EXECUTIVE SUMMARY
Toluene is a colorless liquid that is widely used as raw material in the
production of organic
compounds and as a solvent (U.S. EPA, 1990). It is readily absorbed from
the gastrointestinal and
respiratory tracts, and to a lesser degree through the skin. Toluene is
distributed throughout the body, with
accumulation in tissues with high lipid content. It is metabolized in the
liver, primarily to hippuric acid and
benzoyl glucuronide, compounds that are rapidly excreted in the urine
(U.S. EPA, 1990; ATSDR, 1989).
In humans and animals, the primary effect associated with inhalation
exposure to toluene is central
nervous system (CNS) depression. Short-term exposure of humans to 100-1500
ppm has elicited CNS
effects such as fatigue, confusion, incoordination, and impairments in
reaction time, perception, and motor
control and function (NTP, 1990). Exposure to concentrations ranging from
10,000 to 30,000 ppm has
resulted in narcosis and deaths (WHO, 1985). Prolonged abuse of toluene or
solvent mixtures containing
toluene has led to permanent CNS effects. Exposure to high concentrations
of toluene (1500 ppm) has
produced hearing loss in rats (Pryor et al., 1984). Hepatomegaly and
impaired liver and kidney function
have been reported in some humans chronically exposed to toluene
(Askergren, 1984; Szilard et al., 1978;
Greenburg et al., 1942). Toluene vapors may cause eye irritation (Andersen
et al., 1983) and prolonged
or repeated dermal contact may produce drying of skin and dermatitis
(ATSDR, 1989; NIOSH, 1973).
In experimental animals, subchronic inhalation exposure to $2500 ppm
toluene resulted in increased
liver and kidney weights (rats and mice), increased heart weights (rats),
increased lung weights, and
centrilobular hypertrophy of the liver (mice) (NTP, 1990). Chronic
inhalation exposure to 600 or 1200
ppm for 2 years produced degeneration of olfactory and respiratory
epithelia of rats and minimal
hyperplasia of bronchial epithelia in mice (NTP, 1990).
Subchronic oral administration of toluene at doses ranging from 312 to
5000 mg/kg/day produced clinical
signs of neurotoxicity at $2500 mg/kg in rats and mice. Other effects in
rats observed at the higher doses
included increased relative liver, kidney, and heart weights (females
only), and necrosis of the brain and
hemorrhage of the urinary bladder (NTP, 1990).
There is equivocal evidence that exposure to toluene in utero causes an
increased risk of CNS
abnormalities and developmental delay in humans (Goodwin, 1988; Hersh et
al., 1985; Holmberg, 1979).
Animal studies, in which toluene was administered by inhalation, showed
that toluene exposure results in
fetotoxicity and delayed skeletal development but does not cause internal
or external malformations in rats
(Courtney et al., 1986; Litton Bionetics, 1978). An oral study noted an
increased incidence of embryonic
deaths, cleft palate, and maternal toxicity in mice administered 1 mL/kg
toluene during gestation (Nawrot
and Staples, 1979).
An oral reference dose (RfD) of 2 mg/kg/day for subchronic exposure (U.S.
EPA, 1993) and 0.2
mg/kg/day for chronic exposure (U.S. EPA, 1992) to toluene was calculated
based on a no-observedadverse-
effect level (NOAEL) of 223 mg/kg/day and a lowest-observed-adverse-effect
level (LOAEL)
of 446 mg/kg/day from a 13-week subchronic gavage study in rats (NTP,
1990). Increased liver and
kidney weights in males were identified as the critical effects. A
subchronic (U.S. EPA, 1993) and
chronic inhalation reference concentration (RfC) of 0.4 mg/m3 (U.S. EPA
1992) was calculated based on
results of a battery of neurological tests with occupationally exposed
female subjects (Foo et al., 1990).
An increased incidence of hemolymphoreticular neoplasms was reported in
rats exposed to 500
mg/kg of toluene by gavage for 2 years (Maltoni et al., 1985); however,
results from two long-term
inhalation studies (NTP, 1990; Gibson and Hardisty, 1983) indicate that
toluene is not carcinogenic at
concentrations up to 1200 ppm. Based on U.S. EPA guidelines, toluene was
assigned to weight-ofevidence
group D, not classifiable as to human carcinogenicity (U.S. EPA, 1992).
1. INTRODUCTION
Toluene (C6H5CH3; CAS No. 108-88-3), also known as methylbenzene and
phenylmethane, is a
colorless liquid with a sweet pungent odor (HSDB, 1992). It has a
molecular weight of 92.15, a density of
0.8669 g/mL at 20°C, and an octanol/water partition coefficient of 2.79
(Lide, 1991; Mabey et al., 1982).
Toluene is isolated by distillation of reformed or pyrolized petroleum and
coal tar; however, most of the
toluene produced remains as a benzene-toluene-xylene (BTX) mixture for use
in gasoline. The primary
use of isolated toluene is in the production of benzene and for
backblending into gasoline to increase
octane ratings (U.S. EPA, 1990). Toluene is also used as raw material in
the production of benzyl
chloride, benzoic acid, phenol, cresols, vinyl toluene, TNT, and toluene
diisocyanate (U.S. Air Force,
1989), and as a solvent for paints and coatings, and in adhesives, inks,
and pharmaceuticals (U.S. EPA,
1990).
Inhalation is the primary route of exposure to toluene for the general
population and for
occupationally exposed individuals. Evaporation of gasoline and automobile
exhaust is the largest source
of toluene in the environment, and industries that use toluene as a
solvent are the second largest source
(U.S. EPA, 1984). Toluene is also a common indoor contaminant due to
releases from common
household products and from cigarette smoke (ATSDR, 1989). Non-atmospheric
releases of toluene are
relatively small (e.g., to water and soil) and are estimated to comprise
less than 1% of total toluene
releases (ATSDR, 1989). In the atmosphere, toluene is degraded by reaction
with hydroxyl radicals, with
a typical half-life of about 13 hours. It is highly volatile and
volatilization is likely to be the predominant
removal process from soil and water. Toluene is also subject to microbial
degradation. Because of
volatilization and biodegradation, toluene levels in the environment are
not expected to increase over time
(U.S. EPA, 1990; ATSDR, 1989).
2. METABOLISM AND DISPOSITION
2.1. ABSORPTION
Toluene is readily absorbed from the respiratory and gastrointestinal
tracts, and to a lesser extent
through the skin. Animal studies suggest that absorption from the
gastrointestinal tract is complete.
Absorption data for humans and animals indicate that pulmonary absorption
is 85-90% during brief
exposures, but nearer to 50% during extended exposures (<1 hour). In
humans, toluene has been
detected in the arterial blood within 10 seconds after initiation of
inhalation exposures. Cutaneous
absorption is approximately 1% of that absorbed by the lungs when there is
exposure to the vapor;
however, dermal absorption of the liquid may be higher. Because toluene
evaporates readily, it is unlikely
that significant absorption will occur by this route. Exercise greatly
increases the absorption of toluene
(U.S. EPA, 1990).
2.2. DISTRIBUTION
Distribution of toluene following absorption occurs throughout the body,
with accumulation in
adipose tissue, other tissues with high fat content, and highly vascular
tissues. High levels of toluene were
found in the brain and liver of an individual who had died following an
episode of glue sniffing (Paterson
and Sarvesvaran, 1983). Autoradiography studies using mice indicate that
immediately after inhalation
exposure, a high level of radioactivity is present in the body fat, bone
marrow, spinal nerves, spinal cord,
and white matter of the brain. Radioactivity was also observed in the
blood, kidney, and liver, but at lower
levels (Bergman, 1979). In one individual who died 30 minutes after
ingestion of toluene, the liver had the
highest concentration of toluene, followed by the pancreas, brain, heart,
blood, body fat, and cerebrospinal
fluid (Ameno et al., 1989). Since retention time of toluene is usually
considered to be less than 24 hours,
bioaccumulation of toluene is unlikely (U.S. EPA, 1990).

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