TOLUENE
Repository Material
Permanent Collection
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
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CRITERION DOCUMENT
TOLUENE ^^
CRITERIA
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.
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Introduction
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.
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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
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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.
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REFERENCES
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.
16.
Shell, F.D., and L.S. Ettre. eds. 1971. Encyclopedia of
Industrial Chemical Analysis. Interscience Publishers,
John Wiley and Sons. Inc., New York.
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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-
cation)
Walker, P. 1976. Air pollution assessment of toluene.
MTR-7215. Mitre Corp. McLean, Va.
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AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
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
concentrations.
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
Guidelines.
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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).
Residues
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
made.
Miscellaneous
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).
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CRITERION FORMULATION
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
available.
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
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effects on freshwater aquatic organisms have been reported to be
caused by concentrations lower than 'the 24-hour average concen-
tration.
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.
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Table 1. Freshwater fish acute values for toluene
Bioaseay Teat Time
Cone.**
Ad lusted
LC50 LC&O
ug/11 (uq/l>
Keferfence
OD
1
cn
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
1966
1966
1966
1966
1966
* 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
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Table 2. Freshwater invertebrate acute values for toluene (U.S. EPA, 1978)
Adjusted •
Bioaaaay Test Time LC50 LC60
flgfrhoj* cone.** jhre) (ug/l>
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Table 3. Freshwater plant effects for toluene
Organism
Concentration
Effect
Reference
Alga.
Chlorella yulgaris
Alga,
Selenastrum
capricornutum
Alga.
Selenastruro
capricornutum
EC50 24-hr
cell numbers
96-hr EC50 for
chlorophyll a
production
96-hr EC50 for
cell numbers
245.000
>433.000
>433,000
Kauss & Hutchlnson, 1975
U.S. EPA. 1978
U.S. EPA. 1978
Lowest plant value •> 245,000 Mg/1
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Table 4. Other freshwater data for toluene (Wallen, et al. 1957)
Organism
Test
Puratigq Effect
Result
Mosquitofish.
Gambusla affinis
96 hrs LC50 in turbid water 1,180,000
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SALTWATER ORGANISMS
Introduction
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
ug/1.
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
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shrimp, and bay shrimp are used to derive the Final Invertebrate
Acute Value of 230 ug/1; this value also becomes the Final Acute
Value.
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.
Residues
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
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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
made.
Miscellaneous
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.
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CRITERION FORMULATION
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.
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Table. 5. Marine fish acute values for toluene
Adjusted
S3
M
U)
Bicassay
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***
50,000
M 96 6,300 4,470
Keference
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
7,324
3.7
= 2,000 pg/1
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Table 6. Marine invertebrate acute values for toluene
bioassay Test
*
Adjusted•
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
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Table 7. Marine fish chronic values for toluene (U.S. EPA. 1978)
Chronic
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
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Table 8. Marine plant effects for toluene
Concuritrat-ion
Organism
Effect
Reference
Kelp,
Macrocystis pyrifera
Alga
Amphidinium carteri
Alga,
Chlorella sp.
Alga.
Chlorella sp.
Alga.
Cricosphaera carterae
Alga,
00 Dunaliella tertiolecta
1
£ Alga ,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
SUeletonema costatum
Photosynthesis
Growth
Photosynthesis
respiration
Photosynthesis
respiration
Growth
Growth
Growth
96-hr EG50 for
chlorophyll a
production
96-hr EC50 for
reduction in cell
numbers
10,000
100 , 000
34,000
85,000
100,000
100,000
8,000
>433,000
>433,000
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
1975
1975
1975
1975
Lowest marine plant value = 8,000,)ig/l
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Table 9. Other marine daCa for coluene
Organism
Grass shrimp,
Palacmonetes pugjp
Shcepshead minnow,
Cyprlnodon varlegatua
Teat
Duration Eti ect
15 mins Narcosis
96 hrs LC50
Result
Reference
''19,800 Potera, 1975
>277.000 U.S. EPA, 1978
<485.000
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TOLUENE
REFERENCES
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:
165.
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.
B-18
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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.
University.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-01-
4646.
Wallen, I.E., et al. 1957. Toxicity to Gambusia affinis
of certain pure chemicals in turbid waters. Sewage Ind.
Wastes. 29: 695.
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Mammalian Toxicology and Human Health Effects
EXPOSURE
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.
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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
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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.
C-3
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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:
C-4
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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.
C-5
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Inhalation
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 ''(
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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
inebriated.
Dermal
Dermal exposures of significance are primarily restric-
ted to occupational or,home use settings;
f-t
C-7
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PHARMACOKINETICS
Absorption
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.
C-8
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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
2
absorption in man to be 14 to 23 mg/cm /hour.
C-9
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Distribution
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
/C-10
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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.
Metabolism
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
C-ll
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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-
(C-12
-------
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
C-/13
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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.
Excretion
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
C-14
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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,
C-15
-------
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).
EFFECTS
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
C-16
-------
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-
C-17
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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)
C-18
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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
C-19
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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
C-20
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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.
C-21
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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,
C-22
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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
C-23
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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)
C-24
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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
C-25
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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.
I
\
C-26
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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)
59
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
C-27
-------
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
i
]
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
C-29
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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
C-31
-------
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
C-32
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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
C-33
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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,
C-34
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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-
C-35
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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-
pathy.
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,
C-36
-------
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
C-38
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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
C-39
-------
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
conjugation.
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-
C-40
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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
59
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-
lism/elimination.
C-41
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Teratogenicity
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
C-42
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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.
Mutagenicity
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.
C-43
-------
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
C-44
-------
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) .
Carcinogenicity
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
C-45
-------
(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.
C-47
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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
C-48
-------
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
C-49
-------
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
function.
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.
C-50
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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
C-51
-------
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).
C-52
-------
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
1000
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
C-53
-------
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
level.
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.
C-54
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