational

Safety and Health (1973)  and are alluded to as they relate

to potential adverse health effects and pharmacokinetics

in the relevant sections of this document.  Similarly,  injurious

effects seen in individuals who abuse toluene are discussed

in the document.   Inhalant abusers are unique in that they

repeatedly subject themselves to extremely high vapor levels

of toluene and other volatile hydrocarbons in order to become



     Dermal exposures of significance are  primarily restric-

ted to occupational or,home use settings;


     The pharmacokinetics  of  toluene  has been extensively
studied in both human  and  animal  subjects.   The majority
of these studies have  involved  inhalation exposure to the
chemical.  Astrand,  et al.   (1972),   subjected volunteers
to 100 ppm and 200 ppm of  toluene vapor  and detected toluene
in their arterial blood within  ten seconds after -initiation
of the exposure. The toluene  concentrations in the blood
increased rapidly during the  first few minutes of 30- and
60-minute toluene inhalation  sessions, then rose more slowly
during the remainder of each  session.  The average arterial
blood toluene  levels appeared to  approach equilibrium between
20 and 30 minutes of exposure time.   During this relatively
stable phase the blood levels were about 1 pg/ml in persons
inhaling 100 ppm toluene and  2  jug/ml  in  persons inhaling
200 ppm toluene while at rest.  The current threshold limit value
 (TLV) for occupational exposure in the U.S. is 100 ppm.
Systemic uptake of  toluene was  doubled by exercise.  Astrand
and her co-workers  (1972)  attributed  this increase in uptake
primarily to increased pulmonary  ventilation.  Carlsson
and Lindqvist  (1977)  similarly  observed  that systemic uptake
of toluene increased when  subjects exercised while inhaling
100 ppm of the chemical.   Furthermore, these investigators
noted that fat subjects retained  more  toluene than did their
thinner counterparts.   Average  uptake  of toluene vapors
by exercising  subjects was approximately 37 percent for
thin subjects  versus 49 percent for obese subjects.

     Relatively little attention has been devoted  to delinea-

tion of the pharmacokinetics of ingested or  topically applied

toluene.  Apparently there are no reports involving  oral

administration of toluene to humans.  Pyykko, et al.  (1977)

recently published the results of a study in which the uptake

of similar quantities of toluene in rats was compared upon

oral versus inhalation exposure.  As would be * anticipated,

the compound was absorbed more rapidly from the lungs  than

from the gastrointestinal tract.  Peak toluene levels  in

most tissues of the rat were observed 15 to 30 minutes  follow-

ing a 10-minute inhalation session, but were not seen  until

2 to 3 hours after gastric intubation.  It should be  noted

that the oral dose of 0.1 ml toluene was given to fasted

animals in 1.9 ml peanut oil.  This volume of oil may have

delayed toluene absorption.  Although peak blood and  tissue

toluene concentrations were substantially higher in the

rats that inhaled the chemical, these levels diminished

rapidly after exposure and after two to three hours were

comparable to the peak levels seen in the orally dosed animals.

Toluene can be absorbed through the skin, though to a consider-

ably lesser degree than through the lung or the gut.   Wahlberg

(1976)  found that 2.0 ml of toluene applied under an impervious

cover on the shaved backs of guinea pigs merely depressed

body weight gain,  while intraperitoneal injection of the

same volume of chemical killed each test subject.   Dutkiewicz

and Tyras (1968)  reported the rate of percutaneous toluene

absorption in man to be 14 to 23 mg/cm /hour.


     Toluene is rapidly  taken up  from  the  bloodstream  into

the various body tissues according  to  their  lipid content.

The arterial blood of human  subjects inhaling  100 or 200

ppm of toluene was found to  contain significantly more of

the solvent than venous  blood,  indicating  ready  tissue uptake

(Astrand, et al. 1972).  Tissue uptake of  organic solvents

is known to be dependent primarily  upon  the  particular tissue's

blood perfusion and  fat  content  (Astrand,  et al. 1975).

Partition coefficients  (tissue:   blood)  for  toluene have

been determined on the basis of a rabbit tissue  experiment

(Sato, et al. 1974).  The  partition coefficient  for adipose

tissue was 50 times  greater  than  for other tissues.  The

partition coefficient  for  bone marrow  was  approximately

15 times greater, while  that for  brain and liver was roughly

twice the values for lung, kidney,  heart,  and  muscle.  Because

the brain is well perfused with blood  and  contains consider-

able lipid, it should  rapidly and preferentially accumulate

toluene upon inhalation  exposure.   Indeed, men exposed to

high concentrations  of toluene vapor experience  central

nervous system  (CNS) depression within minutes (Longley,

et al. 1967).  As will be  related in a subsequent section,

subtle CNS effects appear  to be one of the most  sensitive

indices of toluene inhalation.

     Ingested toluene  is likely to  be  handled  quite differ-

ently, in that the compound  is absorbed  more slowly and

must first pass through  the  liver before reaching the  nervous

system.  As will be  discussed subsequently,  toluene is exten-

sively and rapidly metabolized by the  liver.   Thus, a  dose


of toluene which  is sufficient  to  cause minimal  CNS  effects

when  inhaled will most likely have no  such  effect  when  ingest-

ed because insufficient quantities will reach  the  nervous

system.  Unfortunately, there have not been any  studies

to determine the  lowest oral dose of toluene which will

inhibit CNS function, nor are there data contrasting CNS

levels of toluene immediately after oral and inhalation

exposure.  Pyykko, et al. (1977), did measure  tissue levels

over a period of 15 minutes to  24 hours after  oral and inhala-

tion administration of comparable doses.  Higher tissue

levels were present sooner in the animals that had inhaled

the solvent.  Several hours after the initial  exposures,

similar toluene levels were seen in both oral  and  inhalation

test subjects' tissues.  The adipose tissue was the slowest

to attain its maximal toluene concentration, although it

accumulated much more of the compound than any other tissue.

Body fat provides an extensive  reservoir for uptake of hydro-

carbon solvents.  This is illustrated by the observation

by Bruckner and Peterson (1976)  that saturation of the liver

and brain of mice is not reached after three hours of inhala-

tion of concentrations as high as 4,000 ppm toluene.


     Toluene is believed to be converted by the mixed func-

tion oxidase (MFO) system to benzyl alcohol, which is subse-

quently oxidized to benzaldehyde and benzoic acid and conju-

gated with glycine to form hippuric acid.   Ikeda and Ohtsuji

(1971) demonstrated that pretreatment with phenobarbital,

a classic inducer of MFO activity,  resulted in a pronounced

increase in urinary excretion of hippuric  acid by rats given


an intraperitoneal injection of 1.18 g/kg toluene.  Blood

levels of toluene were depressed and the benzoic acid concen-

tration in the blood increased in the  induced animals.

Ikeda and Ohtsuji  (1971) demonstrated  that the rates of

p-nitrobenzyl alcoholic oxidation and  glycine conjugation

were not affected by the phenobarbital pretreatment.  The

metabolism of p-nitrotoluene  (an analogue of toluene) to

p-nitrobenzoic acid was markedly enhanced ir\ vitro  in liver

microsomes isolated from these animals.  As might be expected,

the duration of toluene-induced sleeping time was signifi-

cantly shorter in the induced animals.  Koga and Ohmiya

(1978) have shown that inhibition of MFC activity by SKF

525-A or carbon tetrachloride will prolong toluene-induced

narcosis and enhance toluene-induced mortality in rats.

These investigators also found pyrazole to have a similar

effect, which indicates the importance of alcoholic oxidation

in the metabolism of toluene.  The peroxidase/catalase system

may also play.a role in the metabolic  pathway of some animals,

in light of its recognized importance  in metabolism of ethanol

in certain species.

     Toluene is rapidly and extensively metabolized to hip-

pur ic acid in experimental animals.  Smith, et al.  (1954)

found that in rabbits given 350 mg/kg  toluene orally, about

18 percent of the dose was eliminated  in the expired air

as the parent compound within 12 hours.  Less than one percent

more was exhaled over an additional 24-hour period.  No

glucuronide or sulfate metabolites were detected in the

urine of these animals.  Work in the same laboratory with

rabbits given a single oral dose of 275 mg/kg toluene re-

 vealed  that  about  74  percent  of  the  total dose could be
 accounted  for  as urinary  hippuric  acid  within 24  hours of
 dosing  (El Masry,  et  al.  1956) .  Thus,  the majority of toluene
 is  rapidly eliminated by  the  rabbit  as  the unmetabolized
 compound in  expired air and as the glycine conjugate of
 benzoic acid in urine.  Very  little  toluene metabolite is
 excreted into  the  bile of  the rat  (Abou-El-Makarem,  et al.
 1967).  Bray,  et al.  (1951)  suggested  that if toluene expo-
 sure  were  so high  that the glycine conjugation mechanism
 was overwhelmed, glucuronide conjugation  might then  occur.
 Bray  and his colleagues did demonstrate glucuronide  conju-
 gates in the urine of rabbits given  large  doses of benzoic
 acid.  It  seems likely that should the normal  metabolic
 pathway be blocked, more of the unmetabolized  compound would
 simply be  eliminated  via exhalation.  Bakke and Scheline
 (1970) administered 100 mg/kg toluene orally to rats and
 found that 0.5 to 1.1 percent of the total  dose was  converted
 to p- and o-cresol, with the former predominating.   These
metabolites were excreted in the urine as  glucuronide  and
apparent sulfate conjugates.  Small amounts of benzyl  alcohol
were also detected in the rat urine.
     Toluene appears to be metabolized and eliminated by
humans in much the same manner as  it is in animals.  Ogata,
et al. (1970) subjected humans to  200 ppm  toluene vapors
for up to seven hours.  It was found that 68 percent of
the estimated amount of solvent absorbed systemically was
recovered as urinary hippuric acid.  This metabolite appeared
in the urine soon after  initiation of the exposure, an indi-
cation of rapid metabolism of toluene to this  principal


metabolite.  Nomiyama and Nomiyama  (1974) similarly observed

a rapid increase  in urinary excretion of hippuric  acid  in

men and women inhaling 107 ppm  toluene.  Urinary hippuric

acid excretion reached its maximum  the second hour during

four-hour exposures, and decreased  rapidly upon cessation

of the exposures.  Furthermore, Nomiyama and Nomiyama  (1974)

found an average  of 18 percent  of the total amount of toluene

absorbed systemically by the  subjects was eliminated in

expired air.  Urinary metabolites other than hippuric acid

have not been reported in the literature.  Thus, it would

appear that man metabolizes toluene much the same  as other

species, in both  a qualitative  and  quantitative sense.


     Toluene is rapidly excreted from the body. Most of

a dose of toluene can be accounted  for within the  first

12 hours as the parent compound in  expired air and as hippur-

ic acid in the urine.  Upon termination of inhalation ses-

sions, toluene levels in the  alveolar air and blood of human

subjects drop rapidly  (Astrand, et  al. 1972; Nomiyama and

Nomiyama, 1974; Sato, et al.  1974;  Carlsson and Lindqvist,

1977) .  Sato, et  al.  (1974) ,  while  analyzing toluene desatura-

tion data in humans, concluded  that the initial rapid phase

of elimination was governed primarily by the rate  of alveolar

ventilation, the  rate of toluene metabolic clearance, and

toluene's blood:  air partition  coefficient.  A slower elimina-

tion rate for females than males was observed.  This was

attributed to the larger proportion of fatty tissue in females,

In view of the greater uptake of toluene seen in fat subjects,

Carlsson and Lindqvist (1977) noted that on prolonged toluene

exposure,  the  fat  individual  will  accumulate more of the

compound and will  eliminate  it more  slowly,  thereby subject-

ing his tissues  to higher concentrations  for longer periods.

     Studies involving elimination of  toluene in  animals

reveal a pattern of  toluene elimination similar  to that

seen in man.   It is  possible  in animal studies  to monitor

levels of  the  chemical in various  bodily  tissues  which  cannot

be measured in man.  Desaturation  occurs  more slowly in

adipose tissue than  in any other tissue of the  rat (Pyykko,

et al. 1977; Carlsson and Lindqvist, 1977).   Interestingly,

elimination of toluene from the bone marrow  is  also relative-

ly slow, apparently  the result of  the  lipoidal  nature of the

marrow.  Toluene is  lost quite rapidly from  the brain,  as

is reflected physiologically  by rapid  recovery  from CNS

depression  (Peterson and Bruckner, 1976;  Savolainen, 1978).

Peterson and Bruckner (1976), while setting  up an  animal

model of human self-intoxication with  toluene,  found it

necessary  to reexpose mice and rats to concentrated  toluene

vapors at  intervals of 10 to  20 minutes in order  to  maintain

an intoxicated state in the animals.

     Measurement of hippuric  acid  excretion  in the  urine

has been advocated as an index of  the  severity of  occupa-

tional toluene exposure.   Ogata,  et al. (1970), while evalu-

ating human subjects exposed  to vapor  levels of 200  ppm,

stated that the quantity of hippuric acid excreted  in the

urine was proportional to total toluene exposure  (i.e. expo-

sure time X vapor concentration).   Other groups of  investi-

gators, however,  have observed wide interpersonal variation

in hippuric acid excretion,  even  among control subjects
not exposed to toluenej (Ikeda and Ohtsuji, 1969; Engstrom,


et al. 1976).  Friborska  (1973) found marked variations

in the same individuals from day to day.  Diet  is undoubtedly

a major source of this variation because many foods contain

hippuric acid precursors  such as benzaldehyde and benzoic

acid.  Analysis of hippuric acid levels in urine is probably

of more value as a qualitative  index of high-level toluene

exposure than as a precise quantitative index,  particularly

at low exposure levels  (Engstrom, et al. 1976).


Acute, Sub-acute, and Chronic Toxicity

     The primary hazard associated with acute exposure to

high levels of toluene  is excessive CNS depression.  The

eight-hour LC5Q in mice was 5,300 ppm  (Svirbely, et al.

1943).  In contrast, the  eight-hour LCcg for benzene was

10,400 ppm.  Kojima and Kobayashi  (1973) found  20,000 ppm

toluene to be lethal to rats after 30 to 50 minutes.  Death

was attributed to CNS depression.  Average concentrations

of toluene in the tissues of the animals that succumbed

were as follows: blood -  330 }ig/g; liver - 700 ;ug/g; brain

- 890 ;ig/g.  Wolf, et al.  (1956) calculated the oral LD5Q

for young adult rats to be 7 g/kg. Kimura, et al.  (1971)

published a similar oral  LD5Q of 6.4 ml/kg for  young adult

rats.  These latter investigators found newborn and 14-day-

old rats to be much more  susceptible to toluene poisoning

than adults. The LD5Q,swere 1 ml/kg for the newborns and

3 ml/kg for the 14-day-old animals.  Kimura, et al. (1971)

stated that the lowest dose at  which gross signs of poisoning

characterized by CNS depression were seen in the young adult

rats was 2 ml/kg.  They divided this dose level by a safety


factor of 1,000  to derive a value of  2  ul/kg, which  they

felt was a reasonable maximum permissible  solvent  residue

limit for single, oral exposures.

     A number of episodes of acute overexposure  to toluene

vapor have been  reported in the medical literature.  Lurie

(1949) and Reisin, et al. (1975) published accounts  of work-

ers who were rendered unconscious by  fumes of the chemical.

Longley, et al.  (1967) related the details of two episodes

in which a number of men were quickly affected upon  inhala-

tion of an estimated 10,000 to 30,000 ppm toluene.   Effects

ranged from exhilaration and light-headedness to dizziness

and unconsciousness.  Recovery was quite rapid, as would

be predicted, since the compound is so rapidly mobilized

from the brain (Savolainen,  1978)  and eliminated from the

body.  Little clinical evidence of tissue injury was seen

in these patients.  Nomiyama and Nomiyama  (1978)  have re-

cently reported several fatal cases involving purposeful

self-intoxication with toluene.  In one instance four persons

were apparently narcotized while sniffing pure toluene in

a car.  Toluene is probably the most popular of a variety

of volatile hydrocarbons that are inhaled intentionally

for their euphoric,  or intoxicating effects (Press and Done,

1967; Natl.   Inst. Drug Abuse,  1977).   Toluene "sniffing"

is a rather unique situation in that the participant repeatedly

inhales high vapor concentrations in order to maintain a

desired state of altered consciousness.   This practice may

be continued for years,  and  thus affords toxicologists an

opportunity to observe consequences of both acute and chronic

high-level toluene exposure.   The situation is often compli-


is often complicated by the participant's  use  of  commercial
products which consist of complex mixtures of  chemicals.
In such cases it  is difficult  to attribute toxicity  to  any
single component.
     With the increase in popularity  of  "glue  sniffing,"
a situation known as "sudden sniffing death" has  been brought
to the attention  of the medical community.  Bass  (1970)
published an account of the sudden, unexpected deaths of
110 solvent abusers.  Toluene  was implicated in a number
of these cases.   The deaths did not appear to  be  due to
suffocation or CNS depression, but rather  to sudden  cardiovas-
cular collapse at light plane  anesthesia levels.   Bass  specu-
lated that cardiac arrhythmias may have  resulted  from a
combined action of solvent, stress or physical activity,
and hypoxia.  Winek, et al.  (1968) also  published an account
of such a fatality involving toluene. Chenoweth  (1946)
was apparently the first to demonstrate  in the laboratory
that toluene and  a variety of  other volatile hydrocarbons
could sensitize the heart to catecholamines.   By  injecting
epinephrine intravenously he was able to induce cardiac
arrhythmias in dogs inhaling various  hydrocarbon  solvents.
Taylor and Harris  (1970) reported a slowed sinoatrial rate,
prolonged P-R interval, and sensitization  to asphyxia-induced
atrioventricular  block in mice subjected to either toluene
or toluene-based  airplane glue fumes. On  the  basis  of  these
findings, it was  suggested that the "sudden death" syndrome
in humans may be  attributed to any one or  combination of
the following: sinus bradycardia; atrioventricular block;
ventricular fibrillation/failure.  Taylor  and  Harris (1970)

pointed out  that not only will  the  stress  and  asphyxia  often

associated with solvent abuse contribute to cardiac arrhyth-

mias, but that hydrocarbons may have direct toxic  effects

on the heart.  Electrocardiogram analysis  of rats  inhaling

toluene has  been reported to reveal adverse effects such

as disorders of repolarization and arrhythmias  (Bereznyi,

et al. 1975; Morvai, et al. 1976).  The latter group of

investigators found the effects of benzene to be much more

intense.  It should be emphasized here that all of the  afore-

mentioned cardiotoxic effects have been seen in humans  and

laboratory animals subjected to very high  vapor concentra-

tions of toluene.  It would appear unlikely that low-level

inhalation or oral toluene exposure would  be detrimental

to the cardiovascular system.  Ogata, et al. (1970) did

report an apparent decrease in pulse rate  in human volunteers

inhaling 200 ppm toluene, but no significant alteration

of blood pressure.  No significant effect on heart rate

was observed in other persons inhaling 100 to 700 ppm toluene

(Astrand,  et al.  1972;  Gamberale and Hultengren, 1972).

     Inhalation of relatively low concentrations of toluene

may be somewhat irritating to mucus membranes and produce

a decrement in psychophysiological functions.   Several stud-

ies involving inhalation exposure of human subjects have

been conducted to determine the lowest vapor level which

will produce subjective complaints and objective evidence

of CNS depression.   Results of these studies form the basis

for the current threshold limit value (TLV) of  100 ppm for

occupational toluene exposure.  Subjective complaints such

as fatigue,  dizziness,  headache, weakness,  and  throat and


eye irritation were made by subjects breathing  toluene concen-

trations of 200 ppm.  More objective measurements of CNS

effects by Ogata, et al.  (1970) and by Gamberale and Hultengren

(1972) also suggest that the  "minimum effect  (vapor) level"

is about 200 ppm.  Ogata and  his co-workers  (1970)  found

a prolongation of eye-to-hand reaction time  in  persons inhal-

ing 200 ppm toluene, but no effect on flicker fusion.  Gamberale

and Hultengren  (1972) noted that inhalation of  300  ppm for

20 minutes by their subjects  increased reaction time, while

700 ppm of the compound was required to diminish perceptual

speed.  Inhalation of 100 ppm toluene for  20 minutes had

no apparent effect on either  index. These  investigators

emphasize, however, that lower  vapor levels may be  inhibitory

on psychophysiological functions after longer periods of

exposure.  They also point out  that substantial differences

were observed in toluene uptake among individual test sub-

jects, suggesting that CNS effects may also vary from person

to person.  Astrand, et al.  (1972) demonstrated that exercise

can double respiratory uptake of toluene.  They advocated

reconsideration of the current  TLV value,  since the preceed-

ing studies of impairment of  performance have involved evalu-

ation of resting subjects.

     Toluene, upon acute exposure, appears to have  only

a limited toxicity potential, other than its capacity to

inhibit CNS function and predispose to cardiac  arrhythmias.

Even exposures to quantities  of toluene sufficient  to produce

unconsciousness fail to produce residual organ  damage in

human victims (Longley, et al.  1967; Reisen, et al. 1975).

Evaluations of experimental animals subjected to large doses


of toluene also  indicate that  the chemical  is  relatively

non-toxic.  Svirbely, et al.  (1943) could find no conspicuous

pathologic changes in organs of mice exposed to  high vapor

concentrations of toluene.  Bruckner and Peterson  (1976)

detected only slight, transient rises in serum glutamic-

oxaloacetic transaminase activity in mice that inhaled  4,000

ppm toluene for  three hours.  Divincenzo and Krasavage  (1974)

administered 150, 300, 600, and 1,200 mg/kg toluene to  guinea

pigs by intraperitoneal injection.  Twenty-four  hours later

they measured serum ornithine-carbamyl transferase  (OCT)

activity and examined the livers for morphologic change.

There was no alteration in OCT activity at any dose level.

Only at the highest dosage was there histological evidence

of lipid accumulation.  Reynolds and Yee (1968)  included

toluene in a hepatotoxicity study because of its similarity

to hepatotoxic aliphatic halocarbon in lipophilic solvent

properties.  In contrast to other chemicals tested, adminis-

tration of a 2.4 g/kg oral dose of toluene to rats had no

effect after 1, 8, or 24 hours on hepatic glucose-6-phosphatase

activity, calcium influx into hepatocytes,  or liver morphology.

In a subsequent investigation, Reynolds (1972)  saw no effect

on a wide battery of hepatotoxicity parameters two hours

after giving 2.4 g/kg of the chemical to rats.   These find-

ings suggest that any lipophilic solvation action on hepato-

cyte membranes by toluene is of little toxicologic conse-

quence.  Holmberg and Malmfors (1974)  provided additional

evidence of the non-toxic nature of toluene by demonstrating

in vitro that concentrations as high as 100 jug/ml had no

cytotoxic effect on suspensions of ascites  tumor  cells.

     Toluene appears to have more toxicity potential on

subacute exposure than it does acutely.  In an effort to

assess the capacity of toluene to elicit injury under condi-

tions approximating human solvent abuse, Bruckner and Peterson

(1978) subjected mice and rats five times weekly, for eight

weeks, to three-hour cycles of alternating fresh air and 12,000

ppm of toluene vapor. The concentration of toluene employed

in this exposure regimen was not lethal, but did produce

inebriation. A battery of standard toxicologic and histopatho-

logic tests failed to reveal evidence of injury to the lung,

liver, or kidney during the eight-week exposure period.

Jenkins, et al.   (1970) found that neither continuous expo-

sure  to 107 ppm toluene for 90 days, nor intermittent  (eight

hours/day, five days/week) exposure to 1,085 ppm for six

weeks affected body weight gain, hematologic parameters,

nor the morphology of a number of organs of the rat, guinea

pig,  dog, or monkey.  Similarly, Carpenter, et al.  (1976)

saw no significant alteration of any of a variety of indices

of toxicity in rats and dogs exposed via inhalation to 988

ppm of toluene concentrate for 13 weeks.  Toluene concentrate

consists of approximately 50 percent toluene, 15 percent

other alkyl benzenes, 14 percent heptane, 10 percent cyclohex-

ane,  and lesser amounts of other hydrocarbons.  Rhudy, et

al.  (1978) recently reported the results of a 90-day pilot

study for a chronic toxicity study of toluene supported

by the Chemical Industry Institute of Toxicology.  Male

and female rats were exposed by inhalation to 30, 100, 300,

or 1,000 ppm of 99.98 percent pure toluene six hours/day,


five days/week for 13 weeks.  There was no significant altera-

tion at any exposure level of a battery of test results

including clinical chemistry, hematology, urinalysis, and

histopathology.  Animal appearance and behavior observations,

food consumption, and mortality were not affected, although

a slight reduction in body weight gain was exhibited by

the high-dose males.  Tahti, et al.  (1977) exposed rats

to 1,000 ppm toluene vapor eight hours daily for one week.

Minimal increases in serum glutamic-pyruvic transaminase

and glutamic-oxaloacetic transaminase activities, as well

as apparent metabolic acidosis, were observed.  This latter

observation is of interest, in that Taher, et al. (1974)

described two cases of metabolic acidosis in humans who

had inhaled toluene for its intoxicating effects.  The condi-

tion was termed renal tubular acidosis, because it was believ-

ed to be due to reversible alteration of the ability of

the distal renal tubule to acidify the urine.

     Short-term administration of toluene may influence

the metabolic capacity of the liver.  It was reported that

Fabacher and Hodgson (1977) saw no modification of liver/body-

weight ratio, microsomal protein content,  0- and N- demethyla-

tion, nor various spectral characteristics of  cytochrome

P-450 in male mice injected intraperitoneally  for three

consecutive days with 100 mg/kg toluene.   Other methylated

benzenes and a methylated napthalene increased liver weight

and microsomal enzyme activity in the mice,  leading  the
authors to speculate that such compounds were  effective
inducers because of their lipophilicity and  persistence
in the body-  Apparently toluene was ineffective because
it was too readily metabolized and excreted.   Ungvary, et
al. (1976) attempted to design a protocol that would eliminate
the problem of toluene's rapid turnover rate.  They  dosed
rats daily by intraperitoneal  (i.p.) or subcutaneous (s.c.)
injection of 0.12 to 1.0 ml/kg analytical grade toluene
for 12 days to 4 weeks.  Dose-dependent increases were seen
in the number and total area of mitochondria per unit cyto-
plasmic area in the liver.  Similarly, dose-dependent decreas-
es in the average nuclear volume were also observed  in hepato-
cytes of animals receiving i.p. injections.  Subcutaneous
injection was much less effective in inducing  these  ultr-
astructural alterations.  The enhanced mitochondrial promi-
nence is interesting in light of a previous  report from
the same laboratory (Aranka, et al. 1975) of a dose-dependent
increase in succinic dehydrogenase activity  and a decrease
in glycogen content of livers of toluene-treated rats. The
toxicological or biological significance of  these findings
is unclear, although the investigators have  suggested that
the mitochondrial changes are associated with  increased
microsomal xenobiotic metabolism.  There is  evidence that
mitochondria are involved in microsomal mixed  function oxi-
dase reactions, possibly serving to transfer reducing equiva-
lents originating from NADPH of NADH through cytochrome b5
to cytochrome P-450 (Schenkman, et al. 1973)

     Although long-term exposure  to  toluene  is  quite  common

 in industry, there are few reports to  suggest that  it has

 produced deleterious health effects  in workers.  One  adverse

 effect which has been tentatively attributed to  toluene

 is myelotoxicity.  Many of the early studies suggesting

 this involved the use of toluene contaminated with  benzene

 (Natl. Inst. Occup. Safety Health, 1973).  The preponderance

 of clinical/epidemiological investigations of workers  routinely

 exposed to toluene vapors have failed to reveal  any significant

 abnormalities of the circulating blood and/or bone  marrow.

 Estimated toluene exposure levels in these negative studies

 were as follows: < 200-400 ppm, Banfer (1961); 80-160  ppm,

 Capellini and Alessio (1971); 50-800 ppm, Friborska (1973);

 60-100 ppm, Matsushita, et al. (1975).  Forni, et al.  (1971)

 did not find a significant difference in the frequency of

 chromosome aberrations in peripheral blood lymphocytes between

 toluene exposed workers and matched controls.  In contrast,

 stable and unstable chromosome aberrations were significantly

 higher in individuals with benzene exposure.   Greenburg,

 et al.  (1942)  examined 61 painters who were exposed to

 solvent mixtures containing largely toluene.   There was

 a mild macrocytosis,  anemia,  and lymphocytosis in some of

 the workers, but no alteration of differential leukocyte

counts, reticulocytosis,  thrombocytopenia,  or leukopenia.

Female employees exposed  to toluene and other compounds

 through their work with varnishes have recently been reported

to exhibit decreased  erythrocyte and thrombocyte indices

 (Syrovadko, 1977).  It should be recognized here that interpre-

 tation of accounts of toxicity in occupational settings


is often complicated by uncertain exposure levels, variable

exposure patterns, exposure to multiple chemicals, and/or

unrecognized predisposing factors.

     Toluene exposures in occupational settings commonly

involve relatively low-level inhalation and dermal exposure.

Intentional toluene inhalation is quite a different situation

in which the participant inhales sufficient quantities to

intoxicate himself.  This practice may be continued for

years.  Despite such extreme exposure conditions and partici-

pation by large numbers of people throughout the world,

hematological abnormalities in toluene abusers are uncommon.

Massengale, et al.  (1963) found no irregularities in the

blood of 27 adolescents who sniffed toluene-based glues.

The only hematologic abnormality in 16 other glue sniffers

examined by Press and Done  (1967) was eosinophilia in 4

of the 16.  A number of persons who developed polyneuropath-

ies upon abusing glues containing large amounts of toluene

and r-hexane, exhibited no evidence of hematotoxicity  (Suzuki,

et al. 1974; Goto, et al. 1974; Shirabe, et al. 1974; Korobkin,

et al. 1975; Towfighi, et al. 1976).  Powars (1965) did,

however, treat six cases of aplastic anemia.  Each of the

victims was a Negro with preexisting sickle-cell disease

who had abused a toluene-based glue.

     Results of evaluations of the myelotoxic potential

of toluene in laboratory animals have generally indicated

that the chemical is non-toxic.  Wolf, et al.  (1956) have

apparently conducted the only long-term toxicity study in

which toluene was given orally.  Female rats received 118,

354, or 590 mg/kg toluene f:|ve times weekly for six months.

Cell counts of bone marrow and circulating blood  revealed

no adverse effects.  Takeuchi  (1969) saw no alterations

in peripheral blood counts in rats exposed eight  hours/day

by inhalation to 200, 1,000, and 2,000 ppm of 99.9 percent

pure toluene for 32 weeks.  Rhudy, et al.  (1978)  failed

to detect any hematologic abnormalities in male and female

rats subjected six hours/day, five days/week for  13 weeks

to 30, 100, 300, or 1,000 ppm of 99.98 percent pure toluene.

This investigation served as a pilot for an ongoing two-

year inhalation exposure study (Gibson, 1979). The primary

difference in experimental design between the two studies

has been a change in the strain of rat and the deletion

of the 1,000 ppm exposure level.   Findings after 18 months

of the chronic study do not indicate an adverse effect at

any vapor level on the circulating blood or bone marrow

of the male or female rats (Gibson, 1979). In a study of

toluene-benzene interaction in mice, Andrews, et al.  (1977)

noted that toluene had no effect on incorporation of   Fe

into developing erythrocytes. Toluene actually protected

against inhibition of this process by benzene.   Yushkevich

and Malysheva (1975)  saw no alteration in erythroblast matura-

tion in the bone marrow of rats subjected four hours daily

for four months to a topical application of 10 g/kg toluene.

This rather unusual dosage regimen was said to impair leukopo-

iesis, as evidenced by an increase in the number of plasmic

and lymphoid reticular cells in the marrow.  Topical applica-

tion of 1 g/kg daily was without  adverse effect in this

regard.  Horiguchi, et al. (1976)  however, observed leukocyto-

sis within ten days in mice that  inhaled 1, 10,  100, or 1,000


ppm toluene six hours/day.  Decreases  in circulating erythro-

cytes were seen in the 100 and 1,000 ppm mice, while throm-

bocytopenia was said to occur in  the 10, 100, and  1,000 ppm

mice. A slight hypoplastic change was  noted  in the bone

marrow of the group subjected to  1,000 ppm toluene.  Dobrokhotov

and Enikeev (1977) also observed  leukocytosis accompanied

by chromosome damage in the bone marrow of rats subjected

four hours daily  for four months  to 112 ppm  of toluene vapor.

Benzene also elicited chromosome  damage, which was additive

to that of toluene when the two chemicals were administered

together.  One month after termination of the exposure,

the leukocytosis  had resolved, but the chromosome  abnormal-

ities persisted.  The "positive"  findings published by

Yushkevich and Malysheva  (1975), Horiguchi,  et al.  (1976),

and Dobrokhotov and Enikeev  (1977) should be interpreted

with caution, in  light of the substantial number of studies

of humans and animals in which no evidence of toluene-induced

myelotoxicity has been seen.  It  is often difficult to fully

appreciate experimental conditions and protocols,  to inter-

pret data, and to judge the validity/significance  of findings

in translations of reports in foreign  languages.   For example,

the purity of the toluene used in each of the three aforemen-

tioned studies is not stated.  However, the  findings of

these.- investigators should not be entirely dismissed.  They

may prove to be subtle, heretofore unrecognized hematopoietic

responses to toluene.

     Several reports have appeared in  the literature which

link long-term solvent exposure to altered immunocompetence.

Lange, and coworkers (1973a) investigated serum complement

                              C-28  I

levels, serum  inununoglobulin levels, and  leukocyte  agglutinins

in persons exposed occupationally to benzene, xylene,  and

toluene.  IgG  and IgA  (Lange, et al. 1973a) and  complement

(Smolik, et al. 1973)  levels were lower in these persons

than in controls.  Ten of 35 solvent-exposed workers had

leukocyte agglutinins  (Lange, et al. 1973b) .  Nevertheless,

it was not possible to attribute these effects to any  single

solvent.  Capurro (1976) described in a recent letter  to

Lancet his observation of changes in gamma globulin fractions

and increased prevalence of colds and susceptibility to

streptococcal  infections in persons who worked at or lived

near chemical plants which utilized large quantities of

solvents. Bernshtein (1972)  did report an inhibitory effect

on phagocytic activity of leukocytes taken from  rats exposed

via inhalation to 185 ppm toluene four hours daily for six

months.  In contrast, Priborska (1973)  noted increases in

alkaline phosphatase, acid phosphatase, and lactic dehydrogenase

activity in leukocytes and/or lymphocytes of workers exposed

to toluene.   The authors associated these alterations with

increased functional capacity of the cells.

     Solvent exposure has also been tentatively  linked with

induction of autoimmune disease.  A substantial number of

patients diagnosed as having glomerulonephritis were found

to have had a history of intensive,  long-term solvent expo-

sure (Beirne and Brennan, 1972;  Zimmerman, et al. 1975).

These investigators noted that individual host susceptibility

was likely to be an important factor here, since so many

persons are routinely exposed to solvents without developing

the disease.  As was the case for the alterations  seen  by

Lange and associates, no individual component  of the  complex

solvent mixtures utilized by the glomerulonephritis patients

could be singled out as the potential toxicant.

     Long-term exposure of toluene appears  to  have little

capacity to injure the liver and most other organs.   The

only report suggesting an adverse effect of toluene on  the

liver in an occupational setting was in an  early paper  by

Greenburg, et al.  (1942).  They observed an increased inci-

dence of hepatomegaly in painters exposed from two weeks

to five years to solvent mixtures in which  toluene was  the

major component.  Analyses of air samples taken from  the

work environment revealed exposure levels ranging  from  100

to 1,100 ppm toluene.  Capellini and Alessio (1971) saw

no changes in liver function in 17 workers  exposed for  sev-

eral years to approximately 125 ppm toluene.   There has

also been a surprisingly low incidence of hepatorenal injury

in persons who purposefully inebriate themselves with toluene.

Litt, et al.  (1972), for example, found modest elevations

of serum glutamic-pyruvic transaminase levels  in only two

percent and elevated alkaline phosphatase levels in five

percent of a group of 982 glue sniffers.  Massengale, et

al.  (1963) and Barman, et al.  (1964) failed to detect hepato-

renal injury in groups of abusers of toluene-based glues.

Press and Done  (1967) saw slight but transient abnormalities

in urinalyses of a small percentage of the  glue sniffers

they examined. No evidence of liver injury  was detected.

These investigators concluded that should any  adverse effects

occur, they are transient and followi very closely  upon  inten-

                              C-30  1

sive solvent exposure.  This  supposition is supported by

a study by Bruckner and Peterson  (1976), who demonstrated

that intensive  inhalation  exposure  of  mice  to toluene is

followed by small, reversible increases  in  serum levels

of certain cytoplasmic enzymes.   Signs of liver  (Weisenberger,

1977) and kidney  (Kelly, 1975)  injury  in toluene abusers

being treated for behavioral  problems, cleared spontaneously

during hospitalization.

     Clinical findings from evaluations  of  solvent  abusers

should be interpreted with caution  when  considering the

toxicity of specific chemicals  such as toluene.   Patterns

and frequency of exposure may differ markedly among individ-

uals.  The commercial products  favored by many abusers  are

usually complex mixtures of different  compounds.  The formula

for any given product often varies  from  one  manufacturer

to another and can be changed at  any time.   The  abuser  may

use a variety of solvent-containing products,  often in  combin-

ation with alcohol and other  drugs.  Thus,  the stage  is

set for chemical or drug interactions which  may  protect

the participant or place him  at risk.  O'Brien,  et  al.  (1971),

for example, reported a case  of serious  hepatorenal  injury

in an adolescent who drank beer and inhaled  a  cleaner contain-

ing 80 percent toluene.  A number of serious  cases  of polyneu-

ropathy were seen in persons  who  abused  products comprised

largely of toluene and n-hexane.  Signs  of hepatorenal  injury

and hematotoxicity, however,  were notably absent  (Shirabe,

et al.  1974; Suzuki,  et al. 1974; Korobkin,  et al.  1975;

Towfighi,  et al. 1976).  An individual who claimed  to have

restricted his sniffing to pure toluene exhibited hepatomeg-
aly and impaired liver function when hospitalized for a
psychiatric disorder  (Grabski, 1961).  This same patient
was seen at a later time when he developed severe hepatorenal-
toxicity from sniffing carbon tetrachloride vapors  (Knox
and Nelson, 1966).
     Long-term animal studies have generally revealed little
evidence of any residual toxic effect of toluene.  Two investi-
gations which deserve special attention at present are a
six-month oral dosing study by Wolf and his co-workers (1956)
and an ongoing two-year project (Gibson, 1979).  Wolf, et
al. (1956) gave female rats 118, 354, and 590 mg/kg of toluene
in olive oil by stomach tube five times weekly for 193 days.
No adverse effects on growth, mortality, appearance and
behavior, organ/body weights, blood-urea nitrogen levels,
bone marrow counts, peripheral blood counts, or morphology
of major organs were noted.  Thus, on the basis of these
findings, it would be concluded that the minimum toxic oral
dose of toluene must be greater than 590 mg/kg/day.  After
18 months of the ongoing two-year inhalation study, no signi-
ficant effects attributable to toluene have been seen in
male or female rats subjected six hours/day, five days/week
to 30, 100, or 300 ppm of 99.98 percent pure toluene  (Gibson,
1979).  Parameters being evaluated include food consumption,
body-weight gain, mortality, general appearance and behavior,
peripheral blood counts, clinical chemistry indices, urinalyses
indices, organ weights, and histopathology of 42 tissue

specimens and of any tissue mass from each animal.

     Considerably more is known about the acute effects

of toluene on the central nervous system  (CNS) than potential

adverse neurological effects of chronic exposure to the

chemical.  Depressant or inhibitory effects of toluene on

the CNS are usually considered rapidly reversible. Their

duration is dependent upon the rate of desaturation, or

clearance of toluene from the CNS.  Peterson and Bruckner

(1976) found a high degree of correlation between the degree

of performance inhibition and the toluene concentration

in the brain of the mouse.  Several cases of residual CNS

damage have been reported involving individuals who sniffed

toluene or solvent mixtures containing toluene over a period

of years.  One of the earliest reports was by Grabski (1961) .

This clinician examined a 21-year-old male who had inhaled

toluene vapors on a regular basis for two years.   The pa-

tient's CNS signs were said to be consistent with cerebellar

degeneration.  After several more years of toluene abuse,

the same patient was reexamined by Knox and Nelson (1966)

who diagnosed the man as having diffuse encephalopathy and

cerebral atrophy.  Satran and Dodson (1963)  related the

case of a man who exhibited personality changes including

increased irritability and exaggerated swings in  mood over

a ten-year period of toluene abuse.   Although his neurologi-

cal exam was normal, non-specific abnormalities were observed

in his EEC.   Satran and Dodson (1963)  termed the  condition

diffuse encephalopathy.  Another report of cerebellar damage

was recounted by Kelly  (1975).  In this case a teenage

girl with a past record of multiple drug and solvent abuse

was found to have residual cerebellar dysfunction after

1% years of inhaling vapors of a toluene-based paint.  Two

additional cases of cerebral  involvement, each apparently

the result of inhalation of 99 percent pure toluene, have

recently been described by Boor and Hurtig  (1977).  One

of the patients had abused toluene for ten years before

being hospitalized because of ataxia.  No abnormalities

were evident in his EEG, but  a computerized brain scan showed

diffuse cerebral atrophy.  An electromyogram and nerve conduc-

tion studies of all limbs showed no abnormalities of nerve

or muscle.  Although the condition of the patient improved

significantly, the central neurological abnormalities were

still evident upon examination nine months later.  The second

patient was exposed occupationally to toluene.  He had gradu-

ally developed a number of bothersome problems, including

fatigae, clumsiness of his left side, mildly slurred speech,

impairment of sense of hearing and smell, and disturbance

of memory and power of concentration.  He showed daily im-

provement and recovered completely without specific treatment.

Recovery from cerebellar dysfunction, coupled with optic

neuropathy, has also been described in an individual who

inhaled vapors from a toluene-based paint on a daily basis

for tnree years  (Keane, 1978).  On the basis of the aforemen-

tioned accounts, it would appear that prolonged, intensive

inhalation of toluene may result in damage of the central

nervous system, with impairment of pyramidal, cognitive,

and cerebral functions.  The adverse effects are  largely
reversible, particularly when exposure has not been too
extreme.  Cases such as these, however, seem to be a rare
occurrence even among toluene abusers.
     It has been suggested that toluene may influence the
neurotoxic potential of n-hexane  (Suzuki, et al.  1974),
or even damage peripheral nerves  (Goto, et al. 1974), since
a number of persons have developed peripheral neuropathies
upon sniffing mixtures of toluene and n-hexane.   These neuro-
pathies can apparently be either sensory of the "glove and
stocking" type, or >sensorimotor, with or without  amyotrophy
(Shirabe, et al. 1974).  It should be recalled that the
patient of Boor and Hurtig (1977), who experienced cerebral
dysfunction upon intensive inhalation of 99 percent pure
toluene, exhibited no sensory or neuromuscular involvement.
In the majority of reported cases involving hexane-toluene
mixtures the victims had abused products containing large
amounts of toluene but no n-hexane for years without apparent
difficulty (Shirabe, et al. 1974;  Korobkin, et al. 1975;
Towfichi, et al. 1976).  Only a few weeks to months after
switching to products containing n-hexane, they experienced
progressive weakness and numbness of the extremities.   No
report can be located in the literature in which peripheral
neuropathy is attributed to the inhalation of toluene alone.
The possible contribution of toluene to n-hexane"s neurotoxic
potential is discounted by findings of Suzuki,  et al.  (1974).
These investigators administered 910 mg/kg of n-hexane alone,
and in combination with 1.18 g/kg of toluene,  by  intraperito-

neal injection to rats.  The  toluene  had  no  effect  on  the
rate of elimination of n-hexane  from  the  blood,  nor did
n-hexane influence urinary excretion  of toluene's major
metabolite, hippuric acid.  It was  suggested that the  two
compounds do not influence one another because each is metabo-
lized by a different enzyme system.   Apparently, no one
has determined experimentally whether toluene can influence
the time of onset and/or magnitude  of n-hexane-induced neuro-
     In light of the apparent residual CNS effects  in  certain
individuals who subject themselves  to extreme toluene  expo-
sure, it is of interest to consider the likelihood  of  CNS
damage occurring in an occupational setting  where exposure
levels are lower.  Other than the transient  CNS  depressant
effects already discussed, few reports have  implicated tol-
uene in cases of neurological impairment  in  industry.  Matsushita,
et al.  (1975) did report finding abnormal tendon reflexes,
reduced grasping power, and decreased agility of the fingers
of 38 female shoemakers chronically exposed  to solvents
including 60 to 100 ppm toluene.  Toluene exposure  was con-
firmed by the finding of elevated urinary hippuric  acid
excretion in these subjects.  Hanninen, et al.  (1976)  also
observed moderate clumsiness  of  the hands of car painters
exposed for years to solvents.   Thorough  analyses of the
air in the painters' working  environment  revealed the  major
component to be toluene (average level =  30.6 ppm), with
lesser amounts of xylene, methyl isobutyl ketone, isopropanol,
white spirit, and other solvents.  Hanninen,  et  al.  (1976)
also observed impairments in  memory,  ability to  concentrate,

and emotional reactivity in the painters  in contrast  to

age and intelligence-matched controls.  These researchers

emphasize that while the impairments were quite modest,

such effects should not be considered harmless since  they

may reduce one's ability to cope with the various demands

of everyday life.  Lindstrom (1973) conducted a similar

study of 168 workers routinely exposed to hydrocarbon sol-

vents, 51 of whom were said to be exposed primarily to tol-

uene or toluene and xylene.  Visual accuracy, psychomotor

and sensorimotor speed performances of the solvent-exposed

workers were inferior to performances of matched controls.

Axelson, et al. (1976)  recently reported the results of

an epidemiologic study of workers exposed routinely to hydro-

carbon solvents.  These investigators concluded that such

individuals had a higher risk of non-specific neuropsychi-

atric disorders, and that the risk increased with the number

of years of exposure.  Axelson, et al. (1976)  emphasized

that such disturbances, e.g. nervousness, irritability,

insomnia, impairment of memory and reasoning,  are so non-

specific and occur in such variable patterns that they are

often not recognized, nor is their etiology appreciated.

     A very limited number of studies have been conducted

using laboratory animals to assess CNS effects of toluene

other than acute depression.  Takeuchi and Hisanaga (1977)

studied the influence of inhalation of 1,000,  2,000, and

4,000 ppm toluene for four hours on the behavior and EEC

of rats with chronically implanted electrodes.   An increase

in rearing throughout the exposure was seen in rats inhaling

2,000 ppm. Increased rearing during the first hour was seen

in rats inhaling 4,000 ppm. This early -increase  in activity
at the highest exposure level diminished rapidly, so that
the rats became ataxic from hour two until the end of the
exposure session.  In contrast, Peterson and Bruckner (1976)
saw a gradual, but progressive decrement over a  three-hour
period in unconditioned reflexes/performances tested at
15-minute intervals in mice and rats inhaling 4,000 ppm
toluene.  The inhibitory action of toluene was rapidly rever-
sible upon cessation of exposure in each of the  aforemention-
ed studies.
     Takeuchi and Hisanaga  (1977) also described EEC changes
which were associated with disturbances in the sleep cycle
of their toluene-exposed rats.  It was suggested that these
changes might be relevant to the human situation in which
sleep disturbances have been attributed to toluene exposure.
Although the toxicologic/physiologic significance of the
EEC changes in rats is uncertain, Takeuchi and Hisanaga
(1977) speculated that there could be a relationship between
the sleep related changes and abnormal EEC patterns reported
in glue sniffers  (Miyaska, et al. 1971) and persons with
prolonged occupational exposure to organic solvents (Mabuchi,
et al. 1974) .
     Ikeda and Miyake  (1978) conducted an investigation
to determine whether long-term toluene exposure, under condi-
tions approximating those in glue sniffing, could have a
detrimental effect on learning and memory.  Rats were sub-
jected two hours daily to 4,000 ppm of toluene vapor for
60 dc/s.  Several days later spontaneous activity, emotion-
ality , and memory-learning on three different schedules


were evaluated.  No influence of the toluene regimen was

seen on any parameter except one of the memory-learning

tests.  The particular test which was affected was the most

complicated or difficult for the rats to perform, suggesting

that higher cognitive processes may be impaired by toluene

abuse.  Recovery from this impairment had not occurred 80

days after the final toluene exposure.  Microscopic examin-

ation of several areas of the brain of these animals did

not reveal any damage.  Furnas and Hine (1958)  also failed

to defect histopathologic damage of sections of brain, spinal

cord, and sciatic nerve of rats 24 hours after they had

been subjected to 20,000 ppm of toluene vapor for six consecu-

tive 30-minute exposures.  Ishikawa and Schmidt (1973) found

no histopathologic lesions in brains of rats that developed

a tendency to circle in their cages after inhaling high

concentrations of toluene for a week.   This condition, termed

"forced turning," was reversible.  Inoue (1975)  reported

that mice which inhaled 1, 10, 100, and 1,000 ppm toluene

six hours daily showed a decrease in wheel turning activity

within six to ten days.  This finding  seems questionable,

in light of the lack of inhibition of  spontaneous activity,

such as wheel turning, in rats which inhaled 4,000 ppm toluene

two hours daily for 60 days (Ikeda and Miyake,  1978).

Synergism and/or Antagonism

     Toluene, in sufficient amounts, would appear to have

the potential to significantly alter the metabolism and

resulting bioactivity of certain other chemicals.   The time

at which exposure to toluene occurs, relative to exposure

to a second chemical, could be quite  important.   Prolonged
preexposure to toluene may induce, or  stimulate MFO  activity,
thereby enhancing metabolism of  the second  chemical.   Should
concurrent exposure occur, toluene, which  is  readily hydroxy-
lated by the microsomal mixed-function oxidase  (MFO)  system,
would be expected to  inhibit the metabolism of other compounds
which are acted upon  by this same system.   This phenomenon
would be anticipated  to result in a prolonged half-life
of both toluene and the other compound.  Inhibition  of metabo-
lism of a second compound may be beneficial or detrimental
from the standpoint of adverse effects, depending upon the
toxicity of the parent compound  versus its  metabolite(s).
It might also be noted that toluene undergoes alcoholic
oxidation and conjugation reactions subsequent to the initial
hydroxylation reaction.  Therefore, a  substantial dose of
toluene could conceivably interfere with the  metabolism
of compounds which undergo alcoholic oxidation and glycine
     Several animal studies have demonstrated that toluene
can significantly influence the  biological  fate and  bioef-
fects of other agents.  Ikeda  (1974) demonstrated that 430
mg/kg of toluene, given to rats  by intraperitoneal injection
in combination with trichloroethylene, reduced the metabolism
of the trichloroethylene.  Toluene's metabolism was  also
diminished.  Ikeda, et al. (1972) found that  simultaneous
intraperitoneal administration of toluene and benzene to
rats resulted in suppression of  the metabolism of both com-
pounds.  The mutual suppression  was reflected in  diminution
of urinary excretion  of phenol and hippuric acid.  Co-adminis-

tration of toluene and styrene was also shown to decrease

styrene metabolism.  Pretreatment of the rats with phenobarbi-

tal alleviated the suppressant effects of toluene.  Andrews,

et al.  (1977), co-administered 440 or 880 mg/kg benzene

and 1,720 mg/kg toluene intraperitoneally to mice and observ-

ed a marked reduction in urinary excretion of benzene metabo-

lites, coupled with a compensatory increase in pulmonary

excretion of unmetabolized benzene.  It was demonstrated

using liver microsomes in vitro that toluene is a competitive

inhibitor of benzene metabolism.  When toluene and benzene

were given concomitantly by subcutaneous injection, it was

determined that toluene did not significantly reduce the

total amount of benzene appearing in bodily tissues, but

markedly reduced the concentration of benzene metabolites

in various tissues including bone marrow.   Toluene was also

found to protect against the inhibitory effect of benzene

on   Fe incorporation into developing erythrocytes, suggest-

ing that toluene may guard against benzene myelotoxicity

by inhibiting benzene metabolism in bone marrow.

     It has been suggested that toluene may play a role

in induction of peripheral neuropathy seen in some abusers

of n-hexane/toluene mixtures.   However,  as previously discussed,

available evidence indicates that n-hexane is responsible

for the neurotoxicity and is not affected  by toluene.  Suzuki,

et aJ. (1974) showed that n-hexane and toluene given concur-

rently to rats had no apparent effect on one another's metabo-



     Toluene does not appear to be teratogenic in laboratory

animals or in man.  Roche and Hine (1968) concluded that

neither benzene nor toluene was teratogenic to the rat

fetus or the chick embryo.  Parameters evaluated by these

investigators included body weight, bone length, and inci-

dence of gross abnormalities.  Hudak and Ungvary (1978)

also concluded that benzene and toluene, as well as xylene,

were not teratogens in mice and rats.  These researchers

assessed a battery of indices of teratogenicity.  Mice expos-

ed 24 hours/day on days 6 to 13 of pregnancy gave birth

to underweight offsprings.  Some retardation of body weight

and skeletal growth were seen in fetuses of rats exposed

continuously to 399 ppm toluene on days one to eight of

pregnancy.  No effects were noted in a variety of other

indices including the incidence of external and internal

malformations.  Inhalation of 266 ppm toluene for eight

hours each day of days 1 to 21 of pregnancy had no apparent

influence on any index in the rat.  Hudak and Ungvary  (1978)

concluded from quite limited data that toluene exposure

during early pregnancy might retard fetal development and

should therefore be avoided.  It was noted that toluene

should readily pass the placental barrier and reach embryonal

cells.  Syrovadko (1977) recently reported that a group

of women occupationally exposed to toluene and other solvents

through the use of varnishes, exhibited a relatively high

incidence of menstrual disorders.  The newborn children

of these women were said to experience more frequent  fetal

asphyxia, to be more often underweight, and not to nurse

as well as "normal" infants.  Matsushita, et al.  (1975)

found dysmenorrhea to be a frequent complaint of  female

shoemakers exposed chronically to 60 to 100 ppm toluene.

There are no accounts, however, of a teratogenic  effect

in humans being linked to toluene exposure.


     There is no conclusive evidence that toluene is muta-

genic.  In a recent review of the genetic toxicology of

toluene and related compounds, Dean (1978) states that no

data are available on mutagenicity testing of toluene in

bacterial systems.  Dean (1978) notes that since  toluene

is a lipophilic solvent, high concentrations could conceiv-

ably alter the penetration of other substances into cells.

Lyapkalo (1973) was able to produce chromatid breaks and

gaps in 11.5 percent of bone marrow cells of rats by inject-

ing the animals with 1 g/kg of toluene daily for 12 days.

Benzene, in contrast,  caused chromosome damage in 57 percent

of cells examined.  Dobrokhotov and Enikeev (1977) found

that inhalation of 112 ppm toluene four hours daily for

four months resulted in chromosome damage in 21.6 percent

of bone marrow cells and in leukccytosis in rats.   Although

inhalation of benzene caused a similar incidence of chromo-

some damage,  leukopenia rather than leukocytosis occurred.

The myelotoxic effects of toluene and benzene were found

to be additive when both chemicals were inhaled together.

One month post exposure, the abnormalities in peripheral
blood had resolved, but the chromosome aberrations persisted.
Dobrokhotov and Enikeev (1977) estimated that 0.8 g/kg/day
of toluene induced the same frequency of chromosome damage
in their rats as 0.2 g/kg/day of benzene.  In a study of
peripheral blood lymphocytes of humans who had been exposed
to an average of 200 ppm toluene for as long as 15 years,
Forni, et al. (1971) did not detect any greater incidence
of chromosome abnormalities than in controls.  Workers with
benzene exposure, however, did exhibit a significantly higher
proportion of unstable and stable chromosome aberrations
than did the controls.  Dean  (1978) concluded that in light
of the apparent absence of chromosome damage in humans and
the exceedingly high concentrations of toluene required
to induce aberrations in animals, the current TLV of 100
ppm will most likely protect against chromosome damage in
occupational exposure settings.
     It seems unlikely that metabolites of toluene will
induce mutations in animals exposed to toluene.  Benzoic
acid and hippuric acid, the principal metabolites of toluene,
are rapidly excreted and generally regarded as innocuous
chemicals.  Cresols are relatively minor metabolites of
toluene which have been examined for their ability to damage
chromosomes by Sharma and Ghosh  (1965).  These investigators
found that high concentrations could produce chromosomal
aberrations in cells from root tips of Aliiurn cepa bulbs.
Of the three isomers, m-cresol caused the most pronounced

changes.  It will be recalled that urinary cresols  repre-

sented only about one percent of a total dose of toluene given

to rats, and that no m-cresol was detected (Bakke and Scheline,

1970) .


     Toluene has not been demonstrated to be positive in

any iri vitro mutagenicity/carcinogenicity bioassay system,

nor to be carcinogenic in animals or man.  Fluck, et al.

(1976) tested toluene and benzyl alcohol for their carcino-

genic potential in an E^_ coli screening system and found

both compounds to be negative.  These researchers, however,

discounted the applicability of the system for evaluation

of lipophilic chemicals due to the chemicals' insolubility

in the aqueous test medium.  Toluene has been utilized exten-

sively as a solvent for lipophilic chemicals being tested

for their carcinogenic potential when applied topically

to the shaved backs of animals.  Poel (1963), for example,

topically applied toluene throughout the lifetime of mice

being used as controls and found no carcinogenic response.

Doak, et al. (1976)  applied toluene to the skin of mice

for one year and failed to elicit skin neoplasms or an in-

creased frequency of systemic tumors.  It is not clear in

these papers, however, whether the toluene was applied under

an occlusive dressing or simply allowed to evaporate. Lijinsky

and Garcia (1972)  did report a skin papilloma in one mouse

and a skin carcinoma in a second mouse in a group of 30

animals which were subjected to topical applications of

16 to 20 ul of toluene twice a week for 72 weeks.  Mazzucco

(1975) found a reduction in collagen content of the skin

of mice subjected to epidermal paintings with toluene three

times weekly for ten weeks.  There was a shorter  latency

period in these animals for tumor development when toluene

rather than acetone was used as the solvent for 3-methylchol-

anthrene.  There has been no increase in tumor incidence

in experimental rats over controls after 18 months of a

two-year toluene inhalation study  (Gibson, 1979).  In this

study, male and female rats have breathed 30, 100, or 300

ppm toluene six hours/day, five days/week.  Forty-two tissue

specimens per animal, as well as any detectable tissue mass,

are being subjected to histopathological evaluation.

      There have been no accounts in the literature in which

cancer in human populations has been attributed specifically

to toluene.  Some researchers have, however, suggested that

chronic exposure to hydrocarbon solvents may predispose

certain individuals to certain types of cancer.   Capurro

(1976) reported four cases of lymphoma and two cases of

pancreatic cancer among workers and persons living near

chemical plants where mixtures of hydrocarbon solvents were

said  to be present often.  Capurro  (1976) felt that both

forms of cancer were so rare that it was unlikely they would

have  occurred in such a small population by chance.  McMichael,

et al. (1975) conducted an epidemiological study  of rubber

industry workers who were routinely exposed to a  variety

of solvents.  The investigator/s found a greater than expected

risk  of death from car.cer, with the largest mortality exces-

ses from lymphosarcoma, Hodgliin's disease, lymphatic leukemia,

                           /  C-46

and myeloid leukemia.  Upon testing the hypothesis  that

the excess in cancers was due to hydrocarbon solvent  exposure,

an association was established between duration and intensity

of solvent exposure and incidence of lymphatic leukemia.

Curtes, et al. (1973) reported the case history of a man

who had worked with solvents/ including toluene, who  subse-

quently developed chronic myeloid leukemia.  McMichael and

his associates point out that benzene does not appear to

cause lymphatic leukemia, but rather the hemocytoblastic

and myeloblastic forms of the disease.  Thus, it is suggested

that another solvent, or other chemical may be responsible

for lymphatic leukemia and other forms of cancer seen in

the study.  The researchers also stress that there has been

inadequate carcinogenicity testing in animals and insufficient

epidemiological studies in man of the carcinogenic potential

of many solvents generally regarded as non-carcinogenic.

It should be recognized here that situations involving persons

with occupational exposure to solvents are characterized

by considerable job mobility and exposure to a variety of

chemicals in varying patterns.  Wolff, et al. (1977),  for

example, found toluene in combination with a number of other

hydrocarbon solvents in adipose samples from workers in

a styrene polymerization plant.   Thus, it is quite difficult

to attribute tumor induction to any single agent.

                    CRITERION FORMULATION

Existing Guidelines and Standards

     The only current guideline for toluene exposure has

been established to prevent adverse health effects  from

the chemical in occupational settings.  The present standard

is 100 ppm  (375 mg/m ), determined as a time-weighted average

exposure for an eight-hour workday/ with a ceiling  of 200

ppm (Natl.  Inst. Occup. Safety and Health, 1973).   Skin and

eye exposure is to be minimized.  This standard was set

primarily on the basis of subjective and objective  signs

of mucus membrane irritation and deficits in central nervous

system function upon acute inhalation exposure of human

subjects to 200 ppm toluene.  Short-term inhalation of 100

ppm was apparently without demonstrable effect in humans.

Reports reviewed by the National Institute for Occupational

Safety and  Health  (1973) also have failed to indicate adverse

effects on  the hematopoietic, hepatorenal, or other systems

of workers  routinely inhaling approximately 100 ppm toluene.

     A review of potentially harmful effects of chemical

contaminants of drinking water was undertaken by the Commit-

tee on Safe Drinking Water of the National Academy  of Sciences

 (1977).  The recommendations of this committee were to be

used by the U.S. EPA as the scientific basis for revision

or ratification of the Interim Primary Drinking Water Regula-

tions promulgated under the Safe Drinking Water Act of 1974.

Toluene was one of the organic chemicals considered here.

Although it was concluded that toluene and its major metabo-

lite, benzoic acid, were relatively non-toxic, the  committee


felt there was insufficient toxicological data available

to serve as a basis for setting a long-term ingestion standard.

It was recommended that studies be conducted to produce

relevant information (Natl. Acad. Sci.f 1977).  Toluene has recently

been considered for a second time by a reorganized Toxicology

Subcommittee of the Safe Drinking Water Committee of the

National Academy of Sciences.  Results of the deliberations

of this group have not yet been made public.

     There are no Federal or State guidelines, nor standards

for general atmospheric pollution by toluene.

Current Levels of Exposure

     Toluene has been detected in raw water and in finished

water supplies of several communities in the United States.

Levels of up to 11 jug/1 were found in finished water from

the New Orleans area (U.S. EPA, 1975a).  In a nationwide

survey of water supplies from ten cities, six were discovered

to be contaminated with toluene (U.S. EPA, 1975b).  Concentra-

tions of 0.1 and 0.7 ^ig/1 were measured in two of these

water supplies.  Toluene was detected in one of 111 communities'

finished drinking waters during a second nationwide survey

(U.S. EPA, 1977).  In a subsequent phase of this survey,

toluene was found in one raw water and three finished waters

out of 11 surveyed (U.S. EPA, 1977).  A level of 19 >ug/l

measured by gas chromatography/mass spectrometry,  was found

in one of these finished waters, and 0.5 jug/1 was found

in another.

     There is a paucity of data available on levels of tolu-

ene in foods.  Toluer.e was detected in fish caught from

polluted waters in the proximity of petroleum and petrochem-
ical plants in Japan  (Ogata and Miyake, 1973).  A concentra-
tion of 5 jug/g was measured in the muscle of one such  fish.
Two major metabolites of toluene, benzaldehyde  and  benzoic
acid, naturally occur in foods or are  intentionally added.
Benzaldehyde is a flavoring agent, while benzoic acid  is
a preservative.  Benzoic acid is also  given in  large oral
doses to humans as a clinical method for measuring  liver
     Although toluene has been detected in the  atmosphere,
concentrations are many times lower than vapor  levels  consid-
ered to be potentially harmful in occupational  settings.
An atmospheric concentration of 39 ppb toluene  was  measured
in Zurich, Switzerland  (Grob and Grob, 1971).   An average
level of 37 ppb toluene was observed in Los Angeles air
in 1966  (Lonneman, et al. 1968).  The  maximum amount detected
there was 129 ppb.  Comparable levels  were found upon  evalu-
ation of air in Toronto, Canada  (Pilar and Graydon, 1973).
The maximum concentration of toluene measured in Toronto
was 188 ppb, while the average concentration was 30 ppb.
The atmospheric levels of toluene in both Toronto and  Los
Angeles varied considerably according  to the  time of day
and sampling location  (Pilar and Graydon, 1973; Altshuller,
et al. 1971).  Thus,  it appears that atmospheric toluene
in urban areas arises primarily from automotive emissions,
with solvent losses as a secondary source.

     The most significant toluene inhalation exposures occur

in occupational and inhalant abuse settings.  Occupational

exposure levels are generally lower than the current standard

of 100 ppm, although short exposures to higher vapor concen-

trations occur.  Purposeful inhalation of toluene vapors

in order to inebriate oneself is a quite different situation,

since the participant may inhale extremely high concentra-

tions repeatedly for months or years.  Toluene concentrations

as high as 20,000 to 30,000 ppm can produce intoxication

within minutes under such circumstances.

Special Groups at Risk

     At present levels of exposure to toluene in the environ-

ment, available toxicological data do not suggest that any

special group in the general population would be at risk.

Exposure to levels of the chemical necessary to produce

physiological or toxicological effects would be anticipated

primarily in occupational or solvent abuse situations.

Environmental contribution of toluene in such settings should

be minimal.

Basis and Derivation of Criterion

     Although acute exposure to high levels of toluene can

result in marked central nervous system depression, this

action is rapidly reversible upon cessation of exposure

in both laboratory animals (Peterson and Bruckner, 1976)

and in man (Longley, et al. 1967).  When administered acutely

in quite large doses to animals, toluene can alter the metabo-

lism and bioactivity of certain chemicals which are degraded

by the mixed function oxidase system.  Toluene appears to

have little capacity to cause residual tissue injury. There

is no conclusive evidence that the parent compound or its


metabolites are mutagenic, although  they have apparently

not been tested in an in. vitro mutagenicity assay  (Dean,

1978) . Toluene has not been  found  to be teratogenic  in  labora-

tory animals  (Roche and Hine, 1968;  Hudak and Ungvary,  1978).

toluene has not been demonstrated  to be carcinogenic when

applied to the skin of mice  (Poel, 1963; Doak, et  al. 1976)

or when administered by inhalation at  concentrations of

up to 300 ppm for as long as 18 months to male and female

rats  (Gibson, 1979). There are no  accounts in the  literature

in which cancer in a human population  is attributed  specifi-

cally to toluene.

     A number of  investigations of the subacute and

chronic toxicity  of toluene  have been  carried out.  Although

the majority of emphasis has been  placed upon inhalation

exposure, Wolf, et al.  (1956) did  conduct a long-term,  oral

dosing study  in which female rats  were given 118,  354,  and

590 mg/kg of toluene in olive oil  by stomach tube  five  times

weekly for 193 days.  No adverse effects on growth, appearance

and behavior, mortality, organ/body  weights, blood urea

nitrogen levels,  bone marrow counts, peripheral blood counts,

or morphology of  major organs were observed at any dose

level. The lack of toxicity  reported here is supported  by

findings of other groups of  investigators who found no  evi-

dence of residual injury in  a variety  of animal species

subjected to toluene vapors  for varying times over periods

as long as 18 months  (Jenkins, et  al.  1970; Carpenter,  et

al. 1976; Bruckner and Peterson, 1978; Rhudy, et al. 1978;

Gibson, 1979).

     Therefore, it seems reasonable  that  the  highest  dose
utilized by Wolf, et al. (1956) , namely 590 mg/kg, might
serve as the basis for calculating an  "Acceptable Daily
Intake" for toluene. Although 590 mg/kg will  be considered
here as a "maximum-no-effeet" dose,  it should be recognized
that the actual "maximum-no-effeet"  dose may  be higher,
since Wolf, et al. (1956) did not determine a "minimum-toxic-
dose." Reynolds and Yee  (1968) saw no effect on several
parameters of hepatotoxicity in rats given a  single oral
dose of 2.4 g/kg toluene.  The oral, acute LD   f°r toluene
in young, adult rats is reported to  be 7.0 g/kg (Wolf, et
al. 1956).  It is possible that the  actual "maximum-no-effeet"
dose may be lower than 590 mg/kg, should alternative  indices
of toxicity be evaluated.  Man may prove to be more sensitive
to toluene than experimental animals.  Thus, assuming a
70 kg body weight, it seems appropriate that a safety factor
of 1,000 be applied in the following calculation:

          590 mg/kg x 70 kg x 5/7 day   = 2g>5 mg/day

Therefore, consumption of 2 liters of water daily and 18.7
grams of contaminated fish having a  bioconce'ntration factor
of 20, would result in, assuming 100 percent gastrointestinal
absorption of toluene, a maximum permissible concentration
of 12.4 mg/1 for the ingested water:

                  29.5 mg/day	    - ,-> A
         (2 liters -r (20 x 0.0187) x 1.0

     This calculation assumes that 100 percent of man's
exposure comes from the water pathway.  Although it is desirable
to arrive at a criterion level for water based upon total
exposure potential, the data base for exposures other than
water is not sufficient to allow a factoring of the criterion
     In summary, based on the use of toxicologic test data
for rats, and an uncertainty factor of 1000, the criterion
level for toluene  is 12.4 mg/1.  Drinking water contributes
84 percent of the  assumed exposure while eating contaminated
fish products accounts for 16 percent.  The criterion level
for toluene can alternatively be expressed as 79.7 mg/1
if exposure is assumed to be from the consumption of fish
and shellfish products alone.


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