vvEPA
United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-075
October 1980
Ambient
Water Quality
Criteria for
Toluene
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AMBIENT WATER QUALITY CRITERIA FOR
TOLUENE
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
, vaxvy
IH30 SfxSa. Dearborn Street
60604
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
ii
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
David J. Hansen, ERL-Duluth
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
James Bruckner (author)
University of Texas Medical School
Steven D. Lutkenhoff (doc. mgr.)
ECAO-Cin
U.S. Environmental Protection Agency
Donna Sivulka, (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
James Lucas, HERL
U.S. Environmental Protection Agency
Albert Munson
Medical College of Virginia
V.M. Sadagopa Ramanujan
University of Texas Medical Branch
Herbert Cornish
University of Michigan
Daniel Couri
Ohio State University
Patrick Durkin
Syracuse Research Corporation
Myron Mehlman
Mobil Oil Corporation
Richard Peterson
Indiana University School of Medicine
Herbert Schumacher
National Center for Toxicological Res,
Technical Support Services Staff: D.J. Reisman, M.A. Garlough B L Zwayer
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper
M.M. Denessen. '
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks
B.J. Quesnell, C. Russom, R. Rubinstein.
IV
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TABLE OF CONTENTS
Page
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-1
Effects B-l
Acute Toxicity B-l
Chronic Toxicity B-2
Plant Effects B-2
Miscellaneous B-3
Summary B-3
Criteria B-4
References B-ll
Mammalian Toxicology and Human Health Effects C-l
Exposure C-l
Ingestion from Water C-l
Ingestion from Food C-3
Inhalation C-5
Dermal C-7
Pharmacokinetics C-7
Absorption C-7
Distribution C-9
Metabolism C-ll
Excretion C-l 3
Effects C-l5
Acute, Subacute, and Chronic Toxicity C-15
Synergism and/or Antagonism C-37
Teratogenicity C-39
Mutagenicity C-41
Carcinogenicity C-43
Criterion Formulation C-46
Existing Guidelines and Standards C-46
Current Levels of Exposure C-47
Special Groups at Risk C-49
Basis and Derivation of Criteria C-49
References C-52
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CRITERIA DOCUMENT
TOLUENE
CRITERIA
Aquatic Life
The available data for toluene indicate that acute toxicity to fresh-
water aquatic life occurs at concentrations as low as 17,500 Mg/l and would
occur at lower concentrations among species that are more sensitive than
those tested. No data are available concerning the chronic toxicity of
toluene to sensitive freshwater aquatic life.
The available data for toluene indicate that acute and chronic toxicity
to saltwater aquatic life occur at concentrations as low as 6,300 .and 5,000
yg/1, respectively, and would occur at lower concentrations among species
that are more sensitive than those tested.
Human Health
For the protection of human health from the toxic properties of toluene
ingested through water and contaminated aquatic organisms, the ambient water
criterion is determined to be 14.3 mg/1.
For the protection of human health from the toxic properties of toluene
ingested through contaminated aquatic organisms alone, the ambient water
criterion is determined to be 424 mg/1.
VI
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INTRODUCTION
Toluene is a clear, colorless, noncorrosive liquid with a sweet, pun-
gent, 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 [National Institute for Occupational Safe-
ty and Health (NIOSH), 1973].
Toluene is produced primarily from petroleum or petrochemical 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 per-
cent 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
estimated 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 constituent in
wastewater.
Toluene, also referred to as toluol, methylbenzene, methacide, and
phenylmethane, is an aromatic hydrocarbon which is both volatile and flamma-
ble (40 FR 194). The molecular structure is distinguished from that of ben-
zene by the substitution of a methyl group for one hydrogen atom.
Toluene has the molecular formula C?H8, a molecular weight of
92.13 g, 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
A-l
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26.03"C, a refractive index of 1.4893 at 24"C (Kirk and Othmer, 1963), and a
log octanol/water partition coefficient of 2.69 (Tute, 1971). 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 alco-
hol, chloroform, ether, acetone, glacial acetic acid, carbon disulfide and
other organic solvents (Shell and Ettre, 1971).
Th.e nucleus of toluene, like that of benzene, undergoes substitution
reactions. Substitution occurs almost exclusively in the ortho (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. Hydrogena-
tion of toluene takes place readily to form methyl-eyelohexane (Kirk and
Othmer, 1963). Toluene may be oxidized with air in the presence of manga-
nese or cobalt naphthenates to form benzoic acid; controlled chlorination of
toluene yields benzol dichloride which may be hydrolyzed to benzaldehyde
(Gait, 1967). Most reactions, however, require specialized conditions and
are carried out commercially.
Although toluene is a volatile compound and has been shown to be readily
transferred from water surfaces to the atmosphere under ideal conditions
(Mackay and Wolkoff, 1973), its transport and persistence under environment-
al conditions is not well known. In the atmosphere, toluene is subject to
photochemical degradation to benzaldehyde and traces of peroxybenzoyl ni-
trate. 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 ug/1 to 11 ug/1. The toluene metabolites benzaldehyde and
benzoic acid were also found in finished water at concentrations up to 19
A-2
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REFERENCES
Bradsher, C.K. 1971. McGraw-Hill Encyclopedia of Science and Technology.
McGraw-Hill Book Co., New York.
Gait, A.J. 1967. Heavy Organic Chemicals. Pergamon Press, Ltd., Oxford.
Kirk, R.E. and D. Othmer. 1963. Kirk-Othmer Encyclopedia of Chemical Tech-
nology. 2nd ed. John Wiley and Sons, Inc., New York.
Mackay, D. and A.M. Wolkoff. 1973. Rate of evaporation of low-solubility
contaminants from water bodies to atmosphere. Environ. Sci. Technol.
7: 611.
National Institute for Occupational Safety and Health. 1973. Criteria for
a recommended standard...Occupational exposure to toluene.
Shell, F.D. and L.S. Ettre (eds.) 1971. Encyclopedia of Industrial Chemi-
cal Analysis. Interscience Publishers, John Wiley and Sons, Inc., New York.
Stecher, P.G. (ed.) 1968. The Merck Index. 8th ed. Merck and Co., Inc.,
Rahway, New Jersey.
Sutton, C. and J.A. Calder. 1975. Solubility of alkylbenzenes in distilled
water and seawater at 25°C. Jour. Chem. Eng. Data. 20: 320.
A-3
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Tute, M.S. 1971. Principles and practice of Hansch analysis: A guide to
structure-activity correlaion for the medicinal chemist. Adv. Drug Res.
5: 1.
Walker, P. 1976. Air pollution assessment of toluene. MTR-7215. Mitre
Corp., McLean, Virginia.
A-4
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Aquatic Life Toxicology*
INTRODUCTION
Acute toxicity tests have been conducted with toluene and a variety of
freshwater fishes and Daphnia magna; the latter appears to be more resistant
than the fishes. All but one of the tests were conducted using static pro-
cedures with unmeasured concentrations.
Three saltwater fish species have been acutely exposed to toluene as
have several invertebrate species. Results of these tests indicate a range
of 50 percent effect concentrations from 3,700 pg/l for the bay shrimp to
1,050,000 Pg/l for the Pacific oyster. All of these tests were conducted
using static procedures although concentrations were measured in several
tests.
EFFECTS
Acute Toxicity
Daphnia magna is the only tested freshwater invertebrate species; and
the 48-hour ECgo values for this species were 60,000 and 313,000 yg/1
(Table 1).
The range of 96-hour LC5Q values for the goldfish, fathead minnow,
guppy, and bluegill is 12,700 to 59,300 yg/1 (Table 1).
Potera (1975) conducted a variety of 24-hour exposures with the grass
shrimp, Palaemonetes pugio, using static procedures with measured concentra-
tions (Table 5). Temperature (10 and 20°C), salinity (15 and 25 g/kg, and
life stage (larvae and adults) were the variables considered. The total
*The reader is referred to the Guidelines for Deriving Water Quality
Criteria for the Protection of Aquatic Life and Its Uses in order to better
understand the following discussion and recommendation. The following
tables contain the appropriate data that were found in the literature, and
at the bottom of each table are calculations for deriving various measures
of toxicity as described in the Guidelines.
B-l
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range of LC50 values for the six tests was 17,200 to 38,100 ug/1 which
relatively small difference indicates that the variables did not have a very
great effect. The LCrn values for the bay shrimp, grass shrimp, mysid
shrimp, and Pacific oyster range from 3,700 to 1,050,000 yg/1 (Table 1).
The 96-hour LC5Q values for the striped bass (Benville and Korn,
1977) and coho salmon (Morrow, et al. 1975) were 6,300 and between 10,000
and 50,000 ug/1, respectively (Tables 1 and 5). The sheepshead minnow (U.S.
EPA, 1978) appears to be much more resistant to toluene with an LC5Q
between 277,000 and 485,000 ug/1 (Table 5).
Chronic Toxicity
A chronic value of 5,000 ug/1 (Table 2) 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 96-hour IC™
for the sheepshead minnow in the same study (U.S. EPA, 1978) is between
277,000 and 485,000 yg/1 and this results in an acute-chronic ratio between
55 and 97. No chronic data are available for any saltwater invertebrate
species and toluene, nor for any freshwater species.
The species mean acute and chronic values are summarized in Table 3.
Plant Effects
Two freshwater algal species have been exposed to toluene and the re-
sults (Table 4) demonstrate that these species are relatively insensitive
compared to the fishes. There was a 50 percent reduction in cell numbers of
the alga, Chlorella vulgaris, at 245,000 yg/1 (Kauss and Hutchinson, 1975).
Several studies have been conducted with saltwater algal species and
one has been conducted with kelp, Macrocystis pyrifera (Table 4). Effects
on growth, respiration and photosynthesis occurred at toluene concentrations
B-2
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fro. 3,000 to greater than 433,000 „,/!. The results are quite variable
since these extreme values are for the same species, Skeletonema costatun,.
Miscellaneous
Wallen et al. (1957) exposed mosauitofish to toluene in the presence of
high concentrations of suspended solids and calculated a 96-hour LC50
value of 1,180,000 ug/1 (Table 5).
Most of the data for saltwater species has been discussed. In addi-
tion, Potera (1975) observed narcosis of grass shrimp within 15 minutes dur-
ing an exposure to 19,800 wg/l. and obtained 24-hour LC5Q values of 24,200
and 74,200 for a saltwater copepod species (Table 5).
Summary
Five freshwater species have been acutely tested with toluene, and the
cladoceran, Daphnia magna, was more resistant than four fish species. The
EC5Q and LC50 values for all species were in the range of 12,700 to
313,000 ug/1. The ECgo values for two algal species were 245,000 wg/l and
higher. No chronic tests have been conducted with toluene and freshwater
species.
There was a wide range of EC5Q and LC50 values for saltwater
species of 3,700 vg/l for the bay shrimp to 1,050,000 wg/l for the Pacific
oyster. An embryo-larval test has been conducted for the sheepshead minnow
and effects were observed at 7,700 wg/l but not at 3,200 ug/1. The acute-
chronic ratio for this species is between 55 and 97. Several saltwater
algal species and kelp have been tested and effects were observed between
8,000 and greater than 433,000 Mg/l. Studies with the grass shrimp resulted
in no observed effect of salinity, temperature, or life stage on acute
lethality.
B-3
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CRITERIA
The available data for toluene indicate that acute toxicity to
freshwater aquatic life occurs at concentrations as low as 17,500 ug/l and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
toluene to sensitive freshwater aquatic life.
The available data for toluene indicate that acute and chronic toxicity
to saltwater aquatic life occur at concentrations as low as 6,300 and 5,000
wg/1, respectively, and would occur at lower concentrations among species
that are more sensitive than those tested.
B-4
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Table 1. Acute values for toluene
LC50/EC50 Species Acute
(ug/|) Value (tig/1)
03
I
Ul
FRESHWATER SPECIES
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Goldfish,
Carasslus auratus
Goldfish,
Carasslus auratus
Fathead minnow,
Plmephales promelas
Fathead minnow.
Plmephales promelas
Guppy,
Poecllla retlculata
Bluegll 1,
Lepomls macrochlrus
Blueglll,
Lepomls macrochlrus
Pacific oyster.
Crassostrea glgas
Mysld shrimp,
Mysldopsls bah la
Bay shrimp,
Crago franclscorum
Grass shrimp,
Pa 1 aemonetes puglo
S, U 60,000
S, U 313,000
FT, M 22,800
S, U 57,680
S, U 34,270
S, u 42,330
S, U 59,300
S, U 24,000
S, U 12,700
SALTWATER
S, U 1,050,000
S, U 56,300
S, M 3,700
S, U 9,500
-
137,000
-
22,800
-
38,100
59,300
-
17,500
SPECIES
1,050,000
56,300
3,700
9,500
Reference
Brlngman & Kuhn, 1959
U.S. EPA, 1978
Brennlman, et at. 1976
Pickering 1 Henderson,
1966
Pickering i Henderson,
1966
Pickering i Henderson,
1966
Pickering 4 Henderson,
1966
Pickering 4 Henderson,
1966
U.S. EPA, 1978
LeGore, 1974
U.S. EPA, 1978
Benvllle and Korn, 1977
Tatem, 1975
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Table 1. (Continued)
LC50/EC50 Species Acute
Species Method* (uq>l) Value (ug/I) Reference
Striped bass, S, M 6,300 6,300 Benvllle and Korn, 1977
Morone saxatIlls
* S = static, FT = flow-through, U » unmeasured, M = measured
No Final Acute Values are calculable since the minimum data base requirements are not met.
CO
I
CTi
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Table 2. Chronic values for toluene (U.S. EPA, 1978)
Method*
SALTWATER SPECIES
Chronic
Limits Value
Sheepshead minnow,
Cyprlnodon ^arlegatus
* E-L = embryo-larva I
Acute-Chronic Ratio
Species
Chronic
Value
(ug/D
I
-j
Sheepshead minnow, 5,000
r.yprlnodon varlegatus
Acute
Value
(U9/U
277,000-
485,000
E_l_ 3,200- 5,000
7,700
Ratio
55-97
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Table 3. Species Mean acute and chronic values for toluene
i
00
Number
5
4
3
2
1
6
5
4
3
2
1
Species
Cladoceran,
Daphnla magna
Guppy,
Poecllla reticulata
Fathead minnow,
Plmep hales promelas
Goldfish,
Carassius auratus
Blueglll,
Lepomls macrochlrus
Pacific oyster,
Crassostrea glgas
Sheepshead minnow,
Cyprlnodon varlegatus
Mysld shrimp,
Mysldopsls bah la
Grass shrimp,
Palaemonetas puglo
Striped bass,
Morone saxatl 1 is
Bay shrimp,
Crago franc Iscorum
Species Mean Species Mean
Acute Value* Chronic Value
(ug/l) (ug/l)
FRESHWATER SPECIES
137,000
59,300
38,100
22,800
17,500
SALTWATER SPECIES
1 ,050,000
277,000- 5,000
465,000
56,300
9,500
6,300
3,700
Acute-Chronic
Ratio**
55r97
* Rank from high concentration to low concentration by species mean acute value.
**See the Guidelines for derivation of this ratio.
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Table 4. Plant values for toluene
CO
Species
Effect
••i • ••
Result
(ug/l)
Reference
FRESHWATER SPECIES
Alga,
Chlorel la vulgarls
A 1 — a
Alga,
Sel enastrum capricornutum
A 1 --~
Alga,
Sel enastrum capricornutum
Cel 1 numbers
24-hr EC50
96-hr EC50 for
chlorophy 1 1 _a
production
Ce 1 1 numbers
96-hr EC50
245,000
>433,000
>433,000
Kauss i Hutch Inson,
1975
U.S. EPA, 1978
U.S. EPA, 1978
SALTWATER SPECIES
Kelp,
Macrocystls pyrlfera
A 1 nS4
A iga,
Amphldlnlum carter 1
Alga,
Chlorel la sp
Alga,
Chlorel la sp
A 1 i~isa
Alga,
Cricosphaera carterae
Al a
Puna 1 lei j_a tertlolecta
A 1 na
Alga,
Skeletonema costatum
A 1 na
Aiga,
Skeletonema costatum
A 1 *-is»
Alga,
Skeletonema costatum
Photosynthesis
Growth
Photosynthesis
respiration
Photosynthesis
respiration
Growth
Growth
Growth
96- hr EC50 for
ch lorophy 1 1 j±
production
96- hr EC50 for
reduction in
r-ol 1 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
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Table 5. Other data for toluene
CO
I
Species
Mosqultoflsh,
Gambusia afflnis
Copepod,
Nltocra splnlpes
Copepod,
Nltocra splnlpes
Grass shrimp (adult),
Palaemonetes puglo
Grass shrimp (adult),
Palaemonetes puglo
Grass shrimp (adult),
Palaemonetes puglo
Grass shrimp (adult),
Palaemonetes puglo
Grass shrimp (larva),
Palaemonetes puglo
Grass shrimp (larva),
Palaemonetes puglo
Grass shrimp,
Palaemonetes puglo
Coho salmon,
Oncorhynchus klsutch
Sheepshead minnow,
Cyprlnodon varlegatus
96 hrs
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
15 mlns
96 hrs
96 hrs
FRESHWATER SPECIES
LC50 In
turbid
water
SALTWATER SPECIES
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
Marcos 1 s
LC50
LC50
Result
(ug/l) Reference
1,180,000 Wai ten, et a I. 1957
24,200 Potera, 1975
74,200 Potera, 1975
20,200 Potera, 1975
17,200 Potera, 1975
37,600 Potera, 1975
38,100 Potera, 1975
30,600 Potera, 1975
25,800 Potera, 1975
19,800 Potera, 1975
10,000- Morrow, et al. 1975
50,000
>277,000 U.S. EPA, 1978
<485,000
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REFERENCES
Anonymous. 1964. An investigation of the effects of discharged wastes on
kelp. Calif. State Water Control Bd., Publ. No. 26: 58.
Benville, P.E., Jr. and S. Korn. 1977. The acute toxicity of six mono-
cyclic aromatic crude oil components to striped bass (Morone saxatilis) and
bay shrimp fCrago franciscorum). Calif. Fish and Game. 63: 204.
Brenniman, 6.. et al. 1976. A continuous flow bioassay method to evaluate
the effects of outboard motor exhausts and selected aromatic toxicants on
fish. Water. Res. 10: 165.
Bringman, G. and R. Kuhn. 1959. Vergleichende wasser - toxikologische
untersuchungen an bakterien, algen und kleinkrebsen. Gesundheits -
Ingenieur. 80: 115.
Ounstan, 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 vulgaris Beijernck.
Environ. Pollut. 9: 157.
LeGore, R.S. 1974. The effect of Alaskan crude oil and selected hydro-
carbon compounds on embryonic development of the Pacific oyster, Crassostrea
gigas. Ph.D. Dissertation. Univ. of Washington. 190 pp.
B-ll
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Morrow, J.E., et al. 1975. Effects of some components of crude oil on
young coho salmon. Copeia. 2: 326.
Pickering, Q.H. and C. Henderson. 1966. Acute toxicity of some important
petrochemicals to fish. Jour. Water Pollut. Control Fed. 38: 1419.
Potera, F.T. 1975. The effects of benzene, toluene and ethylbenzene on
several important members of the estuarine ecosystem. Ph.D. Dissertation.
Lehigh University.
Tatem, H.E. 1975. Toxicity and physiological' effects of oil and petroleum
hydrocarbons on estuarine grass shrimp Palaemonetes pugio. Ph.D. Disser-
tation. Texas A. and M. University.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, 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.
B-12
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Mammalian Toxicology and Human Health Effects
EXPOSURE
Ingest ion 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 ug/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 identi-
fied 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 10 cities (U.S. EPA, 1975b).
Six of the ten water supplies contained toluene. Levels of 0.1 and
0.7 ug/1 were measured in the two water supplies where quantitative
results were available. Benzaldehyde, a toluene metabolite, was
identified in three water supplies. Fifteen ug/1 of benzoic acid,
a second metabolite, was found in another city's water.
A second nationwide survey of levels of organic chemicals in
the Nation's water supplies, the National Organic Monitoring Survey
(NOMS), was conducted in three phases in 1976 (U.S. EPA, 1977). In
the first phase of this survey, toluene was apparently not included
in the analytical screen. Toluene was, however, detected in 1 of
111 community finished water supplies during the second phase of
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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 ug/1 was measured by gas chromato-
graphy/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
ug/1 of benzaldehyde were present in the drinking water of two
cities.
Although little information is apparently available concern-
ing potential sources of organics in drinking water, investigations
of the phenomenon are underway (U.S. EPA, 1975b). Suspected sourc-
es include industrial effluents, spills, discharges of oil and gas-
oline from boats, municipal waste treatment facilities, agricultur-
al runoff, and landfills. Volatile hydrocarbons such as benzene
and toluene would be expected to evaporate rapidly into the atmo-
sphere 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 min-
utes, although the vapor pressure of benzene is about three times
that of toluene. This discrepancy can be explained by the higher
water solubility of benzene, 1,780 mg/1, versus 515 mg/1 for tolu-
ene. Mackay and Wolkoff (1973) point out that actual rates of
evaporation in the environment may be substantially reduced from
these estimates, due to insufficient diffusion of organics in water
to the air-water interface to replace those organics being lost by
evaporation. Insufficient diffusion can be the result of inade-
quate mixing of the water and absorption/solubilization of the or-
ganic on or in particulates and sediments. The half-life would
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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
Very little data on levels of toluene in foods are available.
Apparently this is largely due to the lack of concern for toxicity
of the chemical. Ogata and Miyake (1973) detected toluene in sea-
water and fish after an offensive odor appeared in fish caught from
harbor waters in the proximity of petroleum and petrochemical
plants near Mizushima, Japan. Identification of toluene was con-
firmed by gas chromatography, infrared absorption spectrometry,
ultraviolet absorption spectrometry, and mass spectrometry. The
flesh of one representative fish was found to contain toluene at 5
tfg/g of flesh. 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 wastes or
toluene and other aromatic hydrocarbons were added. In a sub-
sequent publication (Ohmori, et al. 1975), the same group of inves-
tigators reported that eel liver homogenate was inferior to that of
rats in the metabolism of p-nitrotoluene and p-nitrobenzyl alcohol,
analogues of toluene and benzyl alcohol. The authors speculated
that this metabolic deficit might contribute to accumulation of
toluene in fish.
Two of the major metabolites of toluene, benzaldehyde and ben-
Zoic acid, are found in substantial levels in foods. Benzaldehyde
occurs as a natural constituent of bitter almond, peach, and apri-
cot kernel oils and is added intentionally as a flavoring agent.
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Benzole acid is used as an antimicrobial agent or food preservative
(National Academy of Sciences (NAS), 1972). Benzoic acid appears
to have a very large margin of safety in animals and man (World
Health Organization (WHO), 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 concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus, the per capita
ingestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average per-
cent lipids of consumed fish and shellfish, and a steady-state BCF
for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
the same species to estimate that the weighted average percent
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
No measured steady-state bioconcentration factor (BCF) is avail-
able for toluene, but the equation "Log BCF = (0.85 Log P) - 0.70"
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can be used (Veith, et al. 1979, to estimate the BCF for aquatic
organisms that contain about 7.6 percent lipids
-------
atmospheric levels of toluene in Los Angeles were largely associat-
ed with motor vehicle emissions. Pilar and Graydon (1973) measured
a maximum level of 188 ppb toluene 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 abundant aromatic
hydrocarbon. Its concentration was more than twice that of benzene
or m-xylene, the next most abundant aromatics. Comparison of tolu-
ene: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 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 coatings. The majority of sol-
vents which are produced eventually evaporate into the atmosphere,
either intentionally or unintentionally (NAS, 1976). A relatively
small proportion enters water. In data reviewed by NAS (1976) on
estimated solvent usage in the United States in 1968, toluene was
the fifth most extensively 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
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and their associated exposure levels are reviewed by the National
Institute for Occupational Safety and Health (NIOSH, 1973) and are
alluded to as they relate to potential adverse health effects and
pharmacokinetics in the relevant sections of this document. Sim-
ilarly, 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 in-
ebriated.
Dermal
Dermal exposures of significance are primarily restricted to
occupational or home use settings.
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 toluene vapor at 100 ppm and 200 ppm
and detected the compound in their arterial blood within 10 sec-
onds 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 ;ug/ml in persons inhaling 100 ppm toluene
and 2 jig/ml in persons inhaling 200 ppm toluene while at rest.
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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. Fur-
thermore, these investigators noted that obese subjects retained
more toluene than did their thinner counterparts. Average uptake
of toluene vapors by exercising subjects was approximately 37 per-
cent for thin subjects versus 49 percent for obese subjects.
Relatively little attention has been devoted to delineation 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
following 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 absorp-
tion. 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 2 to 3 hours,
were comparable to the peak levels seen in the orally dosed ani-
mals. Toluene can be absorbed through the skin, though to a
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considerably lesser degree than through the lungs or the gut.
Wahlberg (1976) found that 2.0 ml of toluene applied under an im-
pervious cover to the shaved backs of guinea pigs merely depressed
body weight gain, while intraperitoneal injection of the same vol-
ume of chemical killed each test subject. Dutkiewicz and Tyras
(1968) reported the rate of percutaneous toluene absorption in man
to be 14 to 23 mg/cm2/hour.
Distribution
Toluene is rapidly taken up from the bloodstream into the var-
ious body tissues according to their llpid 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). Tis-
sue 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 exper-
iment (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 per-
fused with blood and contains considerable llpid, it should rapidly
and preferentially accumulate toluene upon inhalation exposure.
indeed, men exposed to high concentrations of toluene vapor experi-
ence central nervous system (CNS) depression within minutes (Long-
ley, et al. 1967). As will be related in a subsequent section,
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subtle CNS effects appear to be one of the most sensitive indices
of toluene inhalation.
Ingested toluene is likely to be handled quite differently, 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 extensively and rapidly metabo-
lized by the liver. Thus, a dose of toluene which is sufficient to
cause minimal CNS effects when inhaled will most likely have no
such effect when ingested 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 inhalation 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 inha-
lation test subjects' tissues. The adipose tissue was the slowest
to attain its maximal toluene concentration, although it accumu-
lated much more of the compound than any other tissue. Body fat
provides an extensive reservoir for uptake of hydrocarbon 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 inhalation of toluene concentrations
as high as 4,000 ppm.
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Metabolism
Toluene is believed to be converted by the mixed function oxi-
dase (MFO) system to benzyl alcohol, which is subsequently oxidized
to benzaldehyde and benzoic acid and conjugated with glycine to
form hippuric acid. Ikeda and Ohtsuji (1971) demonstrated that
pretreatment with phenobarbital, a classic inducer of MFO activity,
resulted in a pronounced increase in urinary excretion of hippuric
acid by rats given an intraperitoneal injection of 1.18 g/kg tolu-
ene. Blood levels of toluene were depressed and the benzoic acid
concentration in the blood increased in the phenobarbitol-pretreat-
ed (induced) animals. Ikeda and Ohtsuji (1971) demonstrated that
the rates of p-nitrobenzyl alcoholic oxidation and glycine conjuga-
tion were not affected by the phenobarbital pretreatment. The
metabolism of p-nitrotoluene (an analogue of toluene) to p-nitro-
benzoic acid was markedly enhanced jin vitro in liver microsomes
isolated from these animals. As might be expected, the duration of
toluene-induced sleeping time was significantly shorter in the in-
duced animals. Koga and Ohmiya (1978) have shown that inhibition
of MFO 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 spe-
cies.
Toluene is rapidly and extensively metabolized to hippuric
acid in experimental animals. Smith, et al. (1954) found that in
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rabbits given 350 mg/kg of toluene orally, about 18 percent of the
dose was eliminated in the expired air as the parent compound with-
in 12 hours. Less than 1 percent more was exhaled over an addi-
tional 24-hour period. No glucuronide or sulfate metabolites were
detected in the urine of these animals. Work in the same labora-
tory with rabbits given a single oral toluene dose of 275 mg/kg re-
vealed that about 74 percent of the total dose could be accounted
for as urinary hippuric acid within 24 hours of dosing (El Masry,
et al. 1956). Thus, the majority of toluene is rapidly eliminated
by the rabbit as the unmetabolized compound in expired air and as
the glycine conjugate of benzoic acid in urine. Very little tolu-
ene metabolite is excreted into the bile of the rat (Abou-El-
Makarem, et al. 1967). Bray, et al. (1951) suggested that if tolu-
ene exposure were so high that the glycine conjugation mechanism
was overwhelmed, glucuronide conjugation might then occur. Bray
and his colleagues did demonstrate glucuronide conjugates in the
urine of rabbits given large doses of benzoic acid. It seems like-
ly that should the normal metabolic pathway be blocked, more of the
unmetabolized compound would simply be eliminated via exhalation.
Bakke and Scheline (1970) administered toluene at 100 mg/kg 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 de-
tected 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)
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subjected humans to 200 ppm toluene vapor for up to seven hours. It
was found that 68 percent of the estimated amount of solvent ab-
sorbed systemically was recovered as urinary hippuric acid. This
metabolite appeared in the urine soon after initiation of the expo-
sure, an indication of rapid metabolism of toluene to this princi-
pal 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 in the second hour of 4-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 ap-
pear that humans metabolize 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 par-
ent compound in expired air and as hippuric acid in the urine. Upon
termination of inhalation sessions, 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), after analyzing toluene
desaturation data in humans, concluded that the initial rapid phase
of elimination was governed primarily by the rate of alveolar ven-
tilation, the rate of toluene metabolic clearance, and the blood/
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air partition coefficient of toluene. A slower elimination 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 obese subjects, Carlsson and
Lindqvist (1977) noted that on prolonged toluene exposure, these
individuals will accumulate more of the compound and will eliminate
it more slowly, thereby subjecting their tissues to higher concen-
trations 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. Desatura-
tion 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
relatively 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 re-expose mice and
rats to concentrated toluene vapors at intervals of 10 to 20 min-
utes 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 occupational toluene expo-
sure. Ogata, et al. (1970-), while evaluating human subjects ex-
posed to vapor levels of 200 ppm, stated that the quantity of
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hippuric acid excreted in the urine was proportional to total toluene
exposure (i.e., exposure time X vapor concentration). Other groups
of investigators, however, have observed wide interpersonal varia-
tion in hippuric acid excretion, even among control subjects not
exposed to toluene (Ikeda and Ohtsuji, 1969; Engstrom, et al.
1976). Friborska (1973) found marked variations in the same indi-
viduals 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, parti-
cularly at low exposure levels (Engstrom, et al. 1976).
EFFECTS
Acute, Subacute, and Chronic Toxicity
The primary hazard associated with acute exposure to high
levels of toluene is excessive CNS depression. The 8-hour LC5Q in
mice was 5,300 ppm (Svirbely, et al. 1943). In contrast, the 8-
hour LC5Q for benzene was 10,400 ppm. Kojima and Kobayashi (1973)
found 20,000 ppm toluene to be lethal to rats after 30 to 50 min-
utes. Death was attributed to CNS depression. Average concentra-
tions of toluene in the tissues of the animals that succumbed were
as follows: blood - 330 ug/g; liver - 700 ug/g; and brain - 890
ug/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 LD5Qs were 1 ml/kg for
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the newborns and 3 ml/kg for the 14-day-old animals. Kimura, et
al. (1971) stated that the lowest dose at which gross signs of
poisoning characterized by CNS depression were seen in the young
adult rats was 2 ml/kg. They divided this dose level by a safety
factor of 1,000 to derive a value of 2 jul/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 workers who were ren-
dered 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 inhalation 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 recently 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 which 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
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altered consciousness. This practice may be continued for years,
and thus affords toxicologists an opportunity to observe consequen-
ces of both acute and chronic high-level toluene exposure. The
situation is often complicated by the participant's use of commer-
cial products which consist of complex mixtures of chemicals. In
such cases it is difficult to attribute toxicity to any single com-
ponent.
With the increase in popularity of "glue sniffing," a situa-
tion known as "sudden sniffing death" has been brought to the at-
tention 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 ap-
pear to be due to suffocation or CNS depression, but rather to sud-
den cardiovascular collapse at light plane anesthesia levels. Bass
speculated that cardiac arrhythmias may have resulted from a com-
bined 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 car-
diac arrhythmias in dogs inhaling various hydrocarbon solvents.
Taylor and Harris (1970) reported a slowed sinoatrial rate, pro-
longed P-R interval, and sensitization to asphyxia-induced atrio-
ventricular 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
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attributed to any one or combination of the following: sinus
bradycardia, atrioventricular block, or ventricular fibrilla-
tion/failure. Taylor and Harris (1970) pointed out that not only
will the stress and asphyxia often associated with solvent abuse
contribute to cardiac arrhythmias, 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 aforementioned cardiotoxic effects
have been seen in humans and laboratory animals subjected to very
high vapor concentrations of toluene. It would appear unlikely
that low-level inhalation or oral toluene exposure would be detri-
mental to the cardiovascular system. Ogata, et al. (1970) did
report an apparent decrease in pulse rate but no significant alter-
ation of blood pressure in human volunteers inhaling 200 ppm tolu-
ene. 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 studies involving inhala-
tion 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 NIOSH (1973) recommendation of 100 ppm for
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occupational toluene exposure. Subjective complaints such as fa-
tigue, dizziness, headache, weakness, and throat and eye irritation
were made by subjects breathing toluene concentrations of 200 ppm.
More objective measurements of CNS effects by Ogata, et al. (1970)
and by Gamberale and Hultengren (1972) also suggest that the "mini-
mum effect (vapor) level" is about 200 ppm. Ogata and his co-
workers (1970) found a prolongation of eye-to-hand reaction time in
persons inhaling 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 func-
tions after longer periods of exposure. They also point out that
substantial differences were observed in toluene uptake among indi-
vidual test subjects, 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 exposure limit, since the preceeding
studies of impairment of performance have involved evaluation 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 subjects 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.
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1967; Reisen, et al. 1975). Evaluations of experimental animals
subjected to large doses of toluene also indicate that the chemical
is relatively nontoxic. Svirbely, et al. (1943) could find no con-
spicuous 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 trans-
aminase (SCOT) activity in mice that inhaled 4,000 ppm toluene for
three hours. Divincenzo and Krasavage (1974) administered toluene
at 150, 300, 600, and 1,200 mg/kg 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 evi-
dence of lipid accumulation. Reynolds and Yee (1968) included tol-
uene in a hepatotoxicity study because of the similarity of its
lipophilic solvent properties to those of hepatotoxic aliphatic
halocarbons. In contrast to other chemicals tested, administration
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 in-
flux into hepatocytes, or liver morphology. In a subsequent in-
vestigation, 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 findings suggest that any lipophilic sol-
vation action on hepatocyte membranes by toluene is of little toxi-
cologic consequence. Holmberg and Malmfors (1974) provided addi-
tional evidence of the nontoxic nature of toluene by demonstrating
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in vitro that concentrations as high as 100 ug/ml had no cytotoxic
effect on suspensions of ascites tumor cells.
Toluene appears to have more toxicity potential on subacute
exposure than it does acutely. In an effort to assess the capacity
of toluene to elicit injury under conditions approximating human
solvent abuse, Bruckner and Peterson (1978) subjected mice and rats
five times weekly, for eight weeks, to 3-hour cycles of alternating
fresh air and toluene vapor at 12,000 ppm. The concentration of
toluene employed in this exposure regimen was not lethal, but did
produce inebriation. A battery of standard toxicologic and histo-
pathologic tests failed to reveal evidence of injury to the lung,
liver, or kidney during the 8-week exposure period. Jenkins, et
al. (1970) found that neither continuous exposure to 107 ppm tolu-
ene for 90 days nor intermittent (8 hours/day, 5 days/week) expo-
sure to 1,085 ppm for six weeks affected body weight gain, hema-
tologic parameters, or 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 to toluene concentrate at 988
ppm for 13 weeks via inhalation. Toluene concentrate consists of
approximately 50 percent toluene, 15 percent other alkyl benzenes,
14 percent heptane, 10 percent cyclohexane, 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 sup-
ported by the Chemical Industry Institute of Toxicology. Male and
female rats were exposed by inhalation to 99.98 percent pure tolu-
ene at 30, 100, 300, or 1,000 ppm for 6 hours/day, 5 days/week
C-21
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for 13 weeks. At any exposure level there was no significant al-
teration 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 glu-
tamic-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 meta-
bolic acidosis in humans who had inhaled toluene for its intoxi-
cating effects. The condition was termed renal tubular acidosis,
because it was believed 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 meta-
bolic capacity of the liver. It was reported that Fabacher and
Hodgson (1977) saw no modification of liver/bodyweight ratio,
microsomal protein content, O- and N-demethylation, nor various
spectral characteristics of cytochrorae P-450 in male mice injected
intraperitoneally for three consecutive days with toluene at 100
mg/kg body weight. Other methylated benzenes and a methylated
napthalene increased liver weight and microsomal enzyme activity in
the mice, leading the authors to speculate that such compounds were
effective inducers because of their lipophilicity and persistence
in the body. Apparently toluene was ineffective because it was too
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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 analytical grade toluene
at 0.12 to 1.0 ml/kg for 12 days to 4 weeks. Dose-dependent in-
creases were seen in the number and total area of mitochondria per
unit cytoplasmic area in the liver. Similarly, dose-dependent de-
creases 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 ultrastructural altera-
tions. The enhanced mitochondrial prominence is interesting in
light of a previous report from the same laboratory (Aranka, et al.
1975) of a dose-dependent increase in succinic dehydrogenase activ-
ity and a decrease in glycogen content of livers of toluene-treated
rats. The toxicological or biological significance of these find-
ings 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 oxidase reactions, possibly
serving to transfer reducing equivalents originating from NADPH or
NADH through cytochrome b5 to cytochrome P-450 (Schenkman, et al.
1973).
Although long-term exposure to toluene is quite common in
industry, there are few reports to suggest that it has produced
deleterious health effects in workers. One adverse effect which
has been tentatively attributed to toluene is myelotoxicity. Many of
the early studies suggested this effect involved the use of toluene
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contaminated with benzene (NIOSH, 1973). The preponderance of
clinical/epidemiological investigations of workers routinely ex-
posed to toluene vapor has failed to reveal any significant abnor-
malities 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); and 60-100 ppm, Matsushita,
et al. (1975). Forni, et al. (1971) did not find a significant dif-
ference in the frequency of chromosome aberrations in peripheral
blood lymphocytes between toluene-exposed workers and matched con-
trols. 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 tolu-
ene and other compounds through their work with varnishes have re-
cently been reported to exhibit decreased erythrocyte and thrombo-
cyte indices (Syrovadko, 1977). It should be recognized here that
interpretation of accounts of toxicity in occupational settings is
often complicated by uncertain exposure levels, variable exposure
patterns, exposure to multiple chemicals, and/or unrecognized pre-
disposing 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
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participant inhales sufficient quantities to intoxicate himself.
This practice may be continued for years. Despite such extreme
exposure conditions and participation by large numbers of people
throughout the world, hematological abnormalities in toluene
abusers are uncommon. Massengale, et al. (1963) found no irreg-
ularities 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 polyneuropathies upon abusing
glues containing large amounts of toluene and n-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 demonstrated pre-existing sickle-cell
disease and 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
nontoxic. Wolf, et al. (1956) have apparently conducted the only
long-term toxicity study in which toluene was given orally. Female
rats received toluene at 118, 354, or 590 mg/kg five times weekly
for six months. Cell counts of bone marrow and circulating blood
revealed no adverse effects. Takeuchi (1969) saw no alterations in
peripheral blood counts in rats exposed 8 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 ab-
normalities in male and female rats subjected 6 hours/day, 5
days/week for 13 weeks to 30, 100, 300, or 1,000 ppm of 99.98
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percent pure toluene. This investigation served as a pilot for an
ongoing 2-year inhalation exposure study (Gibson, 1979). The pri-
mary 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 circulat-
ing blood or bone marrow of the male or female rats (Gibson, 1979).
In a study of toluene-benzene interaction in mice, Andrews, et al.
59
(1977) noted that toluene had no effect on incorporation of Fe
into developing erythrocytes. Toluene actually protected against
inhibition of this process by benzene. Yushkevich and Malysheva
(1975) saw no alteration in erythroblast maturation in the bone
marrow of rats subjected four hours daily for four months to a
topical application of toluene at 10 g/kg. This rather unusual
dose regimen was said to impair leukopoiesis, as evidenced by an
increase in the number of plasmic and lymphoid reticular cells in
the marrow. Topical application of 1 g/kg daily was without ad-
verse effect in this regard. Horiguchi, et al. (1976) observed
leukocytosis within 10 days in mice that inhaled 1, 10, 100, or
1,000 ppm toluene 6 hours/day. Decreases in circulating erythro-
cytes were seen in the mice exposed to 100 and 1,000 ppm, while
thrombocytopenia was said to occur in those exposed to 10, 100, and
1,000 ppm. A slight hypoplastic change was noted in the bone mar-
row 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 toluene vapor. Benzene also elicited
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chromosome damage, which was additive to that of toluene when the
two chemicals were administered together. One month after termina-
tion of the exposure, the leukocytosis had resolved, but the chro-
mosome abnormalities 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 con-
ditions and protocols, to interpret data, and to judge the valid-
ity/significance of findings in translations of reports in foreign
languages. For example, the purity of the toluene used in each of
the three aforementioned studies is not stated. However, the find-
ings of these investigators should not be entirely dismissed, as
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 levels, serum immu-
noglobulin 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
C-27
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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, Friborska (1973) noted
increases in alkaline phosphatase, acid phosphatase, and lactic
dehydrogenase activities in leukocytes and/or lymphocytes of work-
ers exposed to toluene. The authors associated these alterations
with increased functional capacity of the cells.
Solvent exposure has also been tentatively linked with induc-
tion of autoimmune disease. A substantial number of patients diag-
nosed as having glomerulonephritis were found to have had a history
of intensive, long-term solvent exposure (Beirne and Brennan, 1972;
Zimmerman, et al. 1975). These investigators noted that individual
host susceptibility was likely to be an important factor here,
since so many persons are routinely exposed to solvents without
developing the disease. As was the case for the alterations seen
by Lange and associates, no individual component of the complex
solvent mixtures utilized by the glomerulonephritis patients could
be considered the potential toxicant.
Long-term exposure of toluene appears to have little capacity
to injure the liver and most other organs. The only report sug-
gesting an adverse effect of toluene on the liver in an occupation-
al setting was in an early paper by Greenburg, et al. (1942). They
observed an increased incidence of hepatomegaly in painters exposed
from two weeks to five years to solvent mixtures in which toluene
C-28
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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 several years to approximately
125 ppm toluene. There has also been a surprisingly low incidence
of hepatorenal injury in persons who purposefully inebriate them-
selves with toluene. Litt, et al. (1972), for example, found mod-
est elevations of serum glutamic-pyruvic transaminase levels in
only 2 percent and elevated alkaline phosphatase levels in 5 per-
cent of a group of 982 glue sniffers. Massengale, et al. (1963) and
Barman, et al. (1964) failed to detect hepatorenal injury in groups
of abusers of toluene-based glues. Press and Done (1967) saw
slight but transient abnormalities in urinalyses of a small per-
centage of the glue sniffers they examined. No evidence of liver
injury was detected. These investigators concluded that should any
adverse effects occur, they would be transient and would occur very
soon after intensive solvent exposure. This supposition is sup-
ported 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 cytoplas-
mic enzymes. Signs of liver (Weisenberger, 1977) and kidney
(Kelly, 1975) injury in toluene abusers being treated for behavior-
al problems cleared spontaneously during hospitalization.
Clinical findings from evaluations of solvent abusers should
be interpreted with caution when considering the toxicity of spe-
cific chemicals such as toluene. Patterns and frequency of expo-
sure may differ markedly among individuals. The commercial
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products favored by many abusers are usually complex mixtures of dif-
ferent 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 combination with alcohol and other drugs. Thus, chemical or
drug interactions may either protect the participant or place him
at increased 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 containing 80 percent toluene. A number of
serious cases of polyneuropathy were seen in persons who abused
products comprised largely of toluene and n-hexane. Signs of hepa-
torenal 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 re-
stricted his sniffing to pure toluene exhibited hepatomegaly and
impaired liver function when hospitalized for a psychiatric dis-
order (Grabski, 1961). This same patient was seen at a later time
when he developed severe hepatorenal toxicity from sniffing carbon
tetrachloride vapor (Knox and Nelson, 1966).
Long-term animal studies have generally revealed little evi-
dence of any residual toxic effect of toluene. Two investigations
which deserve special attention at present are a 6-month oral
dosing study by Wolf and his co-workers (1956) and an ongoing 2-
year project (Gibson, 1979). Wolf, et al. (1956) gave female rats
toluene at 118, 354, and 590 mg/kg in olive oil by stomach tube five
times weekly for 193 days. Ten animals were used at each dose
level. No adverse effects on growth, mortality, appearance and
C-30
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behavior, organ/body weights, blood-urea nitrogen levels, bone mar-
row counts, peripheral blood counts, or morphology of major organs
were noted. Thus, on the basis of these findings, it would be con-
cluded that the minimum toxic oral dose of toluene must be greater
than 590 mg/kg/day. After 18 months of the ongoing 2-year inha-
lation study, no significant effects attributable to toluene have
been seen in male or female rats subjected 6 hours/day, 5 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, urinalysis indices, organ
weights, and histopathology of 42 tissue specimens and of any de-
tectable tissue mass from each animal.
Considerably more is known about the acute effects of toluene
on the central nervous system (CNS) than potential adverse neuro-
logical 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 de-
gree 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 mix-
tures containing toluene over a period of years. One of the ear-
liest reports was by Grabski (1961), who examined a 21-year-old
male who had inhaled toluene vapor on a regular basis for two
years. The patient's CNS signs were said to be consistent with
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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 10-year period of toluene abuse.
Although his neurological exam was normal, nonspecific abnormali-
ties were observed in his EEC. Satran and Dodson (1963) termed the
condition diffuse encephalopathy. Another report of cerebellar
damage was recounted by Kelly (1975). In this case a teenage girl
with a past record of multiple drug and solvent abuse wasj. found to
have residual cerebellar dysfunction after lh years of inhaling
fumes 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 10 years be-
fore being hospitalized for ataxia. No abnormalities were evident
in his EEC, but a computerized brain scan showed diffuse cerebral
atrophy. An electromyogram and nerve conduction studies of all
limbs showed no abnormalities of nerve or muscle. Although the
condition of the patient improved significantly, the central neuro-
logical abnormalities were still evident upon examination nine
months later. The second patient was exposed occupationally to
toluene. He had gradually developed a number of bothersome prob-
lems, including fatigue, clumsiness of his left side, mildly
slurred speech, impairment of sense of hearing and smell, and dis-
turbance of memory and power of concentration. He showed daily
C-32
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improvement and recovered completely without specific treatment.
Recovery from cerebellar dysfunction, coupled with optic neuro-
pathy, has also been described in an individual who inhaled fumes
from a toluene-based paint on a daily basis for three years (Keane,
1978). On the basis of the aforementioned accounts, it would ap-
pear that prolonged, intensive inhalation of toluene may result in
damage of the central nervous system, with impairment of pyramidal,
cognitive, and cerebral functions. The adverse effects are largely
reversible, particularly when exposure has not been too extreme.
Cases such as these, however, seem to be a rare occurrence even
among toluene abusers.
It has been suggested that toluene may influence the neuro-
toxic 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 neuropathies 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
for years had abused products containing large amounts of toluene
but no n-hexane without apparent difficulty (Shirabe, et al. 1974;
Korobkin, et al. 1975; Towfighi, et al. 1976). Only a few weeks to
months after switching to products containing n-hexane, they exper-
ienced progressive weakness and numbness of the extremities. No
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report can be located in the literature in which peripheral neuro-
pathy is attributed to the inhalation of toluene alone. The possi-
ble contribution of toluene to neurotoxic potential of n-hexane is
discounted by findings of Suzuki, et al. (1974). These investiga-
tors administered n-hexane at 910 mg/kg alone, and in combination
with toluene at 1.18 g/kg, by intraperitoneal 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
metabolized 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 neuropathy.
In light of the apparent residual CNS effects in certain indi-
viduals who subject themselves to extreme toluene exposure, 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 toluene 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 confirmed by
the finding of elevated urinary hippuric acid excretion in these
subjects. Hanninen, et al. (1976) also observed moderate clumsi-
ness of the hands of car painters exposed for years to solvents.
Thorough analyses of the air in the painters' working environment
C-34
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revealed the major component to be toluene (average level = 30.6
ppm), with lesser amounts of xylene, methyl isobutyl ketone, iso-
propanol, white spirit, and other solvents. Hanninen, et al.
(1976) also observed impairments in memory, ability to concentrate,
and emotional reactivity in the painters in contrast to age and
intelligence-matched controls. These researchers emphasized 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) con-
ducted a similar study of 168 workers routinely exposed to hydro-
carbon solvents, 51 of whom were said to be exposed primarily to
toluene 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 hydrocarbon solvents. These investi-
gators concluded that such individuals had a higher risk of non-
specific neuropsychiatric disorders and that the risk increased
with the number of years of exposure. Axelson, et al. (1976) em-
phasized that such disturbances, e.g., nervousness, irritability,
insomnia, and 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 influ-
ence of inhalation of 1,000, 2,000, and 4,000 ppm toluene for four
C-35
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hours on the behavior and EEGs 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 2 until the end of the expo-
sure session. In contrast, Peterson and Bruckner (1976) saw a
gradual, but progressive, decrement over a 3-hour period in un-
conditioned reflexes/performances tested at 15-minute intervals in
mice and rats inhaling 4,000 ppm toluene. The inhibitory action of
toluene was rapidly reversible upon cessation of exposure in each
of the aforementioned studies.
Takeuchi and Hisanaga (1977) also described EEC changes which
were associated with disturbances in the sleep cycle of their tolu-
ene-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 re-
lationship between the sleep-related changes and abnormal EEC pat-
terns 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 deter-
mine whether long-term toluene exposure, under conditions approxi-
mating those in glue sniffing, could have a detrimental effect on
learning and memory. Rats were subjected two hours daily to 4,000
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ppm of toluene vapor for 60 days. Several days later spontaneous
activity, emotionality, and memory-learning on three different
schedules were evaluated. No influence of the toluene regimen was
seen on any parameter except one of the memory-learning tests. The
particular test which was affected was the most complicated or dif-
ficult 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 expo-
sure. Microscopic examination of several areas of the brain of
these animals did not reveal any damage. Furnas and Hine (1958)
also failed to detect histopathologic damage of sections of brain,
spinal cord, and sciatic nerve of rats 24 hours after they had been
subjected to toluene vapor at 20,000 ppm for six consecutive 30-
minute exposures. Ishikawa and Schmidt (1973) found no histopatho-
logic 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 for six hours daily showed a decrease in wheel turning
activity within 6 to 10 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).
Synerqism and/or Antagonism
Toluene, in sufficient amounts, would appear to have the po-
tential to significantly alter the metabolism and resulting bioac-
tivity of certain other chemicals. The time at which exposure to
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toluene occurs, relative to exposure to a second chemical, could be
quite important. Prolonged pre-exposure to toluene may induce or
stimulate mixed-function oxidase (MFO) activity, thereby enhancing
metabolism of the second chemical. Should concurrent exposure oc-
cur, toluene, which is readily hydroxylated by the microsomal MFO
system, would probably inhibit the metabolism of other compounds
which are acted upon by this same system (Ikeda, 1974; Ikeda, et
al. 1972). This phenomenon would be anticipated to result in a
prolonged half-life of both toluene and the other compound. In-
hibition of metabolism 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 reac-
tion. 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 sig-
nificantly influence the biological fate and bioeffects of other
agents. Ikeda (1974) demonstrated that toluene at 430 mg/kg, given
to rats by intraperitoneal injection in combination with trichloro-
ethylene, reduced the metabolism of the trichloroethylene. Tolu-
ene'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
compounds. The mutual suppression was reflected in diminution of
urinary excretion of phenol and hippuric acid. Coadministration of
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toluene and styrene was also shown to decrease styrene metabolism.
Pretreatment of the rats with phenobarbital alleviated the suppres-
sant effects of toluene. Andrews, et al. (1977), coadministered
benzene at 440 or 880 mg/kg and toluene at 1,720 mg/kg intraperito-
neally to mice and observed a marked reduction in urinary excretion
of benzene metabolites, coupled with a compensatory increase in
pulmonary excretion of unmetabolized benzene. It was demonstrated
using liver microsomes in vitro that toluene is a competitive inhi-
bitor 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 body tissues, but markedly reduced the concentration
of benzene metabolites in various tissues including bone marrow.
Toluene was also found to protect against the inhibitory effect of
benzene on 59Fe incorporation into developing erythrocytes, sug-
gesting 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 induc-
tion of peripheral neuropathy seen in some abusers of n-hexane/tol-
uene mixtures. However, as previously discussed, available evi-
dence indicates that n-hexane is responsible for the neurotoxicity.
Suzuki, et al. (1974) showed that n-hexane and toluene given concur-
rently to rats had no apparent effect on one another's metabolism
elimination.
Teratogenicity
Toluene has been shown to be teratogenic in one recent study
by Nawrot and Staples (1979). Toluene was administered to CD-I
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mice by gavage on days 6 through 15 of gestation at levels of 0.3,
0.5, and 1.0 ml/kg body wt/dose. A significant increase in embry-
onic lethality occurred at all dose levels and decreased fetal
weight occurred at 0.5 or 1.0 ml/kg. in the 1.0 ml/kg group, a
statistically significant increase in the incidence of cleft palate
was noted which did not appear to be due merely to general retarda-
tion in growth rate. The same toluene regime administered on days
12 through 15 yielded only decreased maternal weight gain. Mater-
nal toxicity was not seen after exposure to toluene at any dose
level.
Several researchers have reported that toluene is not terato-
genic. 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 incidence 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 exposed 24
hours/day on days 6 to 13 of pregnancy gave birth to underweight
offspring. Some retardation of body weight and skeletal growth
were seen in fetuses of rats exposed continuously to 399 ppm tolu-
ene on days 1 to 8 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 influ-
ence on any index in the rat. Hudak and Ungvary (1978) concluded
from quite limited data that toluene exposure during early
C-40
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pregnancy might retard fetal development and should therefore be
avoided. It was noted that toluene should readily pass the placen-
tal 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 rela-
tively high incidence of menstrual disorders. The newborn children
of these women were said to experience more frequent fetal asphyx-
ia, 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 terato-
genic effect in humans being linked to toluene exposure.
Mutagenicity
There is no conclusive evidence that toluene is mutagenic. In
a recent review of the genetic toxicology of toluene and related
compounds, Dean (1978) stated that no data are available on muta-
genicity testing of toluene in bacterial systems. Dean (1978)
noted that since toluene is a lipophilic solvent, high concentra-
tions could conceivably 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 injecting
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 leukocytosis
in rats and chromosome damage in 21.6 percent of bone marrow cells.
Although inhalation of benzene caused a similar incidence of
C-41
-------
chromosome damage, leukopenia rather than leukocytosis occurred.
The myelotoxic effects of toluene and benzene were found to be add-
itive when both chemicals were inhaled together. One month post-
exposure, the abnormalities in peripheral blood had resolved, but
the chromosome aberrations persisted. Dobrokhotov and Enikeev
(1977) estimated that toluene at 0.8 g/kg/day induced the same fre-
quency of chromosome damage in their rats as benzene at 0.2
g/kg/day. 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 exposure
limit currently recommended by NIOSH of 100 ppm would most likely
protect against chromosome damage in occupational exposure set-
tings.
A significantly increased frequency of abnormal lymphocytes and
chromosomal breaks has, however, been shown in recent findings on
workers exposed to toluene in a rotoprinting factory and chemical
laboratories (Funes-Cravioto, et al. 1977).
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
C-42
-------
relatively minor metabolites of toluene which have been examined by
Sharma and Ghosh (1965) for their ability to damage chromosomes.
These investigators found that high concentrations could produce
chromosomal aberrations in cells from root tips of Alii* cej>a
bulbs. Of the three isomers, m-cresol caused the most pronounced
changes. It will be recalled that urinary cresols represented 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 In
vitro mutagenicity/carcinogenicity bioassay system, nor to be car-
cinogenic in animals or man. Pluck, et al. (1976) tested toluene
and benzyl alcohol for their carcinogenic potential in an E. coll
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' in-
solubility in the aqueous test medium. Toluene has been utilized
extensively 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 tol-
uene throughout the lifetime of mice being used as controls and
found no carcinogenic response. Doak, et al. (1976) applied tolu-
ene to the skin of mice for one year and failed to elicit skin neo-
plasms or an increased 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. LiJin-
sky and Garcia (1972) did report a skin papilloma in one mouse and a
C-43
-------
skin carcinoma in a second mouse in a group of 30 animals which were
subjected to topical applications of 16 to 20 ul of toluene twice a
week for 72 weeks. Mazzucco (1975) found a reduction in collagen
content of the skin of mice subjected to epidermal paintings with
toluene three times weekly for 10 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-methylcholan-
threne. There has been no increase in tumor incidence in experi-
mental rats as compared to controls after 18 months of a 2-year
toluene inhalation study (Gibson, 1979). In this study, male and
female rats have inhaled 30, 100, or 300 ppm toluene 6 hours/day, 5
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 investigators
found a greater than expected risk of death from cancer, with the
C-44
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largest mortality excesses from lymphosarcoma, Hodgkin's disease,
lymphatic leukemia, and myeloid leukemia. Upon testing the hypo-
thesis that the excess in cancers was due to hydrocarbon solvent
exposure, an association was established between duration and in-
tensity 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 subsequently developed
chronic myeloid leukemia. McMichael and his associates point out
that benzene does not appear to cause lymphatic leukemia, but rath-
er 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 epi-
demiological studies of the carcinogenic potential of many solvents
generally regarded as noncarcinogenic. 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 at-
tribute tumor induction to any single agent.
C-45
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CRITERION FORMULATION
Existing Guidelines and Standards
The Occupational Safety and Health Administration (OSHA) cur-
rently limits occupational toluene exposure to 200 ppm as an 8-hour
time-weighted average (TWA) concentration, with a ceiling of 300
ppm (40 CFR 1910.1000). The National Institute for Occupational
Safety and Health (NIOSH, 1973) has recommended an exposure limit
of 100 ppm as an 8-hour TWA with a ceiling of 200 ppm. This criter-
ion was recommended primarily on the basis of subjective and objec-
tive 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 NIOSH (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 contami-
nants of drinking water was undertaken by the Committee on Safe
Drinking Water of the National Academy of Sciences (NAS, 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 Regulations promulgated under the
Safe Drinking Water Act of 1974. Toluene was one of the organic
chemicals considered by the Committee. Although it was concluded
that toluene and its major metabolite, benzoic acid, were relative-
ly nontoxic, the committee felt there was insufficient toxico-
logical data available to serve as a basis for setting a long-term
C-46
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ingestion standard. It was recommended that studies be conducted
to produce relevant information (NAS, 1977). Toluene has recently
been considered for a second time by a reorganized Toxicology Sub-
committee 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 jag/1 were found in finished water from the New Orleans area
(U.S. EPA, 1975a). In a nationwide survey of water supplies from
10 cities, six were discovered to be contaminated with toluene
(U.S. EPA, 1975b). Concentrations of 0.1 and 0.7 ng/1 were mea-
sured in two of these water supplies. Toluene was detected in one
of 111 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 sur-
veyed (U.S. EPA, 1977). A level of 19 ug/1 measured by gas chroma-
tography/mass spectrometry was found in one of these finished wa-
ters, and 0.5 wg/1 was found in another.
There is a paucity of data available on levels of toluene in
foods. Toluene was detected in fish caught from polluted waters in
the proximity of petroleum and petrochemical plants in Japan (Ogata
and Miyake, 1973). A concentration of 5 ^g/g was measured in
the muscle of one such fish. Two major metabolites of toluene,
C-47
-------
benzaldehyde and benzole 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, concen-
trations are many times lower than vapor levels considered to be
potentially harmful in occupational settings. An atmospheric con-
centration of 39 ppb toluene was measured in Zurich, Switzerland
(Grob and Grob, 1971). An average level of 37 ppb toluene was ob-
served in Los Angeles air in 1966 (Lonneman, et al. 1968). The max-
imum amount detected there was 129 ppb. Comparable levels were
found upon evaluation 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 atmo-
spheric 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 ap-
pears that atmospheric toluene in urban areas arises primarily from
automotive emissions, with solvent losses as a secondary source.
The most significant toluene inhalation exposures occur in
occupational settings or via inhalant abuse. Occupational exposure
levels are generally lower than the current standard of 100 ppm,
although short exposures to higher vapor concentrations occur.
Purposeful inhalation of toluene vapors in order to inebriate one-
self is a quite different situation, since the participant may
inhale extremely high concentrations repeatedly for months or
C-48
-------
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 environment,
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 Criteria
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 metabolism and bioactivity of certain chemicals which
are degraded by the mixed function oxidase system. Toluene appears
to have little capacity to cause residual tissue injury. There is
no conclusive evidence that the parent compound or its metabolites
are mutagenic, although they have apparently not been tested in an
in vitro mutagenicity assay (Dean, 1978). Although toluene has not
been found to be teratogenic in chickens and rats (Roche and Hine,
1968) or rats and mice (Hudak and Ungvary, 1978), one recent study
by Nawrot and Staples (1979) reports teratogenic effects in mice.
Toluene has not been demonstrated to be carcinogenic when applied
to the skin of mice (Poel, 1963; Doak, et al. 1976) or when admin-
istered by inhalation at concentrations of up to 300 ppm for as
C-49
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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 specifically to toluene.
A number of investigations of the subacute and chronic toxi-
city of toluene have been conducted. Although the heaviest empha-
sis has been placed upon inhalation exposure, Wolf, et al. (1956)
did conduct a long-term, oral dosing study in which female rats
were given toluene at 118, 354, or 590 mg/kg 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 evidence of residual injury in
a variety of animal species subjected to toluene vapor for varying
times over periods as long as 18 months (Jenkins, et al. 1970;
Carpenter, et al. 1976; Bruckner and Peterson, 1978; Rhudy, et al.
1978; Gibson, 1979).
Therefore, it seems reasonable that the highest dose utilized
by Wolf, et al. (1956), namely 590 mg/kg, might serve as the basis
for calculating an "Acceptable Daily Intake" for toluene. Although
590 mg/kg will be considered here as a "maximum-no-effeet" dose, it
should be recognized that the actual "maximum-no-effeet" dose may
be higher, since Wolf, et al. (1956) did not determine a "minimum-
toxic-dose." Reynolds and Yee (1968) saw no effect on several
parameters of hepatotoxicity in rats given a single oral dose of
2.4 g/kg toluene. The acute oral LD_ for toluene in young, adult
C-50
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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. Humans
may prove to be more sensitive to toluene than experimental ani-
mals. Thus, assuming a 70 kg body weight, it seems appropriate
that a safety factor of 1,000 be applied in the following calcula-
tion:
590 mg/kg x 70 kg x 5/7 day _ 29.5 mg/day
1,000
Therefore, consumption of 2 liters of water daily and 6.5 g of con-
taminated fish having a bioconcentration factor of 10.7, would
result in, assuming 100 percent gastrointestinal absorption of tol-
uene, a maximum permissible concentration of 14.3 mg/1 for the
ingested water:
29.5 mg/day =14.3 mg/1
(21+ (10.7 x 0.0065) x 1.0
This calculation assumes that 100 percent of man's exposure
comes from water. Although it is desirable to arrive at a criter-
ion 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 1,000, the criterion level for
toluene is 14.3 mg/1. Drinking water contributes 97 percent of the
assumed exposure, while eating contaminated fish products accounts
for 3 percent. The criterion level for toluene can alternatively
be expressed as 424 mg/1 if exposure is assumed' to be from the con-
sumption of fish and shellfish products alone.
C-51
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REFERENCES
Abou-El-Makarem, M.M., et al. 1967. Biliary excretion of foreign
compounds. Benzene and its derivatives in the rat. Biochem. Jour.
105: 1269.
Altshuller, A.P., et al. 1971. Hydrocarbon composition of the
atmosphere of the Los Angeles Basin-1967. Environ. Sci. Tech.
5: 1009.
Andrews, L.S., et al. 1977. Effects of toluene on the metabolism,
disposition and hemopoietic toxicity of (3H) benzene. Biochem.
Pharmacol. 26: 293.
Aranka, H., et al. 1975. Experimental study of the hepatotoxic
effect of toluol. I. Histological and histochemical studies.
Morphol. Igazsagugyi Orv. Sz. 15: 209.
Astrand, I., et al. 1972. Toluene exposure. I. Concentration in
alveolar air and blood at rest and during exercise. Work Environ.
Health. 9: 119.
Astrand, I., et al. 1975. Uptake of solvents in the blood and
tissues of man. A review. Scand. Jour. Work Environ. Health.
1: 199.
C-52
-------
Axelson, O., .t al. 1976. A case-referent study on neuropsychi-
atric disorders amon, workers exposed to solvents. Scand. Jour.
Environ. Health. 2: 14.
Bakke, O.M. and R.R. Scheline. 1970. Hydroxylation of aromatic
hydrocarbons in the rat. Toxicol. Appl. Pharmacol. 16: 691.
Banfer, W. 1961. Studies on the effect of pure toluene on the
blood picture of photogravure printers and helper workers. Zen-
tralbl. Arbeitsmed. 11: 35.
Barman, M.L., et al. 1964. Acute and chronic effects of glue
sniffing. Calif. Med. 100: 19.
Bass, M. 1970. Sudden sniffing death. Jour. Am. Med. Assoc.
212: 2075.
Beirne, G.J. and J.T. Brennan. 1972. Glomerulonephritis associ-
ated with hydrocarbon solvents. Arch. Environ. Health. 25: 365.
Bereznyi, E.A., et al. 1975. Method for the evaluation of elec-
trocardiograms in toxicological experiments using a heart rhythm
histogram series. Tr. Leningr. Sanit. Gig. Med. Inst. Ill: 73.
Bernshtein, L.M. 1972. Phagocytosis reaction in experimental ani-
mals on chronic poisoning by vapors of benzene and its methyl deri-
vatives. Vop. Gig. Tr. Profzabol., Mater. Nauch. Konf.: 53.
C-53
-------
Boor, J.w. and H.I. Hurtig. 1977. Persistent cerebellar ataxia
after exposure to toluene. Ann. Neurol. 2: 440.
Bray, H.G., et al. 1951. Kinetic studies of the metabolism of
foreign organic compounds. I. The formation of benzoic acid from
benzamide, toluene, benzyl alcohol and benzaldehyde and its conju-
gation with glycine and glucuronic acid in the rabbit. Biochem.
Jour. 48: 88.
Bruckner, J.V. and R.G. Peterson. 1976. Evaluation of toluene
toxicity utilizing the mouse as an animal model of solvent abuse.
Pharmacologist. 18: 244.
Bruckner, J.v. and R.G. Peterson. 1978. Effect of repeated expo-
sure of mice and rats to concentrated toluene and acetone vapors.
Toxicol. Appl. Pharmacol. 45: 359.
Capellini, A. and L. Alessio. 1971. The urinary excretion of hip-
pur ic acid in workers exposed to toluene. Med. Lavoro 62: 196.
Capurro, P.U. 1976. Hydrocarbon exposure and cancer. Lancet.
1: 253.
Carlsson, A. and T. Lindqvist. 1977. Exposure of animals and man
to toluene. Scand. Jour. Work Environ. Health. 3: 135.
C-54
-------
carpenter, C.P., et al. 1976. Petroleum hydrocarbon toxicity
studies. XIII. Animal and human response to vapors of toluene con-
centrate. Toxicol. Appl. Pharmacol. 36: 473.
Chenoweth, M.B. 1946. Ventricular fibrillation induced by hydro-
carbons and epinephrine. Jour. Ind. Hyg. Toxicol. 28: 151.
Coleman, W.E., et al. 1976. The Occurrence of Volatile Organics
in Five Drinking Water Supplies Using GC/MS. In: L.H. Keith, (ed.)
tdentification and Analysis of Organic Pollutants in Water, 1st ed.
Ann arbor Science Publishers, Inc., Ann Arbor, Michigan.
Curtes, J.P., et al. 1973. Leucemie myeloide chronique d'origine
toxique. Jour. Eur. Toxicol. 6: 306.
Dean, B.J. 1978. Genetic toxicology of benzene, toluene, xylenes
and phenols. Mutat. Res. 47: 75.
Dec, G., et al. Water solubility and octanol/water partition coef-
ficients of organics: Limitationns of the solubility-partition co-
efficient correlation. (Manuscript)
Divincenzo, G.D. and W.J. Krasavage. 1974. Serum ornithine car-
bamyl transferase as a liver response test for exposure to organic
solvents. Am. Ind. Byg. Assoc. Jour. 35: 21.
C-55
-------
Doak, S.M.A., et al. 1976. The carcinogenic response in mice to
the topical application of propane sultone to the skin. Toxicol-
ogy. 6: 139.
Dobrokhotov, V.B. and M.I. Enikeev. 1977. Mutagenic effect of
benzene, toluene, and a mixture of these hydrocarbons in a chronic
experiment. Gig. Sanit. 1: 32.
Dutkiewicz, T. and H. Tyras. 1968. The quantitative estimation of
toluene skin absorption in man. Int. Arch. Gewerbepath. Gewerbe-
hyg. 24: 253.
El Masry, A.M., et al. 1956. Studies in detoxication. 69. The
metabolism of alkylbenzenes: n-Propybenzene and n-butylbenzene
with further observations on ethylbenzene. Biochem. Jour. 64: 50.
Engstrom, K., et al. 1976. Measurement of toluene and xylene
metabolites by gas chromatography. Int. Arch. Occup. Environ.
Health. 36: 153.
Fabacher, D.L. and E. Hodgson. 1977. Hepatic mixed-function oxi-
dase activity in mice treated with methylated benzenes and methyl-
ated napthalenes. Jour. Toxicol. Environ. Health. 2: 1143.
Fluck, E.R., et al. 1976. Evaluation of a DNA polymerase-defi-
cient mutant of E. Coli for the rapid detection of carcinogens.
Chem. Biol. Inter. 15: 219.
C-56
-------
Forni, A., et al. 1971. Chromosome studies in workers exposed to
benzene or toluene or both. Arch. Environ. Health. 22: 373.
Friborska, A. 1973. Some cytochemical findings in the peripheral
white blood cells in workers exposed to toluene. Folia Haematol.
Leipzig. 99: 233.
Funes-Craviota, P., et al. 1977. Chromosome aberrations and
sister-chromatid exchange in workers in chemical laboratories and
a rotoprinting factory and in children of women laboratory workers.
Lancet. 2: 322.
Furnas, D.W. and C.H. Hine. 1958. Neurotoxicity of some selected
hydrocarbons. Arch. Ind. Health. 18: 9.
Gamberale, F. and M. Hultengren. 1972. Toluene exposure II.
Psychophysiological functions. Work Environ. Health. 9: 131.
Gibson, J.E. 1979. Two year vapor inhalation toxicity study with
toluene in Fischer-344 albino rats: 18-month status summary. Chem-
ical Industry Institute of Toxicology. (Personal communication)
Goto, I., et al. 1974. Toxic polyneuropathy due to glue sniffing.
Jour. Neurol. Neurosurg. Psychiatry. 37: 848.
Grabski, D.A. 1961. Toluene sniffing producing cerebellar degen-
eration. Am. Jour. Psychiatry. 118: 461.
C-57
-------
Greenburg, L., et al. 1942. The effects of exposure to toluene in
industry. Jour. Am. Med. Assoc. 118: 573.
Grob, K. and G. Grob. 1971. Gas-liquid chromatographic/mass spec-
trometric investigation of Cg-C20 organic compounds in an urban
atmosphere. Jour. Chromatogr. 62: 1.
Hanninen, H., et al. 1976. Behavioral effects of long-term expo-
sure to a mixture of organic solvents. Scand. Jour. Work Environ.
Health. 4: 240.
Hansch, C. and A.J. Leo. 1979. Substituent Constants for Correla-
tion Analysis in Chemistry and Biology. Wiley-Interscience, New
York.
Holmberg, B. and T. Malmfors. 1974. The cytotoxicity of some
organic solvents. Environ. Res. 7: 183.
Horiguchi, S., et al. 1976. Studies on industrial toluene poison-
ing. Part IV. Effects of toluene on wheel-turning activity and
peripheral blood findings in mice. Sumitomo Sangyo Eisei. 12: 81.
Hudak, A. and G. Ungvary. 1978. Embryotoxic effects of benzene
and its methyl derivatives: toluene and xylene. Toxicology.
11: 55.
C-58
-------
Ikeda, M. 1974. Reciprocal metabolic inhibition of toluene and
trichloroethylene in vivo and in vitro. Int. Arch. Arbeitsmed.
33: 125.
Ikeda, T. and H. Miyake. 1978. Decreased learning in rats follow-
ing repeated exposure to toluene: Preliminary report. Toxicol.
Lett. 1: 235.
Ikeda, M. and H. Ohtsuji. 1969. Significance of urinary hlppuric
acid determination as an index o£ toluene exposure. Br. Jour. Ind.
Med. 26: 244.
Ikeda, M. and H. Ohtsuji. 1971. Phenobarbital-induced protection
against toxicity of toluene and benzene in the rat. Toxicol. Appl.
Pharmacol. 20: 30.
Ikeda, M., et al. 1972. In vivo suppression of benzene and styrene
oxidation by co-administered toluene in rats and effects of pheno-
barbital. Xenobiotica. 2: 101.
inoue, K. 1975. Studies on occupational toluene exposure. (2) An
animal experiment using inhalation of toluene vapor in mice. Osaka
Shiritsu Daigaku Igaku Zasshi. 24: 791.
ishikawa, T.T. and H. Schmidt, Jr. 1973. Forced turning induced
by toluene. Pharmacol. Biochem. Behav. 1: 593.
C-59
-------
Jenkins, L.J., Jr., et al. 1970. Long-terra inhalation screening
studies of benzene, toluene, o-xylene, and cumene on experimental
animals. Toxicol. Appl. Pharmacol. 16: 818.
Keane, J.R. 1978. Toluene optic neuropathy. Ann. Neurol.
4: 390.
Kelly, T.W. 1975. Prolonged cerebellar dysfunction associated
with paint-sniffing. Pediatrics. 56: 605.
Kimura, E.T., et al. 1971. Acute toxicity and limits of solvent
residue for sixteen organic solvents. Toxicol. Appl. Pharmacol.
19: 699.
Knox, J.W. and J.R. Nelson. 1966. Permanent encephalopathy from
toluene inhalation. New England Jour. Med. 275: 1494.
Koga, K. and Y. Ohmiya. 1978. Potentiation of toluene toxicity by
hepatic enzyme inhibition in mice. Jour. Toxicol. Sci. 3: 25.
Kojima, T. and H. Kobayashi. 1973. Toxicological study on toluene
poisoning by inhalation. Correlation of toluene concentrations for
exposure with mortality and toluene tissue levels. Nippon Hoigaku
Zasshi. 27: 282.
Korobkin, R., et al. 1975. Glue-sniffing neuropathy. Arch.
Neurol. 32: 158.
C-60
-------
Lange, A., et al. 1973a. Serum immunoglobulin levels in workers
exposed to benzene, toluene and xylene. Int. Arch. Arbeitsmed.
31: 37.
Lange, A., et al. 1973b. Leukocyte agglutinins in workers exposed
to benzene, toluene and xylene. Int. Arch. Arbeitsmed. 31: 45.
Lijinsky, W. and H. Garcia. 1972. Skin carcinogenesis tests of
hydrogenated derivatives of anthracene and other polynuclear hydro-
carbons. Z. Krebstorsch. Klin. Onkol. 77: 226.
Lindstrom, K. 1973. Psychological performances of workers exposed
to various solvents. Work Environ. Health. 10: 151.
Litt, I.P., et al. 1972. Liver disease in the drug-using adoles-
cent. Jour. Pediatr. 81: 238.
Longley, E.O., et al. 1967. Two acute toluene episodes in mer-
chant ships. Arch. Environ. Health. 14: 481.
Lonneman, W.A., et al. 1968. Aromatic hydrocarbons in the atmo-
sphere of the Los Angeles Basin. Environ. Sci. Technol. 2: 1017.
Lurie, J.B. 1949. Acute toluene poisoning. South African Med.
Jour. 23: 233.
C-61
-------
Lyapkalo, A.A. 1973. Genetic activity of benzene and toluene.
Gig. Tr. Prof. Zabol. 17: 24.
Mabuchi, C., et al. 1974. Neurological symptoms in chronic intox-
ication by organic solvents. Igaku no Ayumi. 88: 97.
Mackay, D. and A.W. Wolkoff. 1973. Rate of evaporation of low-
solubility contaminants from water bodies to atmosphere. Environ.
Sci. Technol. 7: 611.
Massengale, O.N., et al. 1963. Physical and psychological factors
in glue sniffing. New England Jour. Med. 269: 1340.
Matsushita, T., et al. 1975. Hematological and neuro-muscular
response of workers exposed to low concentration of toluene vapor.
Ind. Health. 13: 115.
Mazzucco, K. 1975. Effect of some solvents (benzene, toluene,
acetone) used for carcinogens on the collagen content of mouse
dorsal skin. Oesterr. Z. Onkol. 2: 49.
McMichael, A.J., et al. 1975. Solvent exposure and leukemia among
rubber workers: An epidemiologic study. Jour. Occup. Med.
17: 234.
Miyaska, M., et al. 1971. Electroencephalographic and polygraphic
studies on sniffers of thinner-bond. Rinsho Nona. 13: 371.
C-62
-------
Morvai, V., et al. 1976. EGG changes in benzene, toluene and
xylene poisoned rats. Acta Med. Acad. Sci. Hung. 33: 275.
National Academy of Sciences. 1972. Food Chemicals Codex. 2nd
ed. Washington, D.C.
National Academy of Sciences. 1976. Vapor phase organic pollut-
ants - volatile hydrocarbons and their oxidation products. Wash-
ington, D.C.
National Academy of Sciences. 1977. Drinking Water and Health.
Washington, D.C.
National Institute on Drug Abuse. 1977. Review of inhalants:
Euphoria to dysfunction. Res. Monogr. 15. Rockville, Maryland.
National Institute for Occupational Safety and Health. 1973. Cri-
teria for a recommended standard...occupational exposure to tolu-
ene. HEW Publ. No. HSM 73-11023. U.S. Gov. Printing Off.,
Washington, D.C.
Nawrot, P.S. and R.E. Staples. 1979. Embryo-fetal toxicity and
teratogenicity of benzene and toluene in the mouse. Teratology.
19: 41A.
C-63
-------
Nomiyama, K. and H. Nomiyama. 1974. Respiratory elimination of
organic solvents in man. Benzene, toluene, n-hexane, trichloro-
ethylene, acetone, ethyl acetate and ethyl alcohol. Int. Arch.
Arbeitsmed. 32: 85.
Nomiyama, K. and H. Nomiyama. 1978. Three fatal cases of thinner-
sniffing, and experimental exposure to toluene in human and ani-
mals. Int. Arch. Occup. Environ. Health. 41: 55.
O'Brien, E.T., et al. 1971. Hepatorenal damage from toluene in a
"glue sniffer." Br. Med. Jour. 2: 29.
Ogata, M. and Y. Miyake. 1973. Identification of substances in
petroleum causing objectionable odor in fish. Water Res. 7: 1493.
Ogata, M., et al. 1970. Urinary excretion of hippuric acid and m-
or p-methylhippuric acid in the urine of persons exposed to vapors
of toluene and m- or p-xylene as a test of exposure. Br. Jour. Ind.
Med. 27: 43.
Ohmori, S., et al. 1975. The metabolism and accumulation of pe-
troleum components in fish: The side chain oxidation of p-nitro-
toluene and p-nitrobenzyl alcohol in liver homogenates of the rat
and eel. Physiol. Chem. Physics. 7: 477.
C-64
-------
Peterson, R.G. and J.V. Bruckner. 1976. Measurement of toluene
levels in animal tissues. Proc. Int. Symp. Deliberate Inhalation
of Industrial Solvents, Mexico City.
Pilar, S. and W.P. Graydon. 1973. Benzene and toluene distribu-
tion in Toronto atmosphere. Environ. Sci. Technol. 7: 628.
Poel, W.E. 1963. Skin as a test site for the bioassay of carcino-
gens and carcinogen precursors. Natl. Cancer Inst. Monogr.
10: 611.
Powars, D. 1965. Aplastic anemia secondary to glue sniffing. New
England Jour. Med. 273: 700.
Press, E. and A.K. Done. 1967. Solvent sniffing. Physiological
effects and community control measures for intoxication from the
intentional inhalation of organic solvents. I and II. Pediatrics.
39: 451.
Pyykko, K., et al. 1977. Toluene concentrations in various tis-
sues of rats after inhalation and oral administration. Arch. Toxi-
col. 38: 169.
Reisin, E., et al. 1975. Myoglobinuria and renal failure in tolu-
ene poisoning. Br. Jour. Ind. Med. 32: 163.
C-65
-------
Reynolds, E.S. 1972. Comparison of early injury to liver endo-
plasmic reticulum by halomethanes, hexachloroethane, benzene, tol-
uene, bromobenzene, ethionine, thioacetaraide and dimethyl-
nitrosamine. Biochem. Pharmacol. 21: 2555.
Reynolds, E.S. and A.G. Yee. 1968. Liver parenchymal cell injury.
VI. Significance of early glucose-6-phosphatase suppression and
transient calcium influx following poisoning. Lab. Invest.
19: 273.
Rhudy, R.L., et al. 1978. Ninety-day subacute inhalation study
with toluene in albino rats. Toxicol. Appl. Pharmacol. 45: 284.
Roche, S.M. and C.H. Hine. 1968. The teratogenicity of some in-
dustrial chemicals. Toxicol. Appl. Pharmacol. 12: 327.
Sato, A., et al. 1974. Pharmacokinetics of benzene and toluene.
Int. Arch. Arbeitsmed. 33: 169.
Satran, R. and V.N. Dodson. 1963. Toluene habituation. Report of
a case. New England Jour. Med. 268: 719.
Savolainen, H. 1978. Distribution and nervous system binding of
intraperitoneally injected toluene. Acta Pharmacol. Toxicol.
43: 78.
C-66
-------
Schenkman, J.B., et al. 1973. The mitochondrial role in hepatic
cell mixed-function oxidations. Ann. N.Y. Acad. Sci. 212: 420.
Sharma, A.K. and S. Ghosh. 1965. Chemical basis of the action of
cresols and nitrophenols on chromosomes. Nucleus. 8: 183.
Shirabe, T., et al. 1974. Toxic polyneuropathy due to glue-sniff-
ing. Report of two cases with a light and electron-microscopic
study of the peripheral nerves and muscles. Jour. Neurol. Sci.
21: 101.
Smith, J.N., et al. 1954. Studies in detoxication. 55. The meta-
bolism of alkylbenzenes. (a) Glucuronic acid excretion following
the administration of alkylbenzenes. (b) Elimination of toluene in
the expired air of rabbits. Biochem. Jour. 56: 317.
Smolik, R., et al. 1973. Serum complement level in workers ex-
posed to benzene, toluene and xylene. Int. Arch. Arbeitsmed.
31: 243.
Stephan, C.E. 1980. Memorandum to J. Stara. U.S. EPA. July 3.
Suzuki, T., et al. 1974. Muscular atrophy due to glue sniffing.
Int. Arch. Arbeitsmed. 33: 115.
Svirbely, J.L., et al. 1943. The acute toxcity of vapors of cer-
tain solvents containing appreciable amounts of benzene and tolu-
ene. Jour. Ind. Hyg. Toxicol. 25: 366..
C-67
-------
Syrovadko, O.N. 1977. Working conditions and health status of
women handling organosiliceous varnishes containing toluene. Gig.
Tr. Prof. Zabol. 12: 15.
Taher, S.M., et al. 1974. Renal tubular acidosis associated with
toluene "sniffing." New England Jour. Med. 290: 765.
Tahti, H., et al. 1977. Toluene toxicity studies on rats after
one week inhalation exposure. Acta Pharmacol. Toxicol.
41(Suppl.): 78.
Takeuchi, Y. 1969. Experimental studies on the toluene poison-
ing - chiefly on the findings of peripheral blood and adrenal
gland. Ind. Health. 7: 31.
Takeuchi, Y. and N. Hisanaga. 1977. The neurotoxicity of toluene:
EEC changes in rats exposed to various concentrations. Br. Jour.
Ind. Med. 34: 314.
Taylor, G.J. and W.S. Harris. 1970. Glue sniffing causes heart
block in mice. Science. 170: 866.
Towfighi, J., et al. 1976. Glue sniffer's neuropathy. Neurology.
26: 238.
C-68
-------
Ungvary, G., et al. 1976. The effect of toluene on the liver as-
sayed by quantitative morphological methods. Exp. Mol. Pathol.
25: 49.
U.S. EPA. 1975a. New Orleans area water supply study. Analysis of
carbon and resin extracts. Prepared and submitted to the lower
Mississippi River Branch, Surveillance and Analysis Division,
Region VI, by the Analytical Branch, Southeast Environ. Res. Lab.,
Athens, Georgia.
U.S. EPA. 1975b. Preliminary assessment of suspected carcinogens
in drinking water. Rep. to Congress, Washington, D.C.
U.S. EPA. 1977. National Organic Monitoring Survey, general re-
view of results and methodology: Phases I-III.
U.S. EPA. 1980. Seafood consumption data analysis. Stanford
Research Institute International. Menlo Park, California. Final
Rep., Task 11, Contract No. 68-01-3887.
Veith, G.D. 1980. Memorandum to C.E. Stephan. U.S. EPA.
April 14.
Veith, G.D., et al. 1979. Measuring and estimating the biocon-
centration factor of chemicals in fish. Jour. Fish. Res. Board
Can. 36: 1040.
C-69
-------
Wahlberg, J.E. 1976. Percutaneous toxicity of solvents. A com-
parative investigation in the guinea pig with benzene, toluene and
1,1,2-trichloroethane. Ann. Occup. Hyg. 19: 115.
Weisenberger, B.L. 1977. Toluene habituation. Jour. Occup. Med.
19: 569.
Williams, I.H. 1965. Gas chromatographic techniques for the iden-
tification of low concentrations of atmospheric pollutants. Anal.
Chem. 37: 1723.
Winek, C.L., et al. 1968. Toluene fatality from glue sniffing.
Pa. Med. 71: 81.
Wolf, M.A., et al. 1956. Toxicological studies of certain alkyl-
ated benzenes and benzene. Arch. Ind. Health. 14: 387.
Wolff, M.S., et al. 1977. Styrene and related hydrocarbons in
subcutaneous fat from polymerization workers. Jour. Toxicol. Envi-
ron. Health. 2: 997.
World Health Organization. 1974. Toxicological evaluation of some
food additives including anticaking agents, antimicrobials, anti-
oxidants, emulsifiers and thickening agents. WHO Food Additive
Ser. No. 5: 34.
C-70
-------
Yushkevich, L.B. and M.V. Malysheva. 1975. Study of the bone mar-
row as an index of experimentally-induced poisoning with chemical
substances (such as benzene and its homologs). Sanit. Toksikol.
Metody Issled. Gig: 36.
Zimmerman, S.W., et al. 1975. Hydrocarbon exposure and chronic
glomerulonephritis. Lancet. 2: 199.
C-71
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