INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 52
TOLUENE
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
Published under the joint sponsorship of
the United Nations Environment Programme,
the International Labour Organisation,
and the World Health Organization
World Health Orgnization
Geneva, 1985
The International Programme on Chemical Safety (IPCS) is a
joint venture of the United Nations Environment Programme, the
International Labour Organisation, and the World Health
Organization. The main objective of the IPCS is to carry out and
disseminate evaluations of the effects of chemicals on human health
and the quality of the environment. Supporting activities include
the development of epidemiological, experimental laboratory, and
risk-assessment methods that could produce internationally
comparable results, and the development of manpower in the field of
toxicology. Other activities carried out by the IPCS include the
development of know-how for coping with chemical accidents,
coordination of laboratory testing and epidemiological studies, and
promotion of research on the mechanisms of the biological action of
chemicals.
ISBN 92 4 154192 X
The World Health Organization welcomes requests for permission
to reproduce or translate its publications, in part or in full.
Applications and enquiries should be addressed to the Office of
Publications, World Health Organization, Geneva, Switzerland, which
will be glad to provide the latest information on any changes made
to the text, plans for new editions, and reprints and translations
already available.
(c) World Health Organization 1985
Publications of the World Health Organization enjoy copyright
protection in accordance with the provisions of Protocol 2 of the
Universal Copyright Convention. All rights reserved.
The designations employed and the presentation of the material
in this publication do not imply the expression of any opinion
whatsoever on the part of the Secretariat of the World Health
Organization concerning the legal status of any country, territory,
city or area or of its authorities, or concerning the delimitation
of its frontiers or boundaries.
The mention of specific companies or of certain manufacturers'
products does not imply that they are endorsed or recommended by the
World Health Organization in preference to others of a similar
nature that are not mentioned. Errors and omissions excepted, the
names of proprietary products are distinguished by initial capital
letters.
CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR TOLUENE
1. SUMMARY AND RECOMMENDATIONS
1.1. Summary
1.1.1. Identity and analytical methods
1.1.2. Production, uses, and sources of exposure
1.1.3. Kinetics, biotransformation, and biological
monitoring
1.1.4. Effects on experimental animals
1.1.5. Effects on human beings
1.1.6. Effects on aquatic and terrestrial organisms in the
environment
1.2. Conclusions and recommendations
1.2.1. Conclusions
1.2.2. Recommendations
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Organoleptic properties
2.4. Conversion factors
2.5. Analytical methods
2.5.1. Sampling procedures
2.5.1.1 Air
2.5.l.2 Water
2.5.1.3 Soils and sediments
2.5.2. Biological monitoring of toluene exposure
2.5.2.1 Blood, expired air, body fluids, and
tissues
2.5.2.2 Urine
2.5.2.3 Human breast milk
2.5.3. Food and food containers
2.5.4. Detection of marketed toluene purity
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Man-made sources
3.2.1. Production levels, processes, and uses
3.2.1.1 Production
3.2.1.2 World production figures
3.2.1.3 Manufacturing processes
3.2.2. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1. Transport and distribution between media
4.1.1. Air
4.1.2. Water
4.1.3. Soil
4.1.4. Entry into the food chain
4.2. Biotransformation
4.2.1. Biodegradation
4.2.2. Bioaccumulation
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Air
5.1.2. Water
5.2. General population exposure
5.3. Occupational exposure during manufacture, formulation, or
use
6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
6.1. Microorganisms
6.2. Aquatic organisms
6.3. Terrestrial organisms
6.4. Population and ecosystem effects
6.5. Effects on the abiotic environment
7. KINETICS AND METABOLISM
7.1. Absorption
7.1.1. Inhalation
7.1.1.1 Rat
7.1.1.2 Dog
7.1.1.3 Human volunteers
7.1.2. Dermal
7.1.2.1 Guinea-pig
7.1.2.2 Human volunteers
7.1.3. Oral
7.2. Distribution
7.2.1. Inhalation
7.2.1.1 Mouse
7.2.1.2 Rat
7.2.1.3 Human volunteers
7.2.2. Oral
7.2.2.1 Rat
7.2.3. Intraperitoneal
7.2.3.1 Rat
7.3. Metabolic transformation
7.3.1. Oral
7.3.2. Inhalation
7.3.2.1 Human beings
7.3.3. In vitro studies
7.4. Elimination and excretion in expired air, faeces, and
urine
7.4.1. Toluene
7.4.1.1 Laboratory animals
7.4.1.2 Human beings
7.4.2. Excretion of metabolites
7.4.2.1 Human beings
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1. Single exposures
8.1.1. Inhalation
8.1.2. Oral
8.1.3. Intraperitoneal and intravenous injection
8.1.4. Subcutaneous injection
8.2. Short-term exposures
8.2.1. Inhalation
8.2.1.1 Mouse
8.2.1.2 Rat
8.2.1.3 Dog
8.2.2. Other animal species and routes
8.2.3. Oral
8.2.3.1 Rat
8.3. Skin and eye irritation; sensitization
8.3.1. Skin
8.3.2. Eye
8.4. Long-term exposures
8.4.1. Inhalation
8.4.1.1 Rat
8.5. Reproduction, embryotoxicity, and teratogenicity
8.5.1. Reproduction
8.5.2. Embryotoxicity and teratogenicity
8.5.2.1 Inhalation
8.5.2.2 Oral
8.6. Mutagenicity and related end-points
8.6.1. DNA damage
8.6.2. Mutation
8.6.3. Chromosomal effects
8.7. Carcinogenicity
8.7.1. Inhalation
8.7.2. Oral
8.7.3. Dermal
8.8. Special studies
8.8.1. Central nervous system (CNS)
8.8.2. Effects on electrical activity in the brain
8.8.3. Effects on neurotransmitters
8.8.4. Behaviour
8.8.5. Liver
8.9. Factors modifying toxicity; toxicity of metabolites
8.9.1. Effects of combined exposure to toluene and other
chemicals
8.9.1.1 Benzene and toluene
8.9.1.2 Xylene and toluene
8.9.1.3 n-Hexane and toluene
8.9.1.4 Toluene and other chemicals
9. EFFECTS ON MAN
9.1. Acute toxicity
9.2. Effect of short- and long-term exposure including
controlled human studies
9.2.1. Controlled human studies
9.2.2. Short- and long-term abuse in the general
population
9.2.3. Epidemiological studies
9.3. Occupational exposure
9.3.1. Skin and mucous membranes
9.3.2. Central nervous system
9.3.3. Peripheral nervous system
9.3.4. Blood and haematopoietic system
9.3.5. Liver and kidney
9.3.6. Menstruation
9.3.7. Chromosome damage
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of human health risks
10.2. Acute and short-term effects on man
10.3. Evaluation of environmental hazards of toluene
11. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR TOLUENE
Members
Dr K.S. Channer, Department of Medicine, Bristol Royal Infirmary,
Bristol and Weston Health Authority, Bristol, United Kingdom
(Rapporteur)
Mr M. Greenberg, Office of Research and Development, Environmental
Criteria Assistance Office, US Environmental Protection Agency,
Research Triangle Park, North Carolina, USA
Dr I. Gut, Institute of Hygiene and Epidemiology, Prague,
Czechoslovakia (Chairman)
Dr J. Mäki-Paakkanen, Institute of Occupational Health, Department
of Industrial Hygiene and Toxicology, Helsinki, Finland
Dr C. Maltonia, Institute of Oncology and Centre for Tumours,
Bologna, Italy
Dr B.O. Osuntokun, Department of Medicine, University of Ibadan,
Ibadan, Nigeria
Dr S.S. Pawar, Department of Chemistry, Marathwada University,
Aurangabad, Maharashtra, India (Vice-Chairman)
Dr Y. Takeuchi, Department of Hygiene, Nagoya University School of
Medicine, Showa-Ku, Nagoya, Japan
Dr GY. Ungvary, Toxicology Section, National Institute of
Occupational Health, Budapest, Hungary
Dr G.D. Veith, Environmental Research Laboratory, US Environmental
Protection Agency, Duluth, Minnesota, USA
Representatives from Other Organizations
Dr J. Wilbourn, International Agency for Research on Cancer, Lyons,
France
Secretariat
Dr H.W. de Koning, Environmental Hazards and Food Protection, World
Health Organization, Geneva, Switzerland
Dr M. Mercier, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr L.A. Moustafa, International Programme on Chemical Safety,
Interregional Research Unit, Research Triangle Park, North
Carolina, USA (Secretary)
Ms F. Ouane, International Register of Potentially Toxic Chemicals,
Geneva, Switzerland
---------------------------------------------------------------------------
a Invited, but unable to attend.
Secretariat (contd.)
Dr C. Xintaras, Office of Occupational Health, World Health
Organization, Geneva, Switzerland
Observers
Dr A. Berlin, Commission of the European Communities, Luxembourg,
Luxembourg
Dr M.-A. Boillat, Department de l'Intérieur et de la Santé
publique, Institut Universitaire de Medecine du Travail et
d'Hygiéne industrielle, Lausanne, Switzerland
NOTE TO READERS OF THE CRITERIA DOCUMENTS
Every effort has been made to present information in the
criteria documents as accurately as possible without unduly
delaying their publication. In the interest of all users of the
environmental health criteria documents, readers are kindly
requested to communicate any errors that may have occurred to the
Manager of the International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland, in order that they may be
included in corrigenda, which will appear in subsequent volumes.
* * *
A detailed data profile and a legal file can be obtained from
the International Register of Potentially Toxic Chemicals, Palais
des Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 -
985850).
ENVIRONMENTAL HEALTH CRITERIA FOR TOLUENE
The WHO Task Group on the Environmental Health Criteria for
Toluene met in Geneva from 3 to 7 September 1984. Dr M. Mercier,
Manager, IPCS, opened the meeting and welcomed the participants on
behalf of the heads of the three IPCS co-sponsoring organizations
(UNEP/ILO/WHO). The Group reviewed and revised the draft criteria
document for toluene and made an evaluation of the risks for human
health and the environment from exposure to toluene.
DR M. GREENBERG, of the US ENVIRONMENTAL PROTECTION AGENCY,
was responsible for the preparation of the first draft, and
DR G.J. VAN ESCH, of Bilthoven, The Netherlands, was responsible
for the final technical editing.
The efforts of all who helped in the preparation and
finalization of the document are gratefully acknowledged.
* * *
Partial financial support for the publication of this criteria
document was kindly provided by the United States Department of
Health and Human Services, through a contract from the National
Institute of Environmental Health Sciences, Research Triangle Park,
North Carolina, USA - a WHO Collaborating Centre for Environmental
Health Effects. The United Kingdom Department of Health and Social
Security generously supported the costs of printing.
1. SUMMARY AND RECOMMENDATIONS
1.1. Summary
1.1.1. Identity and analytical methods
Toluene is the common name for methylbenzene. It is a clear,
colourless liquid that is volatile (vapour pressure of 3.82 kPa),
flammable, and explosive in air. The technical product may contain
small amounts of benzene. Toluene will not react with dilute acids
or bases and is not corrosive. In the atmosphere, it reacts
rapidly with hydroxyl radicals to form a variety of oxidation
products.
Adequate analytical methods have been developed to measure
toluene in air, water, biological tissues and fluids, and food
products, using gas chromatography with conventional flame
ionization detectors. The detection limit for toluene depends on
sampling procedures and matrices, but is of the order of 1 µg/m3 or
1 µg/kg or even lower.
1.1.2. Production, uses, and sources of exposure
Toluene is a commercially-important intermediate chemical
produced throughout the world in enormous quantities (0.5 -1 x 107
tonnes). It is produced both in the isolated form and as a
component of mixtures. Toluene produced in the form of a mixture
is used to back-blend gasoline. Isolated toluene, on the other
hand, is used in: (a) the production of other chemicals; (b) as a
solvent carrier in paints, thinners, adhesives, inks, and
pharmaceutical products; and (c) as an additive in cosmetic
products. Purified toluene usually contains less than 0.01%
benzene, but the industrial grade may contain up to 25% benzene.
The primary man-made sources of toluene released into the
environment are:
(a) inadvertent sources (65%), i.e., emission from motor
vehicles and aircraft exhaust, and losses during
gasoline marketing activities, spills, and cigarette
smoke;
(b) processes in which toluene is used (33%); and
(c) toluene production (2%).
The significance of each of these sources is expected to vary
widely from country to country. On the basis of available data and
estimates, 86% of the toluene produced is eventually released into
the biosphere (predominantly the troposphere). The life-time of
toluene ranges from several days to several months.
In urban areas, a toluene level in ambient air of 0.0001 -
0.204 mg/m3 has been detected. Background levels monitored at
sites throughout the world indicate that the general population is
exposed to trace levels (0.00075 mg toluene/m3). Toluene has been
detected in drinking-water (0 - 0.027 mg/litre), well water (0.005
- 0.1 mg/litre), and in raw water (0.001 - 0.015 mg/litre).
The general population is exposed to toluene mainly through
inhalation of vapour in ambient air, cigarette smoking, and, to a
minor extent, by ingestion of food or water contaminated with
toluene.
Certain groups of individuals are exposed to high levels of
toluene occupationally. Permissible levels of occupational
exposure established in various countries range from 200 to
750 mg/m3 as a time-weighted average (TWA) for an 8-h day and a
40-h week. A maximum allowable concentration (MAC) of 50 - 100
mg/m3 has been adopted by other countries.
A special group exposed to toluene includes individuals who
intentionally abuse solvent mixtures containing toluene (e.g.,
"glue-sniffers") and those who are exposed to toluene accidentally.
Solvent abuse is a world-wide problem, and long-term abusers are
routinely exposed to concentrations exceeding 3750 mg/m3.
1.1.3. Kinetics, biotransformation, and biological monitoring
Studies on laboratory animals and human beings have shown that
toluene is readily absorbed from the respiratory tract with an
uptake of 40 - 60% in human beings. Liquid toluene is also rapidly
absorbed through the skin (14 - 23 mg/cm2 per h), but absorption
from the gastrointestinal tract appears to be slower.
Following absorption, toluene is rapidly distributed, with
highest levels observed in adipose tissue followed by bone marrow,
adrenals, kidneys, liver, brain, and blood. A calculated
brain/blood ratio of 1.56 was reported in rats exposed via
inhalation for 3 h. Controlled studies on volunteers revealed that
the higher the relative uptake of toluene the lower the alveolar
concentration of the solvent. The relationship between arterial
blood and alveolar air concentration was linear and closely
correlated. After exposure at rest for 30 min to 300 mg
toluene/m3, the relative uptake averaged 52%, the alveolar
concentration was 28% of the inspired air concentration, and the
arterial concentration mounted to 0.7 mg/litre of blood. Thus, by
measuring the toluene concentration in alveolar air during
exposure, it is possible to estimate the arterial blood
concentration.
Some 60 - 75% of absorbed toluene is metabolized to benzoic
acid by the microsomal mixed-function oxidase system, with
subsequent conjugation with glycine to form hippuric acid. It is
eliminated in this form through the kidneys. About 10 - 20% of the
absorbed toluene is excreted as benzoyl glucuronide. Small amounts
of toluene undergo ring hydroxylation to form o-, m-, and p-cresol,
which are excreted in the urine as sulfate or glucuronide
conjugates. A proportion of the absorbed toluene (20 - 40%) is
eliminated unchanged in expired air. After a single exposure, the
elimination of toluene and its metabolites is almost complete in
24 h. The half-life of toluene in subcutaneous adipose tissue has
been estimated to be between 0.5 and 2.7 days.
Analysis of expired air and/or blood during exposure reflects
current intake. The determination of the average hippuric acid
concentration in urine collected at the end of the workshift
appears to be the most practical method of evaluating the overall
occupational exposure of workers to toluene levels of more than
375 mg/m3 (100 ppm). An average level of hippuric acid of less
than 2 g/litre (specific gravity = 1016) or per g creatinine
suggests that the atmosphere was probably contaminated by less than
375 mg/m3. The o-cresol assay in urine should be further
investigated for determining exposures to low levels of toluene.
1.1.4. Effects on experimental animals
Acute inhalation data indicate that the species sensitivity
decreases as follows: rabbit, guinea-pig, mouse, and rat.
Inhalation LC50 values have been reported in the range of
approximately 20 0000 - 26 000 mg/m3 for mice and approximately
45 000 mg/m3 for rats. The oral LD50 in the rat is between 2.6 and
7.5 g/kg body weight, depending on the strain, age, and differences
in sex. Toluene is a slight dermal and a moderate eye irritant in
animals and man. Acute dermal toxicity appears to be quite low
(rabbit: LD50 14.1 ml/kg body weight).
In short- and long-term inhalation studies on experimental
animals, no effect was seen with exposure to 375 mg toluene/m3 for
24 months. In oral studies, administration of 590 mg toluene/kg
body weight, per day, for 6 months did not produce any effects. At
low dose levels, in rats, the target organs seem to be the kidneys
and testes, while at high dose levels, liver changes and effects on
the central nervous system are predominantly seen. Reversible
functional and/or morphological changes are dose-related.
Numerous studies using pure toluene have failed to demonstrate
haematopoietic effects. Toluene does not cause permanent
pathological effects on the heart, but high doses (> 4000 mg/m3)
may induce cardiac arrhythmia.
Contradictory results are reported in the existing literature
regarding the pathological effects of toluene on the respiratory
and urinary tracts of dogs, guinea-pigs, and rats.
Toluene primarily affects the central nervous system (CNS). A
biphasic response to toluene exposure, which is typical of a
narcotic drug, has been found with initial excitability followed by
a depression in response. In most studies, behavioural effects
have been observed with exposures in excess of 1875 mg/m3.
Progressive narcosis and seizures have been seen at high exposure
levels (15 000 mg/m3, 4 h/day). Initial depression of cortical
activity resulting in coma was induced in cats at 26 250 mg/m3, 10
min/day, for 40 days. Exposure at 7500 mg/m3, for 24 weeks, caused
interruption of the sleep cycle in the rat. Toluene has not been
shown to cause peripheral neuropathy.
Skin-painting studies on mice, where toluene was used as a
vehicle control, and one inhalation study on rats exposed to pure
toluene (112.5 - 1125 mg/m3, 6 h/day, 5 days/week, for 24 months)
did not reveal any carcinogenic effects.
The results of studies on the mutagenic effects of toluene in
microbial, mammalian-cell, or whole-organism test systems have, in
most cases, been negative. Positive findings were reported in 5
studies using in vivo mammalian assays. In these studies,
however, the purity of the toluene used was not always stated.
Toluene does not appear to be teratogenic in mice, rats, or
rabbits, but embryotoxic/fetotoxic effects were seen in rats at a
dose that was non-toxic for the dams exposed to toluene
concentrations of 1000 mg/m3 air, and spontaneous abortion occurred
in rabbits exposed to 1000 mg/m3 during the entire period of
organogenesis. However, orally administered toluene was reported
to be teratogenic in CD-1 mice. Exposure to 870 mg/kg body weight
on days 6 - 15 significantly increased the incidence of cleft
palate. A level of 430 mg/kg body weight was without effect.
The ability of toluene to interfere with biotransformation and
alter the toxic effects of several solvents has been documented by
several investigators. For example, toluene decreased n-hexane
metabolism and neurotoxicity, and also benzene metabolism and
effects on the haematopoietic system. However, it increased the
hepatotoxicity of carbon tetrachloride.
1.1.5. Effects on human beings
Toxicity studies on human beings have primarily involved
individuals exposed to toluene via inhalation either in
experimental or occupational settings or during episodes of
intentional abuse of solvent mixtures containing toluene.
The primary effect of toluene is on the central nervous system
(CNS). The effect may be depressant or excitatory, with euphoria
in the induction phase followed by disorientation, tremulousness,
mood lability, tinnitus, diplopia, hallucinations, dysarthria,
ataxia, convulsions, and coma.
Acute controlled and occupational exposures to toluene in the
range of 750 - 5625 mg/m3 (200 - 1500 ppm) caused dose-related CNS
effects. Acute exposure to high levels of toluene (e.g., 37 500
mg/m3 or higher for a few min) during industrial accidents was
characterized by initial CNS excitative effects (e.g.,
exhilaration, euphoria, hallucinations) followed by progressive
impairment of consciousness, eventually resulting in seizures and
coma.
Single, short-term exposures to toluene (750 mg/m3 for 8 h)
have reportedly caused transient eye and respiratory tract
irritation with lachrymation at 1500 mg/m3.
Repeated occupational exposures to toluene over a period of
years at levels of 750 - 1500 mg/m3 (200 - 400 ppm) have resulted
in some evidence of neurological effects.
Toluene-containing mixtures have been implicated in the
causation of peripheral neuropathy but, in most cases, known
neurotoxins such as n-hexane or methylethylketone have been
present, and the role of toluene is not clear.
Irreversible neurological sequelae, such as encephalopathy,
optic atrophy, and equilibrium disorders have been described in
adult chronic toluene abusers. Toluene inhalation was reported to
be an important cause of encephalopathy in children (aged 8 - 14
years) and may lead to permanent neurological damage.
Transient abnormalities of hepatic enzyme activities have been
found in abusers of toluene mixtures, but significant permanent
hepatic damage does not occur. Occasional reports of renal damage
in glue-sniffers have appeared, characterized by a form of distal
tubular acidosis. There is no evidence that toluene damages the
haematopoietic tissues or the heart.
No adequate epidemiological studies on human beings exist.
The results of 3 studies indicated an increased frequency of
chromosome damage in the cultured blood lymphocytes of rotogravure
workers occupationally exposed to toluene, but, in 3 other similar
studies, no effects were found. However, in most cases, the number
of subjects studied was small. Moreover, the extent of exposure
differed among the 6 studies and exposure to other, possibly
mutagenic agents, such as benzene and tobacco smoke, had usually
not been adequately considered.
Data on human beings are not adequate for the evaluation of the
teratogenicity of toluene. Subjective complaints of dysmenorrhoea
and disturbances in menstruation have been reported in female
workers exposed concurrently to toluene, benzene, xylene, and other
unspecified solvents. The limited data available do not, however,
specifically associate occupational exposure to toluene with
reproductive effects in female and male workers.
1.1.6. Effects on aquatic and terrestrial organisms in the
environment
Available data indicate that the production and use of toluene
do not adversely affect aquatic and terrestrial ecosystems. The
acute toxicity levels for fish and aquatic invertebrates (LC50)
range from 3.7 to 1180 mg/litre, but most organisms show an LC50 in
the order of 15 - 30 mg/litre. Photosynthesis and respiration by
marine phyto-plankton communities are inhibited by toluene at
34 mg/litre. No adverse effects were seen in long-term studies on
3 species of freshwater and marine fish at concentrations ranging
from approximately 1.4 to 7.7 mg/litre. Spawning fish may detect
and avoid waters containing toluene at 2 mg/litre. The effects of
sublethal exposure to toluene are reversible, and toluene residues
do not accumulate in fish or aquatic food-chains.
Toluene concentrations in industrial waste waters were reported
to range from 0.010 to 20 mg/litre. The biodegradability of
toluene by microorganisms ranged from 63 to 86% after up to 20
days.
The adverse impact of toluene spills will be limited to the
immediate spill area, because of its fast degradation under aerobic
conditions.
The volatility and biodegradability of toluene suggest that it
would have a short half-life on soil surfaces.
Photolysis of toluene in the air, which also contains other
pollutants such as nitrous oxides and ozone, may contribute to smog
production.
1.2. Conclusions and Recommendations
1.2.1. Conclusions
The available data indicate that exposure of the general
population and environment to toluene does not present any health
and/or environmental hazards, at present. However, long-term
occupational exposure and solvent abuse may be associated with
permanent pathological changes and further investigations are
justified.
1.2.2. Recommendations
(a) Environmental monitoring data
Data are needed on the magnitude, frequency, duration, and
extent of exposure(s) to toluene in the general population.
(b) Biological monitoring data
(i) Further investigations are required on the possibility
of using determinations of toluene concentrations in
exhaled air and blood in the evaluation of the
integrated exposure during the previous 24 h; and
(ii) There is a need for a comparative study of the
validity of hippuric acid and cresol determinations in
urine.
(c) Human reproductive effects
Information on the possible reproductive effects of toluene in
males and females is not adequate. Research in this field is
therefore recommended. The similarity of the effects reported on
human fetal growth and those observed in animals draws attention to
the need for further studies on women exposed to toluene. Both
experimental animal and human case studies give information on the
supposed role of toluene in causing teratogenic effects through
toxicokinetic or toxicodynamic interaction. These reports should
stimulate further research on laboratory animals.
(d) Respiratory defence mechanisms
There is a need for further evaluation of the potential effects
of volatile organic substances such as toluene on respiratory
defence mechanisms.
(e) Neurobehavioural toxicity
(i) There is a paucity of data regarding the behavioural
and neurological effects of pure toluene at low levels
(i.e., below 375 - 750 mg/m3). In particular, the
extent and nature (including permanance) of neuro-
behavioural effects and the threshold of exposure to
toluene, below which there are no-observed-adverse
effects, need to be determined to properly evaluate
the potential risks.
(ii) There is a need for further research to define and
refine the tests that are most relevant for neuro-
psychological investigations.
(iii) Toluene inhalation is a cause of encephalopathy in
children and may lead to permanent neurological
damage. Diagnosis is most important if further damage
due to continued abuse is to be prevented, and
sensitive assays should be further investigated (e.g.,
toluene levels in expired air and in blood).
(f) Human studies on the significance of the reported
hepatomegaly and induction and inhibition of microsomal enzyme
systems for the detoxification or metabolic activation of other
chemicals are indicated.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
Toluene is a common name for the chemical formed when one
hydrogen atom of the benzene molecule is replaced with a methyl
group.
Chemical formula: C7H8
Relative molecular mass: 92.13
CAS chemical name: phenylmethane
CAS registry number: 108-88-3
RTECS registry number: XS 5250000 (Tatken & Lewis, 1983)
Common synonyms: methylbenzene
Common trade names: Methacide, Methylbenzol, Toluol
Technical products in which toluene is the principal ingredient
are commonly formed from petroleum in which petroleum fractions
containing methylcyclohexane are catalytically dehydrogenated. The
purification of toluene products may include azeotropic
distillation with paraffinic hydrocarbons, naphthenic hydrocarbons,
or alcohols. Because of the variety of methods used to produce
toluene, the range of impurities varies widely. Benzene is an
important common impurity in technical grades of toluene. Highly-
purified toluene (reagent grade and nitration grade) contains less
than 0.01% benzene, while industrial grade and 90/120 grade toluene
contain a significant quantity of benzene. The 90/120 grade
contains as much as 25% (US NIOSH, 1973).
2.2. Physical and Chemical Properties
Toluene is a volatile liquid that is flammable and explosive.
Some physical and chemical properties of toluene under standard
conditions are presented in Table 1.
Table 1. Physical and chemical properties of toluene
-------------------------------------------------------------------
Melting point -95 °C Weast (1977)
Boiling point (760 mm Hg) 110.6 °C Weast (1977)
Density (g/ml, 20 °C) 0.8669 Weast (1977)
Specific gravity (20 °C) 0.8623 Weast (1977)
Vapour pressure (25 °C) 28.7 mm Hg Weast (1977)
Vapour density (air = 1) 3.20 Weast (1977)
Log partition coefficient 2.69 Tute (1971)
(octanol/water)
Surface tension (20 °C) 28.53 dynes/cm Walker (1976)
Liquid viscosity (20 °C) 0.6 cp Walker (1976)
Refractive index (20 °C) 1.4969 Cier (1969)
Percent in saturated air 3.94 Walker (1976)
(760 mm, 26 °C)
Density of saturated air-vapour 1.09 Walker (1976)
mixture (760 mm; air = 1, 26 °C)
Flammable limits (percent 1.17 - 7.10 Walker (1976)
by volume in air)
Flash point (closed cup) 4.4 °C Walker (1976)
Autoignition temperature 552 °C Walker (1976)
Solubility in:
Fresh water (25 °C) 535 mg/litre Sutton & Calder
Sea water (25 °C) 380 mg/litre (1975)
Saturation in:
Air (25 °C) 112 g/m3 Sutton & Calder
(1975)
-------------------------------------------------------------------
2.3. Organoleptic Properties
Toluene is a clear, colourless liquid at ambient temperature
and has a benzene-like odour. The odour threshold for toluene in
air has been determined to be 9.4 mg/m3. The sensory threshold
(the concentration at which volunteers, when exposed for 15-min
inhalation periods, had olfactory fatigue, mild eye irritation,
"tasting something", "light-headed", and headache, but, neverthe-
less, were willing to work for 8 h) was 700 mg/m3 (section 9.1.2.)
(Carpenter et al., 1976a,b).
2.4. Conversion Factors
In air (1 atm), at 25 °C: 1 ppm (V/V) = 3.75 mg/m3 = 0.0407
mmol/m3;
1 mg/m3 = 0.266 ppm (Katz, 1969)
2.5. Analytical Methods
Many methods have been used to determine the concentration of
toluene in air, water, and soil.
Toluene exhibits characteristic UV, IR, NMR, and mass spectra,
which are useful in many specific control and analytical problems.
Analytical methods have included colorimetry, involving nitration
followed by reaction with various ketones, spectrophotometry,
direct estimation by means of colorimetric indicator tubes, and gas
chromatography (Maffett et al., 1956; Dambrauskas & Cook, 1963;
Whitman & Johnston, 1964; Williams, 1965; Kolekovsky, 1967; Reid,
1968). Gas chromatography (GC) offers the greatest specificity and
sensitivity of the numerous methods of analysis. Both packed
columns using silica gel and capillary columns have been used to
separate toluene from interfering substances (Fett et al., 1968).
Photoionization detectors provide better selectivity and
sensitivity for toluene measurements than flame ionization
detectors (Federal Register, 1979). Nevertheless, the flame
ionization detector is the most common detector used in volatile
hydrocarbon analyses; the use of gas chromatography interfaced with
computerized mass spectrometry has been developed for samples
containing toluene (Jermini et al., 1976; Lingg et al., 1977; Dowty
et al., 1979; Rasmussen & Khalil, 1983). The detection limit for
toluene in the environment depends on sampling procedures and
preparations, but is low, of the order of 1 µg/m3 or 1 µg/litre or
even less.
2.5.1. Sampling procedures
2.5.1.1. Air
When concentrations of toluene are large enough, air samples
can be collected as grab samples using aluminized plastic bags,
Tedler bags, or glass containers (Neligan et al., 1965; Lonneman et
al., 1968; Altshuller et al., 1971; Pilar & Graydon, 1973;
Schneider et al., 1978). When smaller concentrations of toluene
are to be measured, it is quantitatively adsorbed on various large
surface area materials, such as charcoal, through which the air is
passed (Reid & Haplin, 1968; White et al., 1970). Tenax GC(R),
Porapak Q(R), and a variety of molecular sieves have been used as
sorbents for toluene. The sorbent is heated and the enriched
toluene sample is flushed with an inert gas directly into a high-
resolution glass or fused capillary tube for characterization and
measurement by gas chromatography/mass spectrometry/computer
techniques (Krost et al., 1982). Passive air sampling using
charcoal as a sorbent has been designed specifically for the long-
term sampling of indoor and ambient air (Seifert & Abraham, 1982,
1983). If equipment for the thermal desorption of toluene from
sorbents is not available, toluene can be extracted from the
sorbent using carbon disulfide (Reid & Halpin, 1968; Fraser &
Rappaport, 1976; Esposito & Jacobb, 1977; Fracchia et al., 1977).
The detection limit for toluene in air depends on the volume of
air passed through the sorbent, but is approximately 0.1 µg/m3
(Holzer et al., l977). For the passive collection methods,
detection limits of approximately 1 µg/m3 are obtained for ambient
air monitoring (Hester & Meyer, 1979).
Cigarette smoke, a source of toluene for human beings, requires
a special sampling method (Dalhamn et al., 1968b).
2.5.1.2. Water
Other methods, apart from direct aqueous injection and
dichloromethane extraction, have been used to determine toluene in
industrial waste waters (Jungclaus et al., 1976, 1978). The three
most commonly used methods for the determination of toluene in
aqueous media are the purge and trap, headspace, and sorption on
solid sorbents (including different variations of these methods,
concerning the temperature of the purging system, the stripping
rate, the duration of stripping, etc).
Purge and trap
The most widely used method for the determination of toluene in
drinking-water, waste water, and rain-water is the purge and trap
method (Bertsch et al., 1975; Grob & Zurcher, 1976; Lingg et al.,
1977; Bellar & Lichtenberg, 1979; Dowty et al., 1979). The
detection limit is generally 1 µg/litre.
Headspace analysis
This method has not been applied frequently for the analysis of
environmental samples; however, the method was standardized with
water samples spiked with model compounds. Toluene concentrations
of the order of 0.1 - 1.0 µg/litre can be determined by this method
(Vitenberg et al., 1977; Drozd et al., 1978).
Sorption on solid sorbents
This method, which is rarely used, is used for monitoring
toluene in drinking-water (Ryan & Fritz, 1978).
2.5.1.3. Soils and sediments
The purge and trap method has been modified for the
determination of volatile organic compounds in soil and sediment
samples. In general, the recovery of toluene from these samples is
low. A detection limit of approximately 0.2 µg/kg can be attained.
2.5.2. Biological monitoring of toluene exposure
A number of biological tests have been investigated for
evaluating human exposure to toluene: toluene in expired air
and/or in blood and human breast milk; hippuric acid in urine
and/or blood; and benzoic acid, and o-cresol in urine (section
7.4). The time of sampling of biological material is very critical
in all cases, because of the rapid metabolism of toluene. In
addition, the possibility that toluene metabolism might be modified
by the presence of other chemicals must be considered (Waldron et
al., 1983).
2.5.2.1. Blood, expired air, body fluids, and tissues
Toluene in blood has been determined by the GC analysis of
headspace samples (detection limit: 10 µg/litre) (Premel-Cabic et
al., 1974; Anthony et al., 1978; Radzikowska-Kintzi & Jakubowski,
1981; Oliver, 1982). A direct injection method applicable to GC in
the determination of toluene in whole blood has been reported by
Aikawa et al. (1982).
Cocheo et al. (1982) have developed a purge and trap method for
the detection of toluene in blood in which the detection limit is
estimated to be less than 7.5 µg/litre. Bellanca et al. (1982)
described a similar method using GC-FID for detecting toluene and
other organic compounds in tissues and body fluids.
The concentration of toluene in alveolar air samples, collected
during exposure, is related to the intensity of the exposure
(Astrand et al., 1972; Brugnone et al., 1976, 1980; Carlsson,
1982,a,b; Astrand, 1983).
Under steady-state conditions, a constant relationship between
the uptake rate of toluene and toluene concentrations in venous
blood has been observed. Under non-steady-state conditions,
however, no simple relation exists between uptake and the venous
blood concentration of toluene.
Direct measurements confirmed a previous hypothesis that the
concentration of toluene in arterial blood during and after
exposure could be estimated from concentrations in alveolar air.
While there is no unanimity, it can be concluded that analysis
of expired air and/or blood reflects actual intake and may be a
useful indicator of exposure to toluene (King et al., 1981).
2.5.2.2. Urine
Toluene
Trace amounts of absorbed toluene, excreted in the urine, can
be analysed by one of the methods outlined in section 2.5.1.2.
Metabolites of toluene
The major metabolite, hippuric acid, is eliminated in the
urine. It can be determined by a number of methods including
colorimetry, UV spectrometry, and thin-layer chromatography (TLC)
(Umberger & Fiorese, 1963; Pagnotto & Lieberman, 1967; Bieniek &
Wilczok, 1981; Bieniek et al., 1982). The sensitivity of the TLC
method is 6 mg hippuric acid/litre urine. Another sensitive method
for estimating hippuric acid in urine was developed by Caperos &
Fernandez (1977). In this method, the hippuric acid in urine is
extracted, methylated, and quantified by GC-FID. The sensitivity
of the method was determined to be 5 mg/litre urine.
Bergert et al. (1982), Hansen & Dossing (1982), and Poggi et
al. (1982) determined the levels of urinary-hippuric acid and other
metabolites of toluene by a high-performance liquid chromatographic
(HPLC) method.
Hippuric acid is a normal constituent of urine, originating
mainly from food containing benzoic acid or benzoates. For the
occurrence of hippuric acid in the urine of unexposed compared with
that in toluene-exposed persons, see Table 6. The mean urinary-
hippuric acid excretion is higher in females than in males.
Unexposed persons excreted a mean concentration of < 1.0 g
hippuric acid/litre, while workers exposed to toluene excreted
hippuric acid concentrations that were at least 2 - 6 times higher,
depending on exposure levels.
Taking into account the levels of hippuric acid in urine
observed for unexposed persons and the individual variation in
these levels, separation between exposed and unexposed workers
cannot be done on an individual basis. On a group basis, however,
the methods are sufficiently sensitive.
At present, the determination of the average hippuric acid
concentration in urine collected at the end of workshift appears
to be the most practical method for evaluating overall occupational
exposure to toluene levels exceeding 375 mg/m3 air. A group
average of less than 2 g/litre (specific gravity = 1.016) or
g creatinine suggests that the atmosphere was probably contaminated
by less than 375 mg/m3 (100 ppm) toluene. The possibility of using
the determination of toluene in expired air and/or blood and
o-cresol in urine, particularly for exposure to low levels of
toluene, should be further investigated.
Sufficient data are not available to give an opinion about the
measurement of other metabolites such as benzoic acid or o-cresol
in urine to estimate exposure to toluene in the air.
2.5.2.3. Human breast milk
Toluene in human breast milk can be determined by the purge and
trap method, followed by thermal desorption and capillary GC-MS
analysis (Pellizzari et al., 1982).
2.5.3. Foods and food containers
A headspace GC technique for quantification, and a GC-MS
technique for confirmation, were used to determine trace amounts of
toluene in plastic containers. Toluene present in the µg/kg range
can be determined by this method (Hollifield et al., 1980).
2.5.4. Detection of marketed toluene purity
Toluene is marketed in different purity grades. The purity as
well as the number, concentrations, and identity of other
components can be determined by HPLC, GC, and GC-FID methods (Fett
et al., 1968; Grizzle & Thomson, 1982). The toluene content of
high purity samples can be accurately measured by determining the
freezing point (Hoff, 1983).
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural Occurrence
Some types of vegetation are natural sources of toluene in the
environment (US NRC, 1980).
3.2. Man-Made Sources
3.2.1. Production levels, processes, and uses
3.2.1.1. Production
Production of toluene as a by-product of the carbonization of
coal was the major source of toluene during the latter part of the
19th century. Since the second World War, the manufacture of
toluene from petroleum sources has steadily increased, and that
from coke and coal-tar products has decreased. At present, toluene
is principally produced (87%) by the catalytic reforming of
refinery streams (Hoff, 1983). An additional 9% is separated from
pyrolysis gasoline produced in steam crackers during the
manufacture of ethylene and propylene. The other 4% originates as
a by-product of other processes.
3.2.1.2. World production figures
World production figures for toluene are summarized in Table 2,
according to different geographical areas, for the years 1979 - 81.
From Table 2, it is clear that, in 1981, the world production of
toluene was more than 10 000 metric tonnes.
3.2.1.3. Manufacturing processes
Loss into the environment during normal production and handling
The three primary man-made sources of toluene released into the
environment are:
(a) production sources; toluene can be released into the
environment during its production as process losses,
fugitive emissions, and storage losses (approximately
2%);
(b) toluene when used as a solvent; toluene is released
into the ambient air, as a result of evaporation
(approximately 34%);
(c) inadvertent sources; the emission of toluene through
its use in gasoline can occur from three distinct
sources including: evaporative losses from automobile
service stations; evaporation from marketing
activities (handling and transfer of bulk
quantities); and emissions from motor vehicles and
aircraft (approximately 65%).
Table 2. World-wide annual toluene production
in metric tonnes
-----------------------------------------------
Geographical area Total toluene production
1979a 1980a 1981b
-----------------------------------------------
Africa 43
Canada 941
Europe (western) 1179 913 1666
Israel 63
Japan 962 > 2193
Oceania 46
South America 382
Thailand 21c 16c
USA 3273 5104b 6234
USSR > 1179d
-----------------------------------------------
a From: Chemical Industry (1980).
b From: World Petrochemicals (1982) (as cited
by Hoff, 1983).
c From IRPTC (1984) (special inquiry).
d Includes capacity data for three USSR toluene
plants, which may not have been completed.
Other inadvertent sources of toluene emissions into the
environment include other manufacturing processes, by-product
formation, and cigarette smoke (Anderson et al., 1980). There is
substantial contamination of the environment from seepage in the
oceans, on land, and from the weathering of exposed coal strata.
3.2.2. Uses
Toluene is of great importance as a chemical intermediate and
solvent.
Up to 95% of the annually-produced toluene in the USA is
blended directly into the gasoline pool as a component to increase
the pyrolysis of gasoline (to increase the octane number) (Hoff,
1983).
Isolated toluene is much more important as a solvent than
either benzene or xylene. Approximately two-thirds of its use as a
solvent is in paints, inks, thinners, coatings, adhesives,
degreasers, and other formulated products requiring a solvent
carrier (Kumai et al., 1983; Inoue et al., 1983).
Furthermore, toluene is used as a raw material in the organic
synthesis of a large number of chemicals such as toluene
diisocyanate, benzoic acid, benzaldehyde, xylene, toluene-
sulfonylchloride (the o-isomer is converted to saccharin), other
derivatives of toluene used as dye intermediates, resin modifiers,
germicides, etc. Lastly, toluene is used as a denaturant in
specially-denatured alcohol.
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1. Transport and Distribution Between Media
4.1.1. Air
Toluene released into the environment mainly enters the
atmosphere (because of its high vapour pressure) and surface
waters. Transport from the water (low solubility) to the
atmosphere is rapid. MacKay & Wolkoff (1973) and Mackay &
Leiononen (1975) reported the calculated evaporation half-life for
toluene from 1 m deep water to be approximately 5 h; in a state of
equilibrium, only 26% of toluene would be present in the gaseous
phase above sea water (US NRC, 1980).
Atmospheric oxidation of toluene removes 50% of the compound in
less than 2 days (half-life was estimated to be 12.8 h). Because
of this rapid removal, toluene will most probably not remain in the
atmosphere long enough to be removed by air to surface transfer
mechanisms, such as dry deposition or precipitation (US EPA, 1980).
Toluene has been detected in rain water at levels of 0.13 -
0.7 µg/litre (Lahmann et al., 1977).
Toluene does not absorb radiation at wavelengths longer than
295 nm. Although it absorbs insignificant amounts of sunlight in
the lower atmosphere, a charge-transfer complex between toluene and
molecular oxygen absorbs radiation of wavelengths up to 350 nm.
According to Wei & Adelman (1969), it is the photolysis of this
complex that may be responsible for some of the observed
photochemical reactions of toluene related to smog production.
Photolysis of toluene in air that also contains nitrous oxides
yields ozone, peroxyacetylnitrate, and peroxybenzoylnitrate.
Toluene is removed from the atmosphere primarily through free
radical chain processes, of which reactions with hydroxy radicals
are the most important processes (Brown et al., 1975; Perry et al.,
1977). In the atmosphere, there are several free radicals that are
likely to combine with toluene, including hydroxyl radicals (OH),
atomic oxygen (O), and peroxy radicals (RO2), where R is an alkyl
or aryl group, and also ozone (O3). The tropospheric lifetime of
toluene at high latitudes during summer has been estimated to be
about 4 days; in winter, the lifetimes may be of the order of
months. At tropical latitudes, the lifetimes are short (days to
weeks) and do not vary with season. The average concentrations of
toluene found in different regions of the world vary between 0 and
approximately 0.75 µg/m3 air (Rasmussen & Khalil, 1983).
4.1.2. Water
Sauer et al. (1978) concluded, from their studies of the
coastal waters of the Gulf of Mexico, that toluene and other alkyl
benzenes are present at low levels in the marine environment.
The presence of toluene in surface water in the USA has been
monitored by the US EPA STORET system (US EPA, 1980). Only 17% of
all surface waters monitored contained toluene at concentrations
higher than 10 µg/litre. Factors affecting toluene levels in
surface water and groundwater include volatilization, solubility,
and, where groundwater is concerned, degradation and/or adsorption
of toluene during percolation through soils. Toluene was detected
in 85% of the 39 wells tested in 1978. The toluene concentration
in these well waters was below 10 µg/litre. Toluene has been
detected in raw water and in finished water supplies (up to
19 µg/litre) in several communities in the USA (US EPA, 1975a,b,
1977). It has been suggested that toluene may be chlorinated
during the chlorination process of waste water (Carlson et al.,
1975). However, this could not be confirmed in laboratory
experiments, and it was concluded that chlorine added to waste
water would not bind with toluene (US EPA, 1980).
4.1.3. Soil
Toluene probably exists in soils in the adsorbed state. The
adsorption of toluene by clay minerals (bentonite and kaolinite)
was found to follow Freundlich's adsorption isotherm and the
adsorption capacity increased as the pH value decreased (El-Dib et
al., 1978). It can be anticipated, therefore, that a portion of
toluene in soil will be transferred to air and water. The part
that stays in soil may participate in chemical reactions (including
photochemical reactions) and biological degradation and
transformation.
The results of 2 laboratory experiments (US EPA, 1980; Wilson
et al., 1981) showed that, about 40 - 80% of toluene applied to the
surface of sandy soils at 0.9 and 0.2 mg/litre, respectively,
volatilized into the air (estimated half-life of 4.9 h). The
volatilization rate is, for instance, dependent on the nature and
organic content of the soil, and the laboratory studies showed that
toluene moved through sandy soils with low organic carbon content.
The transfer of toluene from soil to groundwaters is of importance
with regard to the contamination of these sources of drinking-
water.
4.1.4. Entry into the food chain
In 59 samples of edible fish (not specified), 95% showed
toluene concentrations of less than 1 mg/kg (w/w) (US EPA, 1980).
Toluene was also detected in fish caught from polluted waters in
the proximity of petroleum and petrochemical plants in Japan (Ogata
& Miyake, 1973, 1978).
4.2. Biotransformation
4.2.1. Biodegradation
Toluene is easily degraded by activated sludge in sewage plants
(Malaney & McKinney, 1966; Matsui et al., 1975) and by bacteria in
estuarine and marine environments (Walker & Colwell, 1976; Tabak et
al., 1981). It is also biodegraded by a variety of soil
microorganisms using toluene (up to 0.1%) as the sole source of
carbon (Tausson, 1929; Kaplan & Hartenstein, 1979; Wilson et al.,
1981).
Biodegradation of toluene accounted for 0.31, 4.81, 0.36, 0.09,
and 18.47% of the total toluene loss in oligotrophic lakes,
eutrophic lakes, clean rivers, turbid rivers, and ponds,
respectively. Using the standard dilution method and a settled
domestic filtered waste-water effluent as the seed to determine the
biochemical oxygen demand, the biodegradability of toluene (percent
bio-oxidized) ranged from 63% to 86% after up to 20 days (Price et
al., 1974; Bridié et al., 1979; Davis et al., 1981).
The degradation of toluene has also been studied in mixed
cultures of bacteria (predominantly Pseudomonas). Chambers et al.
(1963), using these phenol-adapted bacteria, reported 38%
degradation of toluene after 180 min. In another study, Dechev &
Damyanova (1977) grew sludge cultures using phenol, xylene, or
toluene as the sole carbon source and found that phenol-adapted
bacteria proved less able to degrade xylene and toluene, while
toluene-adapted microorganisms showed greater versatility in their
ability to oxidize phenol and xylene. For information on the
metabolism of toluene by various types of microorganisms, see
Gibson (1971), Smith & Rosazza (1974), Subramanian et al. (1978),
and Kaplan & Hartenstein (1979).
4.2.2. Bioaccumulation
The quantities of organic chemicals that accumulate in aquatic
organisms depends on uptake, excretion, and metabolism (Hansen et
al., 1978).
Bioaccumulation of toluene has not been studied adequately.
The log octanol/water partition coefficient is 2.69, a value that
indicates that slight to moderate accumulation takes place.
Roubal et al. (1978) did not find any toluene, while higher
homologues of toluene were present, in the tissues of Coho salmon
(Oncorhynchus kisutch). Berry (1980) detected only small
quantities of 14C activity in different tissues of bluegills
(Lepomis machrochirus). Mean concentrations of 12.4 mg/kg muscle
tissue and 1.5 mg/kg liver tissue were found in eels (Anguilla
japonica) kept in sea water containing 16.1 mg toluene/litre
(Ogata & Miyake, 1978). They showed that the half-life of toluene
was 1.4 days. Berry & Fisher (1979) determined that 14C-toluene in
4th-instar mosquito larvae was transferred to the bluegill stomach
and intestine, but that levels of toluene residues in other organs
and tissues were indistinguishable from those in the controls.
Consequently, it is unlikely that toluene accumulates in an
ecosystem food chain.
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental Levels
5.1.1. Air
The reported concentrations of toluene in air reflect,
undoubtedly, the regional differences in terms of production, use,
and emission patterns, the effects of meteorological processes
affecting transport and fate, sample siting and averaging times,
and differences in sampling, analysis, and detection. The toluene
concentrations in the vicinity of industrial sources of toluene may
represent a burden for the general population in such areas (Smoyer
et al., 1971; Mayrsohn, et at., 1976). Sexton & Westberg (1980)
carried out an ambient air monitoring programme near an automotive
painting plant. Toluene concentrations downwind within 1.6, 6, and
16.5 km of the plant were 0.600, 0.075, and 0.055 mg/m3,
respectively. The background toluene concentration at a distance
of 1.6 km upwind of the plant was 0.0055 mg/m3.
In the period between 1971 and 1980, atmospheric concentrations
of toluene were estimated in Canada, Europe, and the USA. The
average concentrations found varied widely. In rural areas, the
levels were low whereas, in cities and airports, very high
concentrations were found. The average concentrations ranged from
0.0005 to 1.31 mg/m3. The highest level found was 5.5 mg/m3
(Altshuller et al., 1971; Grob & Grob, 1971; Pilar & Graydon, 1973;
Leonard et al., 1976; Lahmann et al., 1977; Johansson, 1978;
Pellizzari, 1979; Arnts & Meeks, 1981; Häsänen et al., 1981;
Brodzinsky & Singh, 1982; Tsani-Bazaca et al., 1982; Wathne, 1983).
Rainwater from a residential area, an airport, and a busy
traffic intersection in Berlin (FRG) showed toluene concentrations
of 0.00013, 0.0007, and 0.00025 mg/m3, respectively (Lahmann et
al., 1977).
5.1.2. Water
Toluene has been detected in the drinking-water supplies of
several communities. The average and maximum concentrations of
toluene in treated Canadian water were reported to be 0.002
mg/litre and 0.027 mg/litre, respectively, with a frequency of 20%
during the months of August and September. The corresponding
values for the raw water were < 0.001 mg/litre and 0.015 mg/litre,
respectively. The frequency of occurrence and the concentration of
toluene in water showed seasonal variation, the summer-time values
being higher than the winter-time values (Otsun et al., 1980).
In a nation-wide survey of water supplies from 17 cities in the
USA, 7 were discovered to be contaminated with toluene (0.0008 up
to 0.011 mg/litre) (US EPA, 1975a,b). Saunders and colleagues
(1975) found that the concentration of the various contaminants
including toluene in tap water fluctuated from week to week, but
that the chemical composition remained the same.
Toluene was detected in well water at 0.005 - 0.1 mg/litre.
The concentration of toluene in a variety of industrial
wastewaters was reported to be in the range of 0.01 up to
10 mg/litre (Jungclaus et al., 1976; Yamaoka & Tanimoto, 1977;
Rawlings & Samfield, 1979; US EPA, 1980).
5.2. General Population Exposure
Human exposure to toluene through the inhalation of urban air
and oral intake is summarized in Table 3. The air intake estimate
is based on a breathing rate of 1.2 m3/h for an adult during waking
hours and 0.4 m3/h during sleep (8 h/day). The average drinking-
water intake and fish consumption have also been considered. It
should be remembered that Table 3 shows estimates of the toluene
uptake per week by human beings under certain conditions of
exposure and not the amount observed. Only 40 - 60% of inhaled
toluene is absorbed by human organs. Also, part of the absorbed
toluene is rapidly excreted from the body (sections 7.1, 7.4).
Rasmussen & Khalil (1983) suggested that 0.75 µg/m3 could be
regarded as an upper background level to which all populations are
exposed. Inferences from the total air monitoring data base
(Brodzinsky & Singh, 1982) suggest that urban residents throughout
the world are likely to be exposed to considerably higher levels
(Table 3).
The three most likely sources that may lead to dermal exposure
to toluene in the general population are the use of vehicular
fuels, toluene-containing solvents, and cosmetic products.
Although cosmetic products may involve smaller exposures compared
with the other two sources, the population exposed is large
(Anderson et al., 1980).
5.3. Occupational Exposure During Manufacture, Formulation, or Use
Available information suggests that particular occupational
subgroups are likely to be exposed to considerably higher levels
than the general population. Such subgroups include, printers,
shoemakers, and those associated with the production of toluene
and/or toluene-containing products. Atmospheric levels such as
those cited in Table 4 can reflect only the conditions prevailing
at the time of an investigation. They do not represent the peak
exposures to which workers may be subjected during such incidents
as breakdown or leakage of process equipment, transfer operations,
etc. However, the adoption of lower exposure limits in several
countries is likely to have decreased actual exposure to toluene at
the work-place.
Table 3. Toluene exposure estimates under different conditions of exposure
----------------------------------------------------------------------------------------------------
Exposure conditions Observed range of Frequency of Total volume of Inhalation or
concentrations exposure exposure or amount ingestion
consumed per week rate (mg/week)
----------------------------------------------------------------------------------------------------
General population
Inhalation
Urban areas 0.1 - 204 µg/m3 168 h/week 156.8 m3 0.02 - 32
Rural and remote areas trace to 3.8 mg/m3 168 h/week 156.8 m3 trace to 0.6
Areas near manufacturing 0.1 - 600 µg/m3 168 h/week 156.8 m3 0.02 - 94
and user sites
Ingestion
Drinking-water 0 - 19 µg/litre 2 litre/day 14 litre 0 - 0.3
Food (fish only) 0 - 1 mg/kg 6.5 g/day 45.5 g 0 - 0.45
Occupational group
Inhalation 377 mg/m3a 40 h/week 48 m3 18 100
Dermal 0 - 170 µg/litreb 0 - 30 min/week 5.9 litre 0 - 1.0
Cigarette smokers
Inhalation 0.1 mg/cigarettec 20 cigarettes/day 140 cigarettes 14
----------------------------------------------------------------------------------------------------
a This value is similar to permissible standards in various countries and represents the worst-case
estimate. In some industries, the exposure level rarely exceeds 37.5 mg/m3.
b This value represents exposure to blood due to dermal contact and represents absorbed levels.
c From: Dalhamn et al. (1968a); toluene content may be higher depending on tobacco type.
Table 4. Concentrations of toluene in the air at work-places
-------------------------------------------------------------------------
Occupation/work-place Toluene concentration Reference
(mg/m3)
----------------------
Range Average
-------------------------------------------------------------------------
24 workers in paint and 750 - 3000; Parmeggiani &
pharmaceutical industry 560 - 7100 Sassi (1954)
rotogravure printers and 750 - 1500 Banfer (1961)
helpers
11 workshops in 8 factories 15 - 828 Ikeda & Ohtsuji
(rotary processes for (1969)
rotogravure printers)
39 workers in:
rotogravure plant 1954/56 0 - 900 Forni et al.
1957/1965 CTR of room 525 - 896 761 (1971)
near fold machine 210 - 1039 761
between machine 1148 - 3090 1616
1967 near fold machine 585
between machine 994
rotogravure printer 68 - 1875 Szadkowski et
al. (1976)
rotogravure printer 200 - 300 3000 Szilard et al.
(1978)
11 leather-finishing plants
-rinsh area 71 - 319 199 Pagnotto &
-washing & topping operations 109 - 731 420 Lieberman (1967)
rubber coating plants 128 - 450 274
(< 1% benzene)
19 workers in V belts for
industrial machine plants
(1) 300 - 600 468.8 Capellini &
(2) 788 - 1125 937.5 Allessio (1971)
rotogravure printer 60 - 615 Ovrum et al.
(1978)
24 workers in 81 - 706 Veulemans et al.
rotogravure printer (1979)
32 workers in 26 - 420 Mäki-Paakkanen
rotogravure printer et al. (1980)
-------------------------------------------------------------------------
Table 4. (contd.)
-------------------------------------------------------------------------
Occupation/work-place Toluene concentration Reference
(mg/m3)
----------------------
Range Average
-------------------------------------------------------------------------
500 women/leather and rubber 250 Michon (1965)
shoe factory
53 women/leather factory 250 Kowal-Gierczak
(1969)
1000 workers/vapour
commercial toluene
1 - 3 weeks exposure 188 - 5625 Wilson (1943)
(1) 188 - 750
(2) 750 - 1875
(3) 1875 - 5625
29 workers spraying approximately
merchant ship 37 500 - 112 500 Longley et al.
2 h after incident 18 750 - 37 500 (1967)
-------------------------------------------------------------------------
6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
The atmosphere is a major reservoir of toluene emissions and
photochemical reactions are capable of rapidly degrading it.
Toluene discharged into natural waters and soils is removed by
volatization and biodegradation. This section reviews the effects
of toluene on organisms in the aquatic and terrestrial
environments.
6.1. Microorganisms
Microorganisms capable of degrading toluene are widely
distributed in the environment (Gibson, 1971; Subramanian et al.,
1978; Bridié et al., 1979; Wilson et al., 1981). Although toluene
can be toxic for microorganisms, microorganisms are of great
importance for the degradation of toluene in natural waters and
soils. The metabolism of toluene in microorganisms is similar to
that in mammals, except that ring hydroxylation to cresols is more
prevalent (Gibson, 1971). In addition, the metabolic pathway
involves oxidation of the benzyl carbon to form benzoic acid, which
is further metabolized as a carbon source.
Bridié et al. (1979) showed that toluene has a biological
oxygen demand (BOD) in conventional waste-water treatment of 69%
(expressed as a percentage of the theoretical demand-ThoD) in a
standard 5-day test. BOD values greater than 50% are indicative of
a readily-degradable chemical that can be adequately treated by
municipal and industrial waste-treatment facilities. Moreover,
toluene spilled in the environment would be expected to be degraded
under aerobic conditions.
6.2. Aquatic Organisms
The threshold for the acute effects of toluene in aquatic biota
is 1 mg/litre. Aquatic organisms are exposed to toluene via
respiration, resulting in changes in gill permeability and internal
carbon dioxide (CO2) poisoning.
Data on environmental factors affecting the toxicity of toluene
are not extensive, but neither temperature nor water hardness have
been found to have any significant effects (US EPA, 1980).
As in mammals, toluene causes adverse effects in aquatic
organisms through the mechanism of narcosis. Symptoms in aquatic
organisms progress from mild stimulation, to lethargy, loss of
equilibrium accompanied by shallow breathing and slowed heart rate,
anaesthesia, and death (Bakke & Skjoldal, 1979; Maynard & Weber,
1981; Veith et al., 1983). The effects are largely reversible
except for residual CNS effects as evidenced by alteration of
schooling behaviour for longer periods after near lethal exposure.
Narcosis is expected to occur at concentrations of 11 mg/litre in
fresh water and 8 mg/litre in seawater.
A summary of aquatic toxicity data for fish and invertebrates
from fresh water and marine environments is presented in Table 5.
Because of the high volatility of toluene, only flow-through tests
and static tests with measured concentrations are included. The
acute LC50 for freshwater organisms varies from 21.5 mg/litre for
mosquito larvae to 29 and 26 mg/litre for day-old fry and juvenile
fathead minnows, respectively. The results of long-term studies
have shown the no-observed-adverse-effect concentration for the
early life stage of fathead minnow to be 4 - 6 mg/litre.
The acute LC50 for marine organisms varies from 3.7 mg/litre in
bay shrimp to 28 mg/litre in the Dungeness crab. However, the
mosquito fish had an LC50 of 1180 mg/litre. Newly-hatched fry from
Coho salmon and pink salmon were slightly less sensitive to toluene
than the bay shrimp with 96-h LC50 values of 5.5 mg/litre and
7.0 mg/litre, respectively. Long-term effects of toluene in marine
organisms were measured in the sheepshead minnow and Coho salmon.
The 28-day no-observed-adverse-effect concentration for the minnow
was between 3.2 and 7.7 mg/litre. The 40-day no-observed-adverse-
effect concentration for the early life-stage of salmon was between
1.4 and 2.8 mg/litre.
Potera (1975) studied the effects of toluene on marine
phytoplankton. Photosynthesis was inhibited at toluene
concentrations of 34 mg/litre. The same concentration caused a 62%
inhibition in respiration.
An important long-term effect of chemicals on fish reproduction
is the avoidance response in spawning areas. Maynard & Weber
(1981) found that Coho salmon could avoid water containing toluene
at concentrations greater than 2 mg/litre.
6.3. Terrestrial Organisms
Data on the toxicity of toluene for terrestrial organisms are
not available.
6.4. Population and Ecosytem Effects
The Task Group was unaware of studies of effects of toluene on
ecosystems within natural populations.
6.5. Effects on the Abiotic Environment
The primary effect of toluene on the abiotic environment is in
contributing to irritating reaction products in the atmosphere.
However, there are no studies reporting the specific contributions
of toluene to smog formation.
Table 5. Toxicity of toluene for fish and aquatic invertebrates
----------------------------------------------------------------------------------------
Species Duration Effect Concentration Reference
(h) (mg/litre)
----------------------------------------------------------------------------------------
Mosquito larvae 24 LC50 21.5 Berry & Brammer (1977)
(Aedes aegypti)
Zebrafish 48 LC50 25 Sloof (1979)
(Brachydanio rerio)
Goldfish 96 LC50 23a; 58b Brenniman et al. (1976)
(Carassius auratus)
Fathead minnow 96 LC50 63 (embryos) Devlin et al. (1982)
(Pimephales promelas) 96 LC50 29 (1-day fry)
96 LC50 26 (juvenile)
32 days no effect 4 - 6
Sheepshead minnow 96 LC50 13 (juvenile) Ward et al. (1981)
(Cyprinodon variegatus) 28 days no effect 3.2 - 7.7 Ward et al. (1981)
Coho salmon 96 LC50 5.5 (fry) Moles et al. (1981)
(Oncorhynchus kisutch) 40 days no effect 1.4 - 2.8
avoidance 2.0 Maynard & Weber (1981)
no effect
Pink salmon 96 LC50 7.0 (fry) Korn et al. (1979)
(Oncorhynchus gorbuscha) 24 LC50 5.4 Thomas & Rice (1979)
Guppy 96 LC50 59.3 US EPA (1980)
(Poecilia reticulata)
Bluegill 96 LC50 24 US EPA (1980)
(Lepomis machrochirus)
Mosquito fish 96 LC50 1180 US EPA (1980)
(Gambusia affinis)
Daphnia magna ? LC50 313 US EPA (1980)
Striped bass 96 LC50 7.3 Benville & Korn (1977)
(Morone saxatilis)
Grass shrimp 24 LC50 17.2 (adult) Potera (1975)
(Palaemonetes pugio) 24 LC50 25.8 (larvae)
Dungeness crab 96 LC50 28 Caldwell et al. (1976)
(Cancer magister) 48 LC50 170 US EPA (1980)
Bay shrimp 96 LC50 3.7 Benville & Korn (1977)
(Crago franciscorum)
----------------------------------------------------------------------------------------
Table 5. (contd.)
----------------------------------------------------------------------------------------
Species Duration Effect Concentration Reference
(h) (mg/litre)
----------------------------------------------------------------------------------------
Brine shrimp 24 LC50 33 US EPA (1980)
(Artemia salina)
Copepode 24 LC50 24.2 - 74.2 US EPA (1980)
(Nitocra spinipes)
Marine algaec
Chlorella vulgaris 24 EC50 245 US EPA (1980)
Selenastrum capri 96 EC50 > 433 US EPA (1980)
cornutum
----------------------------------------------------------------------------------------
a Flow-through system.
b Static system.
c Besides these 2 algae, at least 5 other marine algae were tested, and all had a low
sensitivity.
7. KINETICS AND METABOLISM
7.1. Absorption
7.1.1. Inhalation
7.1.1.1. Rat
In rats exposed to 2156 mg toluene/m3 for up to 240 min, the
estimated asymptotic value of toluene for blood was 10.5 mg/litre
and, for brain, 18 mg/kg tissue. To reach the 95% level during
uptake required 53 min for blood and 58 min for brain (Benignus et
al., 1981).
7.1.1.2. Dog
The respiratory retention of inhaled toluene was studied in
dogs, at concentrations of 400 - 600 mg/m3. Retention in the total
respiratory tract was found to be approximately 90% of the inhaled
toluene. Varying the ventilation rate, tidal volume, or the
concentration of toluene up to 825 mg/m3 did not have any effect on
the respiratory retention (Egle & Gochberg, 1976).
7.1.1.3. Human volunteers
In human studies, uptake of toluene has been estimated by
different authors to be 40 - 60% of the total amount inhaled
(Nomiyama & Nomiyama, 1974a; Astrand, 1975; Carlsson & Lindqvist,
1977; WHO, 1981; Carlsson, 1982a).
Nomiyama & Nomiyama (1974a) measured pulmonary uptake in
volunteers exposed to 431 mg toluene/m3 for 4 h. Uptake at the end
of 1 h was approximately 52% and decreased to 37% at the end of
2 h, remaining constant at that level for the remaining 2 h. This
was later confirmed by Carlsson (1982a) and Astrand (1983).
The asymptote during uptake of toluene was estimated by
different authors. Because of the differences in the methods and
designs used, these data are not comparable, but the values ranged
from 10 - 80 min (Astrand et al., 1972; Gamberale & Hultengren,
1972; Veulemans & Masschelein, 1978a).
Carlsson (1982a) investigated the effects of physical exercise
on the rate of toluene uptake. Twelve male volunteers were exposed
to 300 mg toluene/m3 during 4 consecutive 30-min workloads at 150
watts (W), 100 W, 50 W, and at rest. During the initial 30-min
period at 150 W, the mean relative uptake declined from about 55%
initially to 29% at the end of the period. During continued
exposure at 100 W, 50 W, and rest for 2 h, the relative uptake
averaged 32, 36, and 39%, respectively (Carlsson, 1982a).
Consequently, there was an increase in the relative uptake (from 29
to 39%) with decreasing workloads during exposure. These findings
were confirmed by Astrand (1983). Astrand also found that doubling
the concentration of toluene in inspired air gave a 2-fold uptake,
which is in agreement with the results of Veulemans & Masschelein
(1978b).
7.1.2. Dermal
7.1.2.1. Guinea-pig
Jakobson et al. (1982) monitored the concentration of toluene
in the arterial blood of anesthetized guinea-pigs following
epicutaneous exposure. In this study, a 3.1 cm2 area of clipped
back skin was continuously exposed to liquid toluene by means of a
sealed glass ring. Toluene in the blood increased rapidly within
1 h to a concentration of 1.3 mg/litre, and then decreased, in
spite of continuing exposure, to a plateau concentration of
0.5 mg/litre after 6 h.
7.1.2.2. Human volunteers
In human volunteer studies, Dutkiewicz & Tyras (1968a,b) showed
that absorption through the skin occurred following exposure to
liquid toluene (rate of absorption 14 - 23 mg/cm2 per h), and, to a
much lesser extent, following exposure to saturated aqueous
solutions (rate of absorption 0.16 - 0.6 mg/cm2 per h).
Sato & Nakajima (1978) reported that a maximum toluene
concentration in the blood of 0.17 mg/litre was found when the skin
of volunteers was immersed in liquid toluene for 30 min. In
studies conducted by Riihimäki & Pfäffli (1978), volunteers,
wearing light, loose-fitting clothing and respiratory protection,
were exposed to 2250 mg toluene/m3 for 3.5 h. The authors
estimated, on the basis of toluene measured in expired air, that
uptake through the skin was approximately 1% of the theoretical
uptake through the respiratory system. Similar conclusions were
reached by Piotrowski (1967).
7.1.3. Oral
Oral absorption appears to occur more slowly than that through
the respiratory tract. On the basis of measurements of toluene
excreted unchanged in the expired air (18%) and levels of hippuric
acid in the urine of rabbits, toluene appears to be completely
absorbed from the gastrointestinal tract (Smith et al., 1954; El
Masry et al., 1956).
7.2. Distribution
7.2.1. Inhalation
The dynamic distribution in the body of any organic solvent
vapour, e.g., toluene, is determined by its solubility in the body
fluids and tissues. Determination of the solubility of toluene in
various body fluids, tissues, and tissue components has been
carried out in mammals. The solubility was expressed in terms of
partition coefficients, which numerically equal the Ostwald
solubility coefficients (Sato et al., 1974a,b; Sherwood, 1976; Sato
& Nakajima, 1979a).
7.2.1.1. Mouse
The concentrations of toluene in the liver, brain, and blood of
mice exposed to 15 000 mg toluene/m3 for 3 h rose continuously
throughout the exposure period, to 625 mg/kg in liver, 420 mg/kg in
brain, and 200 mg/kg in blood, at the end of exposure. Intermittent
exposure to about 40 000 mg/m3 in cycles of 5 min on, 10 min off,
or 10 min on, 20 min off, for a total of 3 h, produced tissue and
blood levels approximately 3 times higher than those produced by a
single 10-min exposure and similar to those produced by the 3-h
exposure (Peterson & Bruckner, 1978; Bruckner & Peterson, 1981a).
Whole-body autoradiography techniques were used to study the
distribution and fate of toluene and its metabolites, and
covalently bound reactive intermediates in mice exposed to methyl-
14C-toluene by inhalation. High levels of radioactivity were
observed in adipose tissue, bone marrow, spinal nerves, spinal
cord, and the white matter of the brain. Radioactivity was also
registered in the blood, liver, and kidneys (particularly in the
medullary region). Since the radioactivity in the central nervous
system (CNS), spinal nerves, and adipose tissues was volatile, it
was proposed that it was probably toluene itself. All radio-
activity in the nervous tissues had disappeared by 1 h after
exposure. Toluene was still present in body fat 2 h after exposure
but had been almost cleared from fatty tissues in 4 h. Four hours
after inhalation, only traces of non-volatile radioactivity
remained in the liver; after 24 h, all radioactivity had
disappeared from the body (Bergman, 1978, 1979, 1983).
7.2.1.2. Rat
Benignus et al. (l984a) developed a log-log model relating
venous-blood and brain levels of toluene to inspired air levels.
Groups of 15 Long-Evans hooded rats were exposed to 188, 375, 1875,
or 3750 mg toluene/m3 for 3 h. The data showed that a 3-h exposure
was sufficient to produce toluene levels in both blood and brain
that were close to asymptote. The calculated brain/blood toluene
ratio in rats was estimated to be 1.56. Values reported by, or
that could be estimated from, others compare well, considering the
various exposure times: 1.27 in rats (Pyykkö et al., 1977); 2.50
in rats (Pryor et al., 1978); 1.26 in mice (Ogata et al., 1974);
2.05 mice (Bruckner & Peterson, 1981a). Benignus et al. (1984b)
reported that blood-toluene concentrations rose at a rate that was
independent of dose level (50 - 1000 mg/kg body weight, sc), and
that blood levels fell at different rates, depending on dose level.
After adult male rats were exposed for 1 h through inhalation
to 14C-labelled toluene (1950 mg/m3), the highest concentrations of
radioactivity were found in the adipose tissue and were up to 2
orders of magnitude higher than those found in blood. The next
highest concentration of radioactivity occurred in the adrenals and
kidneys, followed by liver, cerebrum, and cerebellum. Loss of
radioactivity from adipose tissue and bone marrow during the
following 6 h appeared to occur more slowly than the loss from the
other tissues (Carlsson & Lindqvist, 1977; Pyykkö et al., 1977).
Pregnant CFY rats were exposed for 24 h (on days 10 - 13 of
gestation) to 1375 or 2700 mg toluene/m3 (Ungváry, 1984). Toluene
concentrations in maternal blood, 2 h after exposure, were 6.44 and
13.69 mg/litre, at the lower and higher exposure, respectively. In
fetal blood, the concentrations were about 76% of the maternal
levels, and the concentrations of toluene in amniotic fluid were
0.24 and 0.96 mg/litre. Toluene concentrations, 4 and 6 h after
exposure, were similiar to those measured after 2 h.
7.2.1.3. Human volunteers
Male volunteers (19 - 43 years of age) were exposed to a
toluene concentration of 300 mg/m3 for four 30-min periods at rest
and/or during stepwise-increased workload (50 W, 100 W, 150 W).
The relative uptake averaged 52% at rest, and 49%, 40%, and 29% at
50-, 100-, and 150-W workload, respectively, at the end of 30 min
of exposure (section 7.1.1). The corresponding alveolar
concentrations were 29, 39, 53, and 69% of the inspired
concentrations. The arterial concentration amounted to 0.7
mg/litre blood at rest and 3.3 mg/litre blood at 150-W workload for
30 min (Carlsson, 1982b). Consequently, the arterial concentration
increased, not only when the concentration of the inspired solvent
increased, but also with increasing workloads, when the
concentration in the inspired air was constant (Astrand, 1983).
The relationship between the relative uptake and the alveolar
concentration (as a percentage of the concentration in inspired
air) was linear and in close agreement with the ratio found by
other investigators (Astrand, 1975). The higher the relative
uptake, the lower the alveolar concentration of the solvent. The
relationship between arterial-blood and alveolar-air concentrations
for toluene was linear and thus the arterial-blood concentrations
were closely correlated with the alveolar-air concentration. Thus,
by measuring the concentration of toluene in alveolar air during
exposure, it is possible to estimate the arterial-blood
concentration (Piotrowski, 1967; Carlsson & Lindqvist, 1977; Ovrum
et al., 1978; Carlsson, 1982a,b; Astrand, 1983).
In the study carried out with male subjects described above,
Carlsson and co-workers also estimated the toluene concentrations
in subcutaneous fat. At rest, the peak concentration in the fat
was approximately 2 mg/kg. After exercise, the toluene
concentration was 5 - 10 times higher than at rest. Subjects with
the least amount of adipose tissue showed the smallest accumulation
of toluene in body fat and those that were overweight showed a high
accumulation.
In a male subject with about 12% body fat, the estimated
quantity of toluene in this fat amounted to 5% of the total uptake,
after 2 h exposure at rest. After 2 h of exposure at 50 W, it
amounted to 20%. The elimination half-life for toluene in
subcutaneous adipose tissue ranged between 0.5 and 2.7 days, and
increased with increasing amounts of body fat.
The quotients between the concentrations of toluene in
subcutaneous adipose tissue and arterial blood ranged from 1.2
after exposure at rest to 4.7 after exposure combined with a 50-W
work-load. It took about 2 days of continuous exposure to toluene,
at rest, for the concentration in the subcutaneous adipose tissue
to reach 63% of the solvent partial pressure in the arterial blood.
During prolonged exposure, persons with a high body fat content
may be exposed to a more prolonged effect of toluene on the central
nervous system than thin persons, since toluene disappears more
slowly from the adipose tissue and blood.
By increasing the blood circulation, physical exercise produces
conditions favouring a high uptake in the skeletal muscles, heart,
CNS (especially the brain), and adipose tissues. Consequently,
there is a decrease in the toluene concentration in the liver,
kidneys, and gastrointestinal tract (Carlsson & Lindquist, 1977;
Carlsson, 1982a,b).
7.2.2. Oral
7.2.2.1. Rat
Oral administration of 4-3H-toluene (100 µl toluene in 400 µl
peanut oil by intubation) to adult male rats produced a pattern of
tissue distribution similar to that produced with inhalation
exposure. Distribution appeared to be delayed, because of the time
needed for absorption from the digestive tract. Maximum tissue
concentrations occurred 2 - 3 h after administration for most
tissues and 5-h after administration for adipose tissue (Pyykkö et
al., 1977).
7.2.3. Intraperitoneal
7.2.3.1. Rat
Savolainen (l978) observed that after ip injection of rats with
500 µmol methyl-14C-toluene, the concentration of radioactivity in
the CNS was highest in the cerebrum. Toluene was rapidly removed
from the CNS and was almost undetectable after 24 h.
7.3. Metabolic Transformation
7.3.1. Oral
The initial step in the metabolic transformation of toluene to
benzoic acid, after oral administration, appears to be
hydroxylation of toluene to benzyl alcohol (Fig. 1) by the
microsomal mixed-function oxidase system. In rats, rabbits, and
man, approximately 20% of the dose is excreted unchanged via the
lungs, while approximately 80% is converted to benzoic acid and
excreted in the urine unchanged or as its glycine conjugate,
hippuric acid. Furthermore, it has been found that toluene is
excreted as benzylmercapturic acid in smaller quantities in rats.
Small amounts of benzoic acid may be conjugated with glucuronic
acid and excreted as benzoyl glucuronic acid in the urine. Minor
amounts (less than 1%) of toluene undergo ring hydroxylation to
form o-, m, and p-cresol, which are excreted in the urine as
sulfate or glucuronide conjugates (Smith et al., 1954; El Masry et
al., 1956; Daly et al., 1968; Bakke & Scheline, 1970; Angerer,
1976, 1979; Pfäffli et al, 1979; Van Doorn et al., 1980; Woiwode &
Drysch, 1981).
Ikeda & Ohtsuji (1971) demonstrated that the induction of
hepatic mixed-function oxidases, by pretreatment of adult female
rats for 4 days with phenobarbital, increased the metabolism of
toluene when administered ip. A clear (3-fold) increase in
hippuric acid levels in urine was already found after 2 h in
comparison with levels in rats administered only toluene. High
levels of benzoic acid were found in the blood compared with none
in non-induced rats. Treatment of rats with phenobarbital enhanced
the in vivo metabolism of toluene and resulted in increased
tolerance in the rats to the narcotic action of toluene. No
effects of the pretreatment was observed on the rates of oxidation
of aromatic alcohol to the corresponding acid, phenolic
sulfatation, or on the glucuronidation or glycine conjugation of
benzoic acid. Rapid disappearance of toluene from the blood
because of enhanced metabolism, together with reduced sensitivity
of the central nervous system, could explain the shortened sleeping
time after the ip injection of toluene.
7.3.2. Inhalation
7.3.2.1. Human beings
Toluene is metabolized in human beings by the pathway outlined
in Fig. 1. The excretion of hippuric acid in the urine was
elevated within 30 min of the initiation of inhalation exposure,
indicating that the metabolism of toluene is rapid. The urinary
hippuric acid levels reached a steady-state level after 4 h of
continuous exposure (mean toluene concentration in air of
350 mg/m3) under a moderate energy load (Ogata et al., 1970;
Nomiyama & Nomiyama, 1978; Veulemans & Masschelein, 1979). The
maximum rate of transformation of benzoic acid to hippuric acid
seemed to be limited by the availability of glycine (Quick, 1931;
Amsel & Levy, 1969).
During the inhalation of toluene, the rate of uptake was
estimated to equal the full conjugating capacity at toluene
concentrations of about 2950 mg/m3, at rest, or about 1015 mg/m3
during moderately-heavy work (Riihimäki, 1979).
o-Cresol was identified in the urine of workers exposed to 26 -
420 mg toluene/m3 (Angerer, 1979; Pfäffli et al., 1979; Apostoli et
al., 1982; Hansen & Dossing, 1982; Kawai et al., 1984). p-Cresol
may also be a metabolite of toluene as it was present in higher
concentrations in the urine of workers exposed to toluene than in
the urine of unexposed workers (Angerer, 1979). The difference,
however, was not significant. Apostoli et al. (1982) and Woiwode
et al. (1979) reported finding m-cresol and p-cresol in addition
to o-cresol in the urine of workers exposed to 1050 mg toluene/m3.
No m-cresol was detected in the urine of unexposed workers.
7.3.3. In vitro studies
Toluene has been shown to produce a Type I binding spectrum
with cytochrome P 450 (EC 1.14.14.1) from rats and hamsters (Canady
et al., 1974; Al-Gailany et al., 1978).
Incubation of toluene with rat or rabbit liver microsomes
resulted in the production of small amounts of o-cresol and
p-cresol. The migration of deuterium, when toluene was labelled in
the 4-position, and a comparison of the rearrangement products of
arene oxides of toluene with the cresols obtained by microsomal
metabolism of toluene suggest that arene oxides are intermediates
in the metabolism of toluene to o- and p-cresols (Daly et al.,
1968; Kaubisch et al., 1972).
7.4. Elimination and Excretion in Expired Air, Faeces, and Urine
7.4.1. Toluene
7.4.1.1. Laboratory animals
Toluene is rapidly exhaled as the unchanged compound
(approximately 20 - 40% of the absorbed toluene). Only trace
amounts of toluene (about 0.06%) are excreted unchanged in urine.
Whole-body autoradiography of laboratory animals, including mice,
showed that excretion of toluene metabolites took place mainly via
the kidneys. Most of the absorbed toluene was excreted within 12 h
of the end of exposure (Bergman, 1978, 1979, 1983).
Mice exposed to a high initial concentration of methyl-14C-
toluene in a closed chamber for 10 min excreted ~ 10% of the
absorbed dose as volatile material in the exhaled air and about 68%
of the radioactivity in the urine within 8 h (Bergman, 1979).
Rates of urinary hippuric acid excretion in rabbits exposed to
toluene vapour at 1313 mg/m3 for 100 min or 16 835 mg/m3 for 10 min
increased to reach maximum values 1.5 h after exposure (Nomiyama &
Nomiyama, 1978). Excretion rates returned to baseline levels, 7 h
after the initiation of exposure to the lower dose level, and 3 h
after exposure to the higher dose level.
Rats given 50 mg 14C-toluene/kg body weight, ip, excreted less
than 2% of the administered radioactivity in the bile within 24 h
(Abou-El-Markarem et al., 1967). Bergman (1979) showed excretion
of toluene metabolites (benzoic acid) via bile into the intestinal
tract in mice after inhalation of toluene.
In a study in rats, methyl-14C-toluene was administered, sc, in
a dose of 184 mg/kg body weight (Gut, 1983). About 20% of the
radioactivity had been excreted in the urine after 8 h and 50%
after 48 h.
7.4.1.2. Human beings
Human beings exposed through inhalation to toluene
(concentrations ranging from 350 to 700 mg/m3) exhaled 5 - 20% of
the absorbed toluene after exposure was terminated (Srbova &
Teisinger, 1952, 1953; Nomiyama & Nomiyama, 1974a,b). Alterations
in physical activity influenced the elimination rate. Astrand
(1983) reported that the elimination rate was doubled under
conditions of a light workload at 50 W compared with resting
conditions. The concentrations of toluene in the alveolar air, and
arterial and venous blood of human subjects declined rapidly,
immediately after the end of exposure and then the rate of decline
gradually decreased (Astrand et al., 1972; Sato et al., 1974b;
Carlsson & Lindqvist, 1977; Ovrum et al., 1978; Veulemans &
Masschelein, 1979; Carlsson, 1982a,b).
In the desaturation period, male and female volunteers expired
17.6 and 9.4%, respectively, of the total amount of toluene
calculated to have been absorbed during exposure (Nomiyama &
Nomiyama, 1974b). They reported rate coefficients for the rapid
phase of 5.10/h (t1/2 = 8.16 min) for men and 3.22/h (t1/2 = 12.9
min) for women; the rate coefficient for the slow phase was 0.335/h
(t1/2 = 124 min) for both sexes. Toluene retained in the body fat
is eliminated by pulmonary ventilation and by biotransformation.
The half-time for toluene was 0.5 - 3 days (Carlsson, 1982a,
Astrand, 1983). There was a correlation between the half-time and
the individual's content of body fat (section 7.2.1.3).
Brugnone et al. (1983) reported the cases of 2 workers who were
admitted to a hospital because of coma due to an accidental high-
level occupational exposure to a mixture of solvents; the levels of
toluene were, respectively, 823 - 1122 µg/litre in the blood and 52
- 38 µg/litre in the alveolar air, on the second day of admission
(36 h after the accidental exposure). At 112 h after exposure, the
alveolar-toluene concentration was 1 - 3 µg/litre. The blood-
toluene concentrations at 112 h were 45 and 120 µg/litre,
respectively. The mean decline rate of toluene, expressed as half-
life, was calculated to be between 19 and 21 h both in the alveolar
air and in the blood. During the first 2 days, the lung clearance
of toluene was of the order of 350 ml/min in the first worker and
270 ml/min in the second worker.
Dermal exposure of human subjects to toluene liquid or vapour
resulted in the appearance of toluene in the expired air. When
exposure ceased, a rapid decrease in toluene levels in alveolar air
was noticed (Guillemin et al., 1974; Riihimäki & Pfäffli, 1978).
The excretion of toluene in the expired air appeared to consist of
at least 2 exponential phases (Riihimäki & Pfäffli, 1978).
7.4.2. Excretion of metabolites
7.4.2.1. Human beings
Volunteers inhaling toluene at concentrations of approximately
200 - 550 mg/m3, for 3 - 4 h, excreted 60 - 70% of the absorbed
dose as hippuric acid in the urine (Ogata et al., 1970; Veulemans &
Masschelein, 1979).
A relatively wide range of hippuric acid excretion levels has
been reported for groups of workers exposed to toluene during
different operations (Table 6). For example, Pagnotto & Lieberman
(1967) found a range of 2.75 - 6.80 g/litre urine (mean, 3.66
g/litre) for spreaders in the rubber-coating industry exposed to
274 mg toluene/m3. Ikeda & Ohtsuji (1969) reported a range of 2.28
- 3.54 g/litre (mean, 2.84 g/litre) for 8 workers exposed to 469 mg
toluene/m3. In a control group of 17 unexposed workers, a mean
level of 0.95 g/litre (range 0.55 - 1.6 g/litre) was recorded by
Capellini & Alessio (1971).
From the studies carried out by Pagnotto & Lieberman (1967),
Ikeda & Ohtsuji (1969), Ogata et al. (1971), and Apostoli et al.
(1982), it is concluded that the urinary levels of hippuric acid
are proportional to the concentrations of toluene in the air,
though within wide variations.
Ogata et al. (1970) carried out a study on human volunteers and
found that the quantity of hippuric acid excreted was proportional
to the total exposure (mg/m3 x h). In descending order of
precision, the following were also related to exposure: rate of
excretion during the exposure period; concentrations of hippuric
acid in urine corrected to constant urine density; and
concentrations in urine uncorrected for density. With the
exception of the latter, these variables could be used in screening
tests to show whether workers could have been exposed to
concentrations greater than the maximum allowable concentration.
Apostoli et al. (1982) found that, besides a good correlation
between urinary-hippuric acid levels and air levels of toluene,
there was also a good correlation between urinary- o-cresol and
blood-toluene concentrations and toluene concentrations in the air.
Table 6. Hippuric acid excretion levels
----------------------------------------------------------------------------------------------------
Number of workers Toluene concentration Hippuric acid excretion Reference
and/or (mg/m3) levels (g/litre urine)
operation --------------------- --------------------------
Mean Range Mean Range
----------------------------------------------------------------------------------------------------
Spreaders 73 34 - 120 3.66 2.75 - 6.80 Pagnotto & Lieberman (1967)
in rubber
industry
Leather-finishing
industry:
automatic spraying 53 19 - 85 2.38 1.50 - 3.66 Pagnotto & Lieberman (1967)
washing and tapping 112 29 - 195 4.48 2.15 - 5.85 Pagnotto & Lieberman (1967)
unexposed workers 0.8 0.4 - 1.4 Pagnotto & Lieberman (1967)
31 unexposed 0.35 0.20 - 0.62 Ikeda & Ohtsuji (1969)
118 exposed workers 356 15 - 900 3.25 0.45 - 6.48 Ikeda & Ohtsuji (1969)
18 exposed workers 469 300 - 600 2.1 ± 0.83 Capellini & Alessio (1971)
17 unexposed 0.95 ± 0.33 0.55 - 1.6 Capellini & Alessio (1971)
23 male volunteers 375 2.55 ± 0.55 Ogata et al. (1970)
(3-h exposure) 750 5.99 ± 1.20 Ogata et al. (1970)
53 exposed workers 101 2.04 Angerer (1976)
30 unexposed 0.79 Angerer (1976)
20 workers in art- 15 - 164 approximately 0.21 - 2.2 Apostoli et al. (1982)
furniture industry 0.75
----------------------------------------------------------------------------------------------------
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1. Single Exposures
The acute toxicity of toluene by various routes of exposure is
summarized in Table 7.
In all species studied, the symptoms found with increasing dose
were irritation of the mucous membranes, incoordination, mydriasis,
narcosis, tremors, prostration, anaesthesia, and death. From the
acute toxicity studies, especially the inhalation studies, there is
some indication that sensitivity differed between the species
tested. However, it should be kept in mind that the studies are
hardly comparable.
From the oral and inhalation studies, there is evidence that
there is a difference in sensitivity between the rat strains used
and also at different ages.
8.1.1. Inhalation
Bruckner & Peterson (1981a,b) found an age-dependent
sensitivity in outbred male rats (ARS/Sprague Dawley) and male IRC
mice. Animals of 4 weeks of age were found to be more susceptible
to toluene narcosis, when exposed to toluene vapour at 9750 mg/m3
for 3 h, than 8- and 12-week-old animals. In contrast, Cameron et
al. (1938) stated that very young Wister rats (9-day-old) were less
sensitive to toluene exposure than adults.
von Oettingen et al. (1942b) observed that 6 dogs showed an
increase in respiratory rate and a decrease in respiratory volume
after 1 h of exposure to 3188 mg toluene/m3 (containing only 0.01%
benzene).
8.1.2. Oral
Immature 14-day-old Sprague Dawley rats were more sensitive to
ingested toluene (analytical grade) than juvenile or adult males
(Table 7).
8.1.3. Intraperitoneal and intravenous injection
Batchelor (1927) and Cameron et al. (l938) reported the ip
lethal dose for rats and mice to be approximately 1.7 g/kg body
weight. Female mice were less sensitive to toluene than males
(Ikeda & Ohtsuji, 1971).
Keplinger et al. (l959) determined the ip LD50 of toluene in
rats of both sexes at three different environmental temperatures.
It was found that the LD50 was 800 mg/kg body weight at 26 °C,
530 mg/kg at 8 °C, and 225 mg/kg at 36 °C.
Table 7. Acute toxicity of toluene
---------------------------------------------------------------------------------------------------------
Route/species Dose Duration Effect Reference
(h)
---------------------------------------------------------------------------------------------------------
Inhalation
Rat 45 750 mg/m3 6.5 LC50 Cameron et al. (1938)
Rat 15 000 mg/m3 4 16% mortality Smyth et al. (1969a)
Mouse 45 750 mg/m3 6.5 100% mortality Cameron et al. (1938)
Mouse (Swiss) 19 950 mg/m3 7 LC50 Svirbely et al. (1943)
Mouse 26 033 mg/m3 6 LC50 Bonnet et al. (1979)
Dog 3188 mg/m3 1 no mortality von Oettingen et al. (1942b)
Oral
Rat 7.53 g/kg body weight LD50 Smyth et al. (1969a)
Rat (CFY males) 5.90 g/kg body weight LD50 Ungváry et al (1979)
Rat (Sprague Dawley)(male) 5.58 g/kg body weight LD50 Withey & Hall (1975)
14-day-old (both sexes) 2.6 g/kg body weight LD50 Kimura et al. (1971)
juvenile (male) 5.5 g/kg body weight LD50
adults (male) 6.4 g/kg body weight LD50
Dermal
Rabbit 14.1 mg/kg body weight LD50 Smyth et al. (1969a)
Intraperitoneal
Rat (female) 1.64 g/kg body weight LD50 Ikeda & Ohtsuji (1971)
---------------------------------------------------------------------------------------------------------
Paksy et al. (1982) demonstrated that ip administration of 553
or 1843 mg toluene/kg body weight caused muscular weakness and
equilibrium disturbances in male rats, within 30 min of exposure.
Toluene administered iv as a 2 - 5% infusion (2.75 mg/kg body
weight per min) in Intralapid(R), for 1 h, caused vestibular
disturbances in female rats (Tham et al., 1982).
8.1.4. Subcutaneous injection
Quantities of 1.1 - 1.25 g/kg body weight and 4.3 - 8.7 g/kg
have been found to cause death in rats and mice, respectively, when
injected sc (Batchelor, 1927; Cameron et al., 1938). Braier (1973)
reported that all rabbits injected with 3.46 g/kg body weight died
by the end of the second day.
8.2. Short-Term Exposures
8.2.1. Inhalation
8.2.1.1. Mouse
Mice exposed to 3750 mg/m3 for 20 days did not show
histological damage to the lungs and kidneys. However,
leukocytosis, and decreased thrombocyte count and RBC count were
seen, particularly at the highest dose level. There was some
evidence of hypoplasia in bone marrow (Horiguchi & Inoue, 1977).
The same was found by Bruckner & Peterson (1981b) in mice exposed
to 15 000 mg/m3 for 8 weeks.
Effects were found in mice with exposure to 45 000 mg toluene
(99.9% pure)/m3, in cycles of 10 min inhalation exposure with
20-min recovery periods for 7 cycles/day, 5 days/week, for 8 weeks.
These included a depression in body weight gain (food intake was
not measured). The animals became ataxic with blood-toluene levels
of between 40 - 70 g/litre, immobile with levels of 75 - 125
g/litre, drowsy and difficult to arouse with levels of 125 - 150
g/litre, and unconscious with levels exceeding 150 g/litre. Blood-
urea nitrogen (BUN) levels were consistently reduced during the
exposure period. Recovery occurred 2 weeks after exposure. No
detectable histopathological effects were seen in the brain, lungs,
liver, heart, or kidneys, though decreases in kidney, brain, and
lung weights were found. Substantial toluene residues were found
in the brain, 1 h after exposure (Bruckner & Peterson, 1981a,b).
8.2.1.2. Rat
von Oettingen et al. (1942b) reported increasing numbers of
casts in the collecting tubules of rat kidneys during inhalation of
99.9% pure toluene at concentrations of 750, 2250, 9375, and 18 750
mg/m3 for 5 or 15 weeks (7 h/day, 5 days/week). There was no clear
influence on the composition of the blood, with the exception of a
temporary decrease in WBC count at the highest dose level. A few
casts in the kidneys were seen after the third week of exposure at
2250 mg/m3 and earlier at the higher dose levels.
Furnas & Hine (1958) reported on the neurotoxicity of toluene
(pure product) in rats. An initial exposure to 18 750 mg/m3 proved
to be ineffective in producing CNS changes. Exposures were
increased to 37 500 mg/m3 for 20 min and then to 75 000 mg/m3 for
1 h. At the highest level, there was decreased mobility but no
quivering or twitching and no hyperresponse to auditory stimuli.
A significant depression was observed in the relative adrenal
weight in Donryu strain rats exposed to 99% pure toluene at 750,
3750, or 7500 mg/m3 during 8-h daily exposures, for 32 weeks
(Takeuchi, 1969). No influence on blood composition was found.
Histologically, the zona glomerulosa of the adrenal cortex of
toluene-exposed rats was thicker, while the zona fasciculata and
zona reticularis were reduced. The author suggested that toluene
affected the hypothalamo-pituitary-adrenal system. In another
study, it was noted that exposure of male Sprague Dawley rats to
3750 mg toluene/m3, for 8 h daily for 4 weeks, significantly
increased adrenal weight after 2 weeks and that the weight remained
higher after 4 weeks. Eosinophile count increased and, after 4
weeks, it was significantly greater than in the controls (Takeuchi
et al., 1972).
Matsumoto et al. (1971) found degeneration of germinal cells in
the testes in 4 out of 12 Donryu male rats exposed by inhalation to
750 mg toluene/m3, for 8 h/day, 6 days/week, for 1 year. Absolute
testicular weight at 1 year was lower in rats exposed to 375 and
750 mg/m3 in comparison with controls, and there was a trend toward
a decrease in the relative testes weight.
In the studies of Matsumoto et al. (1971), exposure of rats
through inhalation to toluene concentrations of 375, 750, or
7500 mg/m3 for 8 h/day, 6 days/week, for 43 weeks, produced hyaline
droplets in renal tubules. There was an absolute and relative
increase in kidney weight. No change in the morphological blood
picture was found.
Exposure of rats to 4095 mg toluene/m3 for 6 weeks or to 15 000
mg/m3 for 8 weeks did not induce histological changes in the liver
or changes in blood composition (Jenkins et al., 1970; Bruckner &
Peterson, 1981b).
Dose-dependant effects were found in rats with high-level
intermittent exposure to 45 000 mg/m3 (toluene 99.9% pure), in
cycles of 10 min inhalation exposure with 20-min recovery periods
for 7 cycles/day, 5 days/week, for 8 weeks (Bruckner & Peterson,
1981a). After several cycles of exposure, progressive
deterioration in performance was noted in rats after each exposure.
A depression in body weight gain was seen in rats during the 8
weeks of intermittent toluene exposure. Food intake was not
measured. An increase in aspartate aminotransferase (SGOT) (EC
2.6.1.1) levels was noted in rats. An increase in lactate
dehydrogenase (LDH) (EC 1.1.1.27) was also seen. Recovery occurred
2 weeks after exposure. There were no detectable histopathological
changes in brain, lung, liver, heart, or kidneys, though a decrease
in organ weights (kidneys, brain, and lung) was noted in treated
rats (Bruckner & Peterson, 1981b). Substantial toluene residues
were found in the brain, 1 h after exposure. Previous work by
these authors showed that performance was inversely correlated with
the toluene concentration in brain tissue.
A group of rats was exposed to 4000 mg toluene/m3 through
inhalation, for 6 h/day, 5 days/week, for 4 weeks. The toluene
increased myocardial vascular resistance and reduced cerebral
nutritive blood flow. It did not change the ECG, blood pressure,
cardiac output, distribution of cardiac output to the organs,
nutritive blood flow, the circulatory resistance of other organs,
and the histological structure of the heart (Morvai & Ungváry,
1979).
Pyykkö (1983a) reported that inhalation of 7500 mg toluene
vapour/m3 for 8 h/day for 1 - 16 days, caused insignificant changes
in rat kidney microsomes. After discontinuation of exposure, the
activities of enzymes and the concentration of cytochromes returned
to the control level in 1 - 4 days. A decrease in the activities
of monooxygenases and the concentration of cytochrome P-450 (EC
1.14.14.1) of adult male rat lung microsomes after 6 - 24 h toluene
exposure was found, but those of cytochrome-b5 (EC 1.6.2.2) and
NADPH-cytochrome c reductase (EC 1.6.2.4) were not changed (Pyykkö,
1983a).
Gut (1983) demonstrated a post-inhalation, dose-related
increase in cytochrome P-450 content in rats exposed to levels up
to 4000 mg/m3 for 24 h. When rats from this exposure group were
pre-treated with phenobarbital prior to toluene exposure, a
decreased induction of cytochrome P-450 was seen.
Korpela et al. (1983) found an increase in the haemolytic
resistance of the rat erythrocyte in hypotonic medium, in in vitro
studies and in in vivo studies, when animals were exposed to a
toluene concentration of 7500 mg/m3. In vitro dose levels of 200 -
500 mg/litre were tested for the antihaemolytic effect. A maximum
was reached with 300 mg/litre.
8.2.1.3. Dog
Appreciable fat in the convoluted tubules and hyaline casts in
the collecting tubules of the kidneys and congestion in the lungs
were observed in dogs exposed through inhalation to 750, 1500, or
2250 mg/m3 for approximately 20 daily 8-h exposures, then for
7 h/day, 5 days/week for 1 week, and finally to 3188 mg/m3 for 1 h
(von Oettingen et al., 1942b).
At autopsy, hyperaemic renal glomeruli and albuminuria were
observed, but no effects on the bone marrow, in 2 dogs exposed to
7500 mg/m3 (8 h/day, 6 days/week, for 4 months), then 9975 mg/m3
(8 h/day, 6 days/week, for 2 months) (Fabre et al., 1955).
8.2.2. Other animal species and routes
Neither continuous exposure to 389 mg/m3 toluene for 90 days
nor repeated exposure to 4095 mg/m3 for 6 weeks (8 h/day, 5
days/week) affected the liver, kidneys, lung, spleen, heart, or
blood composition in 30 rats, 30 guinea-pigs, 4 dogs, or 6 monkeys,
as assessed by histopathological examination. In addition, no
effects of treatment were seen in the brain or the spinal cord of
dogs or monkeys. No significant changes were observed in any of
the haematological parameters (haemoglobin, haematocrit, or
leukocyte count). All except 2 of 30 treated rats survived
exposure, and all animals in the study gained body weight with the
exception of the monkeys (Jenkins et al., 1970).
Guinea-pigs exposed to toluene at 4688 mg/m3 for 4 h/day,
6 days/week, survived 3 weeks of exposure, though they were
severely affected. At 3750 mg/m3, guinea-pigs were not affected
even after 35 exposures, though there was evidence of degenerative
changes in the liver and kidneys (Smyth & Smyth, 1928).
Reversible morphological changes in the liver were noted when
toluene was injected via the sc and ip routes in CFY male rats.
The dose levels were 1 ml/kg body weight ip for 12 days or sc for
3 weeks, 0.5 ml/kg body weight ip or sc for 3 weeks, and 0.25 or
0.125 ml/kg body weight ip or sc for 4 weeks (Ungváry et al.,
1976). The same changes were observed when toluene was given
orally to guinea-pigs (Divincenzo & Krasavage, 1974).
Subcutaneous injection of rats with toluene at 0.87 g/kg body
weight, twice daily, for 6 months, elicited repolarization
disorders, atrial fibrillation, and in some of the animals,
ventricular extrasystoles. Intravenous injection of 0.4 mg
toluene/kg body weight in rats reduced arterial blood pressure;
however, injection of the same dosage by the ip or sc route did not
have any effects on blood pressure (Morvai et al., 1976).
Rabbits administered sc 300 mg toluene/kg body weight for
6 weeks or 700 mg/kg body weight for 9 weeks in rabbits did not
show any effects on DNA synthesis in bone-marrow cells or
peripheral blood elements (Speck & Moeschlin, 1968). Braier (1973)
found a transient slight granulopenia followed by granulocytosis in
rabbits given 865 mg toluene/kg body weight, sc, for 6 days. No
changes in bone marrow were seen.
8.2.3. Oral
8.2.3.1. Rat
In a short-term oral study, female rats fed up to 590 mg
toluene/kg body weight by intubation, for periods of up to
6 months, did not exhibit toxicological effects as determined by
gross appearance, growth, blood counts, analysis for blood-urea
nitrogen, final body and organ weights, bone-marrow counts, or
histopathological examination of adrenals, pancreas, lungs, heart,
liver, kidneys, spleen, and testes (Wolf et al., 1956).
8.3. Skin and Eye Irritation; Sensitization
8.3.1. Skin
Repeated (10 - 20) applications of undiluted solvent to the
rabbit ear or the shaved skin of the abdomen, for 2 - 4 weeks,
produced slight to moderate irritation (Wolf et al., 1956; Smyth et
al., 1969a) and increased capillary permeability locally (Delaunay
et al., 1950). Cutaneous contact (1 ml as skin depot) in the
guinea-pig resulted in histopathological changes, such as
karyopyknosis, karyolysis, spongiosis, and cellular infiltration in
the dermis, within 16 h (Kronevi et al., 1979).
8.3.2. Eye
Depending on the dose level and the duration of the
application, slight to severe irritation of the conjunctival
membrane was reported following direct application of toluene to
the rabbit eye (Carpenter & Smyth, 1946; Wolf et al., 1956; Smyth
et al., 1969a).
The results of the different studies are summarized in more
detail in Table 8.
8.4. Long-Term Exposures
8.4.1. Inhalation
8.4.1.1. Rat
The long-term toxicity of inhaled toluene was studied in
Fisher-344 rats. Four groups of 120 male and 120 female rats were
exposed to 0, 112, 375, and 1125 mg/m3, for 6 h/day, 5 times per
week, for 24 months. All animals were examined for clinical
changes throughout the course of the study and selected animals
were used for ophthalmological, haematological and clinical
chemistry studies, and urinalysis. A slight, but significant
reduction in haematocrite was observed among female rats exposed to
375 or 1125 mg/m3. Among the 1125 mg/m3 group only, the mean
corpuscular haemoglobin concentration was slightly, but
significantly, increased. No histopathological changes were found
in liver, kidneys, lungs, or other organ systems including spleen
and bone marrow (Gibson & Hardisty, 1983).
8.5. Reproduction, Embryotoxicity, and Teratogenicity
8.5.1. Reproduction
No data are available.
8.5.2. Embryotoxicity and Teratogenicity
A number of studies have been carried out on the chicken embryo
(McLaughlin et al., 1964; Elovaara et al., 1979), but the test is
not considered a suitable test for teratogenicity and thus, the
results have not been recorded in this document.
8.5.2.1. Inhalation
(a) Rat
Hudák et al. (1977) exposed CFY female rats to 6000 mg
toluene/m3 for 24 h/day during days 1 - 8, 9 - 14, or 9 - 21 of
pregnancy. No teratogenic effects were found. However, a definite
embryotoxic effect, which was related to the duration of the
exposure was noted. Seventeen percent of implants died or were
resorbed in the group exposed between 7 and 14 days and, in the
group exposed during days 9 - 21 of pregnancy, fetal and placental
weights were decreased and the bone development was retarded.
In a follow-up study, Hudák & Ungváry (1978) exposed rats to
1000 mg toluene/m3 for 8 h/day on days 1 - 21 of pregnancy, or to
1500 mg toluene/m3 for 8 h/day on days 1 - 8 or 9 - 14 of
pregnancy. There were no signs of maternal toxicity at 1000 mg/m3.
There were no significant effects in toluene-exposed groups on
implants/dam, live fetuses/dam, dead or resorbed fetuses/dam or
malformations. Fetal body weight was signficiantly reduced by 13%
when dams were exposed to 1000 mg/m3 throughout pregnancy, but not
in the 1500 mg/m3 groups exposed in early or mid-pregnancy. There
was a signficant increase in retarded ossification in the 1000
mg/m3 groups exposed throughout pregnancy and in the 1500 mg/m3
group exposed on days 1 - 8 of pregnancy. Significant increases
were also seen in fused and extra ribs in the fetuses, when dams
were exposed to 1500 mg/m3 on days 9 - 14 of pregnancy.
Table 8. Acute effects of toluene on skin and eyes
-----------------------------------------------------------------------------------------
Route/species Dose Duration (h) Effect Reference
-----------------------------------------------------------------------------------------
Skin
Rabbit 435 mg 72 mild irritation (well- RTECS (1984)
defined erythema and
slight oedema)
Rabbit 500 mg 72 moderate-to-severe RTECS (1984)
erythema and moderate
oedema
Guinea-pig 1 ml 16 karyopyknosis, karolysis, Kronevi et al.
perinuclear oedema, spong- (1979)
iosis, junctional separ-
ation, cellular infiltra-
tion in dermis; no liver
or kidney damage
Guinea-pig 2 ml, completely absorbed by 5th - Wahlberg (1976)
covered 7th day; no mortality up to
4 weeks; weight less than
controls for weeks 1 - 3;
no differences at week 4
-----------------------------------------------------------------------------------------
Table 8. (contd.)
-----------------------------------------------------------------------------------------
Route/species Dose Duration (h) Effect Reference
-----------------------------------------------------------------------------------------
Eye
Rabbit 0.005 ml moderately severe injury Smyth et al.
(1969a)
Rabbit 100 mg 30 sec (then mild eye irritation RTECS (1984)
rinsed)
Rabbit 870 µg 72 mild eye irritation RTECS (1984)
Rabbit 2 mg 24 h severe eye irritation RTECS (1984)
-----------------------------------------------------------------------------------------
(b) Mouse
Hudák & Ungváry (1978) concluded from their study that toluene
administered via inhalation at 500 mg/m3, for 24 h/day, from day 6
to 13 of pregnancy, was not teratogenic in mice.
Shigeta et al. (1982) investigated the effects of maternal
exposure to toluene at a concentration of 375 or 3750 mg/m3, for
6 h/day, from the first to the 17th day of gestation, on mouse
embryos, fetuses, and postnatal growth. No significant differences
compared with controls were found. There was a slight increase in
the incidence of resorbed fetuses and rudimentary 14th ribs, and an
increase in the incidence of extra 14th ribs after exposure to
3750 mg toluene/m3 (32.6% compared with a mean incidence in the
control litter of 19.2%).
(c) Rabbit
In a study by Ungváry & Tätrai (l984), New Zealand rabbits were
exposed to 500 or 1000 mg toluene/m3, for 24 h/day, on days 6 - 20
of pregnancy. The toluene caused spontaneous abortions at 1000
mg/m3, but no teratogenic effects were found at either
concentration.
8.5.2.2. Oral
Toluene was administered, by gavage, to CD-1 mice from days 6
to 15 of gestation at doses of 260, 430, or 870 mg/kg body weight
per day and from days 12 to 15 at 870 mg/kg body weight per day.
The vehicle used was cottonseed oil (0.5% of maternal body weight
per dose). A significant increase in embryonic lethality occurred
at all dose levels, when toluene was administered on days 6 - 15,
and a significant reduction in fetal weight was measured in the 430
and 870 mg/kg groups. Exposure to 870 mg toluene/kg on days 6 to
15 also significantly increased the incidence of cleft palate; this
effect reportedly did not appear to be due merely to a general
retardation in growth rate. When toluene was administered at
870 mg/kg on days 12 - 15, however, decreased maternal weight gain
was the only effect observed. Maternal toxicity was not noted
after exposure to toluene on days 6 - 15 at any dose level (Nawrot
& Staples, 1979).
Kostas & Hotchin (1981) studied the effects of toluene in the
drinking-water on mice exposed prenatally, postnatally, or
continuously. The test animals were the offspring of dams given
drinking-water containing 16, 80, or 400 mg toluene/litre during
pregnancy and lactation. After weaning, the test mice were exposed
to the same toluene concentrations as the dams. No effects of
toluene exposure were seen on maternal fluid consumption, offspring
mortality rate, development of eye or ear opening, or surface-
righting response. At 35 days of age, the offspring exposed to
400 mg toluene/litre showed decreased habituation of open-field
activity. Rotorod performance measured at 45 - 55 days of age was
depressed in all exposed groups. Postnatal exposure alone did not
produce similar results.
Although it is generally accepted that toluene readily crosses
the placenta, it does not appear to be teratogenic in mice, rats,
or rabbits (Hudák et al., 1977; Hudák & Ungváry, 1978, Litton
Bionetics, Inc., 1978b; Tätrai et al., 1980; Shigeta et al., 1982;
Ungváry et al., 1983; Ungváry, 1984; Ungváry & Tätrai, 1984). It
is fetotoxic, causing a reduction in fetal weight in mice and rats
and retarded ossification with some increase in minor skeletal
anomalies at doses that are below those toxic for the dam as well
as at toxic doses (Hudák & Ungváry, 1978; Nawrot & Staples, 1979).
8.6. Mutagenicity and Related End-Points
The genetic activity of toluene has been tested in an array
of microbial, isolated mammalian cell, and whole organism test
systems. The results have usually been negative. In the few
studies in which a positive result was found, the purity of the
toluene was not stated.
8.6.1. DNA damage
The ability of toluene to induce DNA damage was evaluated in 2
studies by comparing its differential toxicity for wild-type and
DNA repair-deficient E. coli and S. typhimurium (Matsushita et
al., 1971; Fluck et al., 1976; Mortelmans & Riccio, 1980). Toluene
did not produce any differential toxicity in these tests.
8.6.2. Mutation
Toluene has been reported to be non-mutagenic in the Ames
Salmonella assay when tested with strains TA 1535, TA 1537, TA
1538, TA 98, and TA 100 (Litton Bionetics, Inc., 1978a; Mortelmans
& Riccio, 1980; Nestmann et al., 1980; Bos et al., 1981; Snow et
al., 1981), and in the E. coli WP2 reversion to trp+ prototrophy
assay (Mortelmans & Riccio, 1980).
Toluene (0.05 - 0.30 µl/ml, with and without mouse liver S-9
activation) failed to induce specific locus forward mutations in
the L5178y Thymidine Kinase (TK) mouse lymphoma cell assay (Litton
Bionetics, Inc., 1978a).
Toluene, with and without metabolic activation, was tested for
its ability to induce reversions to isoleucine independence in
S. cerevisiae strain D7 (Mortelmans & Riccio, 1980), mitotic gene
conversion to tryptophan independence in strains D4 (Litton
Bionetics, Inc., 1978a) and D7 (Mortelmans & Riccio, 1980), and
mitotic crossing over at the ade2 locus in strain D7 (Mortelmans &
Riccio, 1980). Toluene did not elicit a positive mutagenic
response in any of these tests.
Donner et al. (1981) reported that pure liquid toluene in doses
of 500 and 1000 mg/kg fed to Drosophila melanogaster males (white
strain), for 24 h, did not induce recessive lethal mutations.
8.6.3. Chromosomal effects
Evans & Mitchell (1980) concluded that toluene did not alter
sister chromatid exchange (SCE) frequencies in cultured Chinese
hamster ovary (CHO) cells. In this study, CHO cells without rat
liver S-9 activation were exposed to 0.0025 - 0.04% toluene for
21.4 h, and CHO cells with activation were exposed to 0.0125 -
0.21% for 2 h.
In an analysis of 720 metaphases from the bone marrow of 5 male
rats that had been injected sc with 0.8 g toluene/kg body weight
per day, for 12 days, chromosomal aberrations were observed in 13%
of the preparations. Sixty-six percent of the aberrations were
chromatid breaks, 24% were chromatid "fractures", 7% were
chromosome "fractures", and 3% involved multiple injuries. The
frequency of spontaneous aberrations in 600 marrow metaphases from
5 control rats injected with vegetable oil averaged 4.16% (34.2%
were chromatid aberrations; 65.8% were breaks); no chromosomal
"fractures" or multiple injuries were recorded. The significance
of the positive clastogenic effects attributed to toluene is
difficult to assess, however, because the purity of the sample
employed was not stated, and because the distinction between
chromatid breaks and "fractures" was not clear (Dobrokhotov,
1972).
Lyapkalo (1973) administered 1 g toluene/kg body weight per day
to 6 rats, by sc injection, for 12 days. Treatment with toluene
resulted in chromosome aberrations in 11.5% of the bone-marrow
cells examined (84 aberrant metaphases/724 cells) compared with
3.87% (40/1033) in olive oil-injected controls. The types of
aberrations that were found consisted of "gaps" (60.47%), chromatid
breaks (38.37%), and isochromatid breaks (1.16%). The purity of
the toluene used in this study was not stated.
Dobrokhotov & Enikeev (1976) exposed rats to 610 mg toluene/m3
via inhalation, for 4 h daily (presumably 6 days/week). After 4
months of exposure, damaged metaphase chromosomes were seen in
21.6% of the bone-marrow cells analysed. The percentage of
metaphases with damaged chromosomes in bone-marrow cells from
control rats was 4.02%. Chromosome damage was observed in the
group with toluene 1, 2.5, and 4 months after the initial exposure.
However, Donner et al. (1981) did not find an increased frequency
of chromosome aberrations in the bone-marrow cells of male Wistar
rats following inhalation exposure to toluene at 1125 mg/m3, for
6 h/day, 5 days/week for 15 weeks. The frequency of SCEs was
significantly increased in rats exposed for 11 and 13 weeks, but
the frequency was in the control range after 15 weeks of exposure.
Pure toluene injected ip into Charles River rats, did not
induce bone-marrow chromosomal aberrations (Litton Bionetics, Inc.,
1978b). Toluene was injected at dosages of 22, 71, and 214 mg/kg
body weight in 2 different studies. In one study, 5 rats were
sacrificed at 6, 24, and 48 h following injection of each dose; in
a second study, 5 rats were dosed daily at each level for 5 days,
and the rats were sacrificed 6 h after injection of the last dose.
Approximately 50 cells per animal were scored for damage. Dimethyl
sulfoxide (the vehicle) was administered ip at 0.65 mg/kg body
weight per rat and served as a negative control, while
triethylenemelamine (TEM) in saline administered at 0.3 mg/kg body
weight was used as a positive control.
Gad-El-Karim et al. (1984) treated 5 male and 5 female CD-1
mice with 1720 mg toluene/kg body weight by oral gavage. An equal
number of control animals was treated with olive oil. The mice
were killed 30 h after dosing. Toluene did not cause any
clastogenic effects (micronuclei or chromosome aberrations) in the
bone marrow of the animals.
Feldt & Zhurkov (1984) studied the clastogenic effect in bone-
marrow cells and the inducibility of dominant lethal mutations in
germ cells of randomly bred SHR male mice treated with different
doses of toluene by gavage. They found a dose-related increase in
the rate of polychromatophilic erythrocytes with micronuclei. The
minimum effective dose was 200 mg toluene/kg body weight. Toluene
did not induce chromosome aberrations in bone-marrow cells or
dominant lethal mutations in germ cells.
The ip administration of toluene to male Swiss mice did not
cause an increase in micronucleated polychromatophilic erythrocytes
in the bone marrow (Kirkhart, 1980). Two doses (separated by 24 h)
of 250, 500, or 1000 mg/kg body weight were administered to groups
of 32 mice. The animals were sacrificed at 30, 48, and 72 h after
the first dose (8 mice/time interval). Five hundred polychromatic
erythocytes per animal were evaluated for the presence of
micronuclei.
Toluene was evaluated for its ability to induce dominant lethal
mutations in the sperm cells of CD-1 male mice (Litton Bionetics,
Inc., 1981). Test mice were exposed, via inhalation, to exposure
levels of 375 and 1500 mg/m3 for 6 h/day, 5 days/week, for 8 weeks.
Following treatment, the males were mated sequentially with 2
females/week for each of 2 weeks. Toluene did not cause any
significant reduction in the fertility of the treated males, and
did not cause increases in either pre- or post-implantation loss of
embryos, compared with the controls. A significant induction of
dominant lethal mutations was observed in the positive control mice
that received triethylene melamine (TEM).
8.7. Carcinogenicity
8.7.1. Inhalation
The carcinogenicity of inhaled toluene (purity 99.98%) was
assessed in Fisher-344 rats (Gibson & Hardisty, 1983). Groups of
120 males and 120 females were exposed to toluene at concentrations
of 112.5, 375, or 1125 mg/m3 for 6 h/day, 5 days/week, for 24
months. No increased incidence of neoplastic lesions was observed
in males or females. Neoplasms were observed in the lungs and
liver, endocrine organs, lympho-reticular system, mammary glands,
skin, testes, and uterus, but the lesions occurred with equal
frequency in both control and treated groups. There were no
differences in mortality between the groups.
8.7.2. Oral
Preliminary results of a study that is still in progress were
reported by Maltoni et al. (1983). Groups of 40 male and 40 female
7-week-old Sprague Dawley rats were given 500 mg toluene/kg body
weight (98.34% purity) by stomach tube in olive oil, 4 - 5
days/week, for 2 years. Results were reported after 92 weeks and
indicated no increase in the incidence of Zymbal-gland, oral-
cavity, nasal-cavity, liver, or mammary-gland tumours, compared
with controls.
Carcinogenicity studies on mice and rats are in progress in
which toluene is being administered orally. The studies fall
within the US National Toxicology Program (no details are
available).
8.7.3. Dermal
Toluene has been used as a solvent for lipophilic chemicals
such as polycyclic aromatic hydrocarbons, in tests for their
carcinogenic potential, when applied topically to the shaved skin
of animals. The results in mice have been mainly negative for
toluene itself (Poel, 1963; Coombs et al., 1973; Doak et al.,
1976).
Lijinsky & Garcia (1972) reported a skin papilloma in one mouse
and a skin carcinoma in a second mouse from a group of 30 animals
subjected to topical applications of 16 - 20 µl of toluene, twice a
week, for 72 weeks.
Frei & Kingsley (1968) examined the promoting effect of toluene
on skin tumour induction in Swiss mice following initiation with
7,12-dimethylbenz[ a]anthracene (DMBA). Results showed that, in
11 out of 35 mice, DMBA plus toluene gave 6 permanent and 5
regressing skin papillomas. With toluene alone, one permanent and
one regressing tumour were observed in 14 mice. It was concluded
from this study that toluene had some weak promotor activity, but
these results were not confirmed by Frei & Stephens (1968).
8.8. Special Studies
8.8.1. Central nervous system (CNS)
Earlier studies on the distribution of toluene demonstrated the
affinity of the compound for organs with a high lipid content, so
it is not surprising that CNS effects have been observed. A
biphasic response to toluene exposure has been found with initial
excitability followed by a depression in response, which is dose
related. This response is typical of a narcotic drug. Toluene has
also been shown to produce seizures in the limbic system, which
identifies it as a CNS stimulant according to the
neuropharmacological scheme of Winters et al. (1972).
8.8.2. Effects on electrical activity in the brain
Studies that were carried out to study the influence of toluene
on electroencephalogram (EEG) changes and sleep rhythms are
summarized in Table 9. These studies were mainly carried out on
rats and the route of administration was by inhalation or ip
injection. In essence, high levels of exposure (above 3750 mg/m3)
produced initial excitability with subsequent depression of
cortical activity resulting in coma (Contreras et al., 1979).
Seizure activity was found with high exposure levels (Takeuchi &
Suzuki, 1975; Takeuchi & Hisanaga, 1977; Contreras et al., 1979).
Short-term exposure to 7500 mg/m3 for 24 weeks caused interruption
of the sleep cycle in rats (Takeuchi et al., 1977, 1979).
8.8.3. Effects on neurotransmitters
Studies on changes in the concentrations of various
neurotransmitters in rat brain following inhalation exposure to
high concentrations of toluene have been reported and details are
summarized in Table 10. The significance of the changes found and
their relationship to behavioural changes is not known.
Repeated exposure of male Sprague Dawley rats to high
concentrations of toluene vapour (1875 - 3750 mg/m3, 6 h/day, for
3 days) led to increased noradrenaline levels in the subependymal
layer of the median eminence (SEL) and to an increase in
noradrenaline turnover within the subependymal layer, and the
paraventricular hypothalamic nucleus (PVI). Increased dopamine
(DA) levels in the lateral palisade zone of the medial palisade
zone (MPZ) were also produced. Measurement of the anterior
pituitary hormone secretion showed a significant increase in
follicle-stimulating hormone (FSH) and delayed increase in
corticosterone secretion, following toluene exposure (Andersson et
al., 1980). The toluene-induced increase in catecholamine turnover
in the MPZ could, in part, reflect an increase in DA turnover in
the MPZ (Fuxe et al., 1978; Andersson et al., 1980).
8.8.4. Behaviour
A number of behavioural studies were carried out on rats and
mice. The exposure route was mainly inhalation. The dose levels
that were studied were in the range of 3.75 - 86 250 mg/m3 during
periods ranging from a few hours to many weeks (Table 11).
The results of some studies suggest that low levels (3.75 mg
toluene/m3) of exposure may have behavioural effects (decreased
wheel-turning activity) in mice (e.g., Horiguchi & Inoue, 1977),
but most have only shown effects with higher concentrations (Table
11).
Repeated exposure of a male mouse to a high concentration of
toluene (22 500 mg/m3) for 30 min/day, 7 days/week, for 7 weeks,
did not result in the development of tolerance to the acute
behavioural effects of toluene. However, by 3 days after cessation
of exposure, responses had returned to baseline levels indicating
that there were no residual effects of toluene (Moser & Balster,
1981).
8.8.5. Liver
In a long-term study on rats exposed to 112, 375, or 1125
mg/m3, for 6 h/day, 5 days/week, for 24 months, no
histopathological evidence of liver damage was observed (Gibson &
Hardisty, 1983). Jenkins et al. (1970) reported that there were no
histopathological liver changes in a variety of species exposed to
4069 mg toluene/m3 during a 6-week inhalation period. Short-term
studies, generally using biochemical and morphological methods to
study the effects of toluene on the liver, have been carried out on
different animal species (rats, mice, guinea-pigs, rabbits, dogs,
and monkeys) using different routes of application, i.e.,
inhalation (Gut, 1971, 1983; Reynolds, 1972; Tähti et al., 1977;
Ungváry et al., 1980, 1982; Töftgard et al., 1982), oral (Wolf et
al., 1956; Reynolds, 1972; Mungikar & Pawar, 1976a; Pyykkö, 1980,
1983; Ungvráy et al., 1980, 1982), dermal, sc, and ip (DiVincenzo &
Krasavage, 1974; Hudák et al., 1975; Ungváry et al., 1976, 1981;
Wahlberg, 1976; Chand & Clausen, 1982).
Alterations observed in the short-term studies of Ungváry et
al. (1980, 1982) are more or less representative of those often
observed in rats and mice exposed to toluene. Though Ungváry and
coworkers did not find any specific histological changes, two
general types of alteration were identified. These included: (a)
biochemical responses such as proliferation of smooth endoplasmic
reticulum; increased enzymatic activity, e.g., succinate
dehydrogenase (EC 1.3.99.1), aniline hydroxylase (EC 1.14.1.1), and
aminopyrine N-demethylase activities; increased cytochrome P-450
(EC 1.14.14.1) and cytochrome b5 (EC 1.6.2.2) concentrations; and
alterations in liver weight (increased), liver glycogen
(decreased), and BSP retention (decreased); and (b) morphological
changes such as non-specific subcellular changes (in 10 - 15% of
hepatocytes); dilatation of rough endoplasmic reticulum (RER),
separation of ribosomes, variability in shape of mitochondria, and
increase in number of mitochondria and autophagous bodies.
Table 9. Central nervous system effects of toluene
---------------------------------------------------------------------------------------------------
Species Route Dose Duration Effects Reference
(mg/m3)
---------------------------------------------------------------------------------------------------
Cat inhalation 25 500 10 min/day restlessness, tachypnoea, Contreras et al. (1979)
x 40 days coughing, sneezing,
salivation, mydriasis,
lachrymation
153 500 10 min/day ataxia, collapse; EEG
x 40 days changes in cerebellum,
amygdala, and visual cortex;
seizures with repeated high-
level exposure; recovery
occurred 12 min after
exposure
Rat inhalation 3750; 4 h/day EEG changes (decreased Takeuchi & Hisanaga (1977)
7500 cortical and hippocampal
components)
15 000 4 h/day increased excitability
followed by depression and
inability to stand; changed
sleep cycle myoclonic
seizures; increased pulse
rate
Rat inhalation 7500 8h/day x decreased threshold for Takeuchi & Suzuki (1975)
8 weeks Bemegride-induced
convulsions
Rat inhalation 3750 6 h/day x increased spontaneous Ikeda et al. (1981)
6 days/week activity during light period
x 4 weeks after repeated exposure;
single exposure did not
influence circadian rhythm
Rat inhalation 7500 4 h/day x interrupted sleep cycle; Takeuchi et al. (1979)
24 weeks decreased duration of REM
sleep
---------------------------------------------------------------------------------------------------
Table 9. (contd.)
---------------------------------------------------------------------------------------------------
Species Route Dose Duration Effects Reference
(mg/m3)
---------------------------------------------------------------------------------------------------
Rat inhalation 26 250 15 min x 1, hind-limb abduction, resting Yamawaki et al. (1982)
7, or 14 tremor, head weaving;
days ataxia, tachypnoea,
salivation, diarrhoea, and
convulsions; frequency
unchanged after 2 weeks of
exposure
Rat inhalation 15 000 4 h/day x changes in sleep cycle and Hisanaga & Takeuchi (1983)
4 weeks EEGs continued 1 week after
exposure
Rat inhalation 3750 24 h increased REM sleep Fodor et al. (1973)
Rat ip 200, single dose no effect on circadian Nakagaki et al. (1983)
400, sleep-waking rhythm; rhythm
or 600 of paradoxical sleep and
mg/kg wakefulness were changed; at
body 600 mg/kg, EEG was abnormal;
weight on second day, 200 mg/kg-
exposed group showed
increase in paradoxical
sleep phase during dark
period; sleep-waking rhythm
returned to normal by third
day
--------------------------------------------------------------------------------------------------------
Table 10. Changes in neurotransmitters after toluene exposure
-----------------------------------------------------------------------------------------------------
Species Route Dose Duration Effects References
(mg/m3)
-----------------------------------------------------------------------------------------------------
Rat inhalation 26 250 15 min/14 days decrease in 5HTa binding in Yamawaki et al. (1982)
whole brain, especially
hippocampus, pons, and
medulla
Rat inhalation 375; 8 h increased DAb levels Rea et al. (1983)
1125
Rat inhalation 3750 8 h increased DAb levels in
striatum; increase NAc in
medulla and midbrain;
increased 5HTa in cerebellum,
medulla, and striatum
Rat inhalation 750, continuous increased DAb in striatum Honma et al. (1983)
1500, exposure for (dose-dependent); reduced
3000 30 days 5HTa in cortex and hippo-
campus, NAc in hypothalamus,
cortex, and hippocampus;
reduced AChd in striatum and
whole brain; cAMPe in
striatum; amino acids: GABAf
increased by mid- and highest
doses while glycine was
reduced by the 750 mg/m3
exposure
Rat inhalation 15 000 8 h glutamine levels in mid-brain Honma et al. (1982)
increased significantly
Rat inhalation 3750 - 8 h Achd increased at low dose Honma (1983)
30 000 and reduced at high dose;
AchEg elevated at both
exposures; ChATh activity
reduced; dose-dependent
-----------------------------------------------------------------------------------------------------
Table 10. (contd.)
-----------------------------------------------------------------------------------------------------
Species Route Dose Duration Effects References
(mg/m3)
-----------------------------------------------------------------------------------------------------
Rat inhalation 1875 6 h/day x increase in catecholamines Andersson et al. (1980)
(Sprague 3 days; killed (DAb + NAc) in lateral
Dawley) 16 - 18 h palisade zone of median
after exposure eminence
3750 6 h/day x 5 increase in catecholamines
days; decap- (DAb + NAc) in subependymal
itated 4 h layer of median eminence;
after exposure increase in FSHi in plasma
and delayed increase in
corticosterone secretion
Rat inhalation 300 6 h/day x 3 decreased DAb levels in Fuxe et al. (1982)
days marginal zone of nucleus,
caudatus, and anterior
nucleus accumbens; DAb
turnover significantly
reduced in all parts of
anterior caudate nucleus
Rat inhalation 1875 6 h/day x 3 reduction in DAb turnover in Fuxe et al. (1982)
days anterior nucleus accumbens
inhalation 5625 6 h/day x 3 effects on DAb in anterior Fuxe et al. (1982)
days nucleus accumbens dis-
appeared, while a selective
increase in DAb in the DAb-
CCKj immunoreactive nerve
terminals
-----------------------------------------------------------------------------------------------------
Table 10. (contd.)
-----------------------------------------------------------------------------------------------------
Species Route Dose Duration Effects References
(mg/m3)
-----------------------------------------------------------------------------------------------------
11 250 6 h/day significantly-increased DAb
x 3 days turnover in tuberculum
olfactorium; significant
increases in amine levels in
DAb-CCKj immuno-reactive-
nerve terminals in the
nucleus accumbens, especially
in the tuberculum olfactorium
-----------------------------------------------------------------------------------------------------
a 5HT = 5-hydroxytryptaline.
b DA = dopamine.
c NA = noradrenaline.
d ACh = acetylcholine.
e cAMP = cyclic 3',5'-adenosine monophosphate.
f GABA = gamma-aminobutyric acid.
g AChE = acetylcholinesterase.
h ChAT = choline acetyltransferase.
i FSH = follicle-stimulating hormone.
j CCK = cholecystokinin.
Table 11. Behavioural effects of different doses of toluene
---------------------------------------------------------------------------------------------------
Species Route Dose Duration Effects Reference
(mg/m3)
---------------------------------------------------------------------------------------------------
Rat inhalation 563 0.5, 1, initial stimulation Geller et al. (1979)
(Sprague 2, or 4 h followed by depression
Dawley) in multiple FR-FI response
schedule performance
Rat inhalation 375, no-observed-adverse-effect Wood et al. (1983)
668, level
2100
3750, 4 h deficit in conditioned
6675, reflex; less when external
11 250 signal cued response
Rat (male) inhalation 2063 - 4 h/day x no effect on avoidance Battig & Grandjean (1964)
3000 3 weeks response
Rat (male) inhalation 7500 8 h/day x process of extinction in Maeda (1970)
52 days conditioned behaviour
worsened
Rat (male) inhalation 11 250 4 h deficit in conditioned Shigeta et al. (1978)
avoidance response
3750 4 h no effect
Rat (male) inhalation 12 000 4 h deficit in conditioned Krivanek & Mullin (1978);
and avoidance response Mullin & Krivanek (1982)
24 000
Rat (male) inhalation 3000 4 h no effect Krivanek & Mullin (1978);
and Mullin & Krivanek (1982)
6000
Rat (male) inhalation 3000 4 h deficit in unconditioned Krivanek & Mullin (1978);
reflexes and simple Mullin & Krivanek (1982)
behaviour
---------------------------------------------------------------------------------------------------
Table 11. (contd.)
---------------------------------------------------------------------------------------------------
Species Route Dose Duration Effects Reference
(mg/m3)
---------------------------------------------------------------------------------------------------
Rat inhalation 15 000 2 h/day x multiple response Ikeda & Miyake (1978)
60 days schedule; no effect on CRF
or FR30; deficit in DRL in
12-second schedule
Rat inhalation 86 250 30 min/day induced forced turning Ishikawa & Schmidt (1973)
(Sprague x 7.6 days
Dawley)
Mice inhalation 3.75, 6 h/day x deficit in wheel-turning Horiguchi & Inoue (1977)
(male) 37.5, 10 days
375,
3750
Mice inhalation 15 000 3 h deficit in visual placing, Peterson & Bruckner (1978)
40 000 10 min grip strength, wire
manoeuvre tail pinch,
righting reflex
Mice inhalation 45 000 3 h/day, 5 deficit in performance Bruckner & Peterson (1976)
days/week tests
for 8 weeks
---------------------------------------------------------------------------------------------------
Ungváry et al. (1980, 1982) observed these changes in both
sexes and found such alterations to be dose-related and reversible.
Alterations in various liver cell enzyme activities have been
reported. No relationship to exposure time was observed. No
changes were noted in the activities of alanine aminotransferase
(SGPT) (EC 2.6.l.2) or aspartate aminotransferase (SGOT) (EC
2.6.1.1).
A dose-dependent induction of the total liver microsomal
concentration of cytochrome P-450 was observed after exposure to
1875, 5625, and 11 250 mg toluene/m3 for 3 days for 6 h/day
(Töftgard et al, 1982). The increase was significant at the 2
highest exposure levels. The authors also reported that the liver
weights and liver to body weight ratio were significantly
increased.
In oral, ip, and sc studies, adaptive responses comparable to
those observed in inhalation studies were seen. Toluene induction
of liver enzymes appeared to be less in adult females than in males
(Pyykkö, 1983). Induced enzyme levels in young rats (13 days old)
of both sexes were comparable to those in adults. Reversible
morphological changes were noted, when toluene was injected sc and
ip in rats (Ungvráy et al., 1976) and when toluene was given orally
to guinea-pigs (DiVincenzo & Krasavage, 1974).
8.9. Factors Modifying Toxicity; Toxicity of Metabolites
8.9.1. Effects of combined exposure to toluene and other chemicals
Occupational groups and, to a minor extent, the general
population are mostly exposed to mixtures of chemicals rather than
to pure toluene. The main exposure route is inhalation. Oral
exposure occurs to a much less extent, and is generally to very low
levels of toluene in the form of contaminants in food and drinking-
water.
This criteria document will not include details of the studies
carried out with mixtures, but they will be mentioned in a general
sense and the available literature referred to for those who would
like to know more.
8.9.1.1. Benzene and toluene
It is clear that, in general, the older studies were mainly
carried out using toluene containing variable quantities of
benzene. Simultaneous administration of benzene and toluene will
result in interference in the metabolism of each chemical in the
liver. The conversion of benzene to its metabolites (such as
phenol) is suppressed by toluene in rats and mice, and the
disappearance of benzene from the blood is delayed. The hippuric
acid excretion metabolites of toluene are reduced by benzene.
Simultaneous sc administration of toluene and benzene in mice
and rats had an ameliorating effect on benzene toxicity. Toluene
decreased the toxic effect of benzene on bone marrow. Furthermore,
toluene diminished the clastogenic effect of benzene but produced
an additive effect on chromosome damage (Ikeda & Ohtsuji, 1971;
Dobrokhotov, 1972; Ikeda et al., 1972; Dobrokhotov & Enikeev, 1976;
Mungikar & Pawar, 1976b; Pawar et al., 1976; Andrews et al., 1977;
Sato & Nakajima, 1979b; Tätrai et al., 1980; Gut et al., 1981;
Tunek et al., 1982; Gut, 1983; Gad-El-Karim et al., 1984).
8.9.1.2. Xylenes and toluene
From the study of Ogata & Fujii (1979), it appears that these
solvents do not significantly interfere with each other.
Riihimaki (1979) studied the possible kinetic interactions
between toluene and xylene and their metabolites and found that
full conjugation capacity with benzoic acid and methylbenzoic acid
was reduced during inhalation of toluene and/or xylene. This
suggests that the body has a relatively large capacity for the
conjugation reaction of toluene and xylene metabolism. However,
the consumption of a large amount of easily-metabolized glycine may
impair the conjugation and hence the excretion of poorer
substrates.
8.9.1.3. n-Hexane and toluene
It seems from a number of animal studies that toluene decreases
the neurotoxicity of n-hexane. Toluene interfered in the
metabolism of n-hexane in rats with a resulting decrease in the
urinary excretion of n-hexane metabolites. The biotransformation
of toluene to o-cresol and hippuric acid was not affected by
n-hexane, as assessed by the urinary concentrations of these
toluene metabolites (Takeuchi et al., 1981a; Honma, 1983;
Perbellini et al., 1982).
8.9.1.4. Toluene and other chemicals
The ability of toluene to interfere with the biotransformation
of several solvents has been reported by numerous authors. It
interferes with the metabolism of styrene (Ikeda & Ohtsuji, 1969),
acrylonitrile (Gut et al., 1981), trichloroethylene (Ikeda, 1974;
Withey & Hall, 1975), and methylethylketone (Iwata et al., 1983).
Further studies have been carried out with toluene and carbon
tetrachloride (Tatrai et al., 1979), ethanol (Morvai & Ungváry,
1979; Sato et al., 1981; Waldron et al., 1983), acetylsalicylic
acid (Ungváry, 1984), and a mixture of paraffins, naphthenes, and
aromatic compounds (Carpenter et al., 1944, 1976a,b; Carpenter &
Smyth, 1946; Wolf et al., 1956; Taylor & Harris, 1970).
9. EFFECTS ON MAN
9.1. Acute Toxicity
The acute effects of single doses of toluene in man are
summarized in Table 12. The lowest dose level of 9.4 mg/m3 seems
to be the odour threshold, while dose levels of 37 500 and higher
are associated with narcosis.
9.2. Effects of Short- and Long-Term Exposure Including Controlled
Human Studies
Many studies are available on the effects of short- and long-
term exposure to toluene including toluene abuse.
It is important to recognize that studies of intentional abuse
and occupational studies have generally involved exposures to
complex mixtures with toluene as the principal constituent. Prior
to 1950-60, benzene was a common contaminant of commercial toluene.
Thus, when evaluating the effects of toluene on human beings, the
purity of the compound must be considered. In instances involving
exposure to complex mixtures, no unequivocal cause-effect
relationship with regard to toluene can be established.
9.2.1. Controlled human studies
Odour thresholds and sensory responses to inhaled vapours of
toluene concentrate were investigated by May (1966) and Carpenter
et al. (1976b). The most probable concentration for odour
threshold, determined in 2 trials on 6 volunteers, was 9.4 mg/m3
(Carpenter et al., 1976b). Mild eye and throat irritation was
noted after an 8-h exposure to 750 mg/m3 and lachrymation at
1500 mg/m3. Based on sensory thresholds for irritation (eye, nose,
throat), dizziness, taste, and olfactory fatigue, 6 out of 6
volunteers indicated their willingness to work for 8 h in a
concentration of 825 mg toluene/m3.
Ogata et al. (1970) reported that 23 Japanese volunteers
exposed to 750 mg/m3 toluene for 3 h or 3 h and 1 h break followed
by an additional 4-h exposure showed a prolonged eye-to-hand
reaction time, but no effect on critical flicker fusion frequency.
No changes in either reaction time or flicker value were observed
after exposure to toluene at 375 mg/m3. Gamberale & Hultengren
(1972) studied the effects of toluene on psychophysiological
functions in 12 healthy male volunteers. There was significant
impairment of reaction time at 1125 mg/m3, which was further
impaired at 1875 and 2625 mg/m3. No impairment was observed at
375 mg/m3. Perceptual speed was unaffected at exposure levels
below 2625 mg/m3.
Table 12. Dose-response relationships for the acute effects in
human beings of single short-term exposures to toluene vapour
-------------------------------------------------------------------
Dose Effect
-------------------------------------------------------------------
9.4 mg/m3 odour threshold
(2.5 ppm)
138.8 mg/m3 probably perceptible to most human beings
(37 ppm)
188 - 375 mg/m3 subjective complaints (fatigue, drowsiness, or
(50 - 100 ppm) very mild headache) but probably no observable
impairment of reaction time or coordination
750 mg/m3 mild throat and eye irritation; prolonged eye-to-
(200 ppm) hand reaction time; some impaired cognitive
function; slight headache, dizziness, sensation of
intoxication; after effects: fatigue, general
confusion, moderate insomnia
1125 mg/m3 detectable signs of incoordination may be expected
(300 ppm) during exposure periods up to 8 h
1500 mg/m3 irritation of the eyes and throat and
(400 ppm) lachrymation; skin paraesthesia, gross signs of
incoordination, and mental confusion expected
during exposure periods up to 8 h
1875 - 2250 anorexia, staggering gait, nausea, nervousness
mg/m3 (500 - (persist to next day), momentary loss of memory,
600 ppm) significant reduction in reaction time
3000 mg/m3 pronounced nausea (after 3-h exposure); confusion,
(800 ppm) lack of self-control; extreme nervousness,
muscular fatigue, and insomnia lasting for several
days
5625 mg/m3 probably not lethal for exposure periods of up to
(1500 ppm) 8 h; incoordination likely; extreme weakness
15 000 mg/m3 would probably cause rapid impairment of reaction
(4000 ppm) time, and coordination exposures of 1 h or longer
might lead to narcosis and possibly death
37 500 - onset of narcosis within a few min; longer
112 500 mg/m3 exposures may be lethal
(10 000 -
30 000 ppm)
-------------------------------------------------------------------
Winneke (1982) noted that exposure to 375 mg toluene/m3 for
3.5 h did not affect psychophysiological performance in 18
volunteers. Simple reaction time began to increase at 1125 mg/m3.
Complex reaction time did not change until vapour concentrations
had reached 1875 mg/m3. The parameters evaluated in this study
included performance in a bisensory (auditory and visual) vigilance
task, psychomotor performance, critical flicker fusion frequency,
and auditory-evoked potentials.
Three human volunteers were exposed repeatedly to toluene
(benzene < 0.01%) for 8-h periods at concentrations ranging from
188 to 3000 mg/m3, in an exposure chamber. A maximum of 2
exposures a week was maintained to allow sufficient time for
recovery between exposures; a total of 22 exposures was performed
over an 8-week period. The design of the study is complex and not
clear. For instance, the number of h per day is different for the
several groups. Seven of the 22 exposures were controls (exposed
to air only) and exposures to particular levels of toluene were
replicated only 1 - 4 times. The effects that were observed at
each toluene concentration are summarized in Table 13. Subjective
complaints of fatigue, muscular weakness, confusion, impaired
coordination, enlarged pupils, and accommodation disturbances were
reported at 750 mg/m3. These effects increased in severity with
increases in toluene concentration until, at 3000 mg/m3, the
subjects experienced severe fatigue, pronounced nausea, mental
confusion, considerable incoordination and staggering gait,
strongly impaired pupillary light reflex, and after-effects
(muscular fatigue, nervousness, and insomnia), which lasted for
several days (von Oettingen, 1942a,b).
Sixteen healthy volunteers were exposed to increasing
concentrations of toluene ranging from 37.5, 150, to 375 mg/m3, by
inhalation, for 6 h/day, for 4 days. At the 375 mg/m3 exposure,
the multipication errors, Landolt's rings, and screw plate tests
were significantly affected in addition to the occurrence of
headache, dizziness, and a reported sensation of intoxication. The
two lower levels did not result in any adverse effects (Andersen et
al., 1983).
Suzuki (1973) found an effect on heart rate, a mean decrease
of 7 beats/min in 5 male volunteers exposed to 750 mg toluene/m3
for 6 h compared with controls. Other studies have shown that
exposure to toluene at levels of 375 - 750 mg/m3 for up to 30 min
(Astrand et al., 1972; Gamberale & Hultengren, 1972) or 188 - 3000
mg/m3 for 8 h (von Oettingen et al., 1942a,b) did not cause any
definite effects on heart rate or blood pressure.
Tähti et al. (1981) studied 46 workers exposed to various
concentrations of toluene in air ranging from 75 to 750 mg/m3, for
10 - 20 years and found no correlation between the occurrence of
chronic diseases and toluene exposure.
No studies have demonstrated a cause-effect relationship
between toluene exposure and teratogenic effects in human beings.
There are, however, a few publications, such as those of Euler
(1967) and Holmberg (1979), in which cases of children with
malformations and central nervous system defects have been
reported, but the studies were all concerned with exposures to
mixtures of solvents. In a study in which 132 women exposed to
mixtures containing toluene were compared with 201 female controls,
the exposed women recorded high percentages of menstrual disorders,
effects on the duration of labour, perinatal mortality, or adverse
effects on the newborn infant (Syrovadko, 1977).
Table 13. Effects of controlled 8-h exposures to pure toluene on
3 human subjectsa,b
---------------------------------------------------------------------
Concentration Number of Effects
exposures
---------------------------------------------------------------------
0 mg/m3 7 no complaints or objective symptoms, except
occasional moderate tiredness toward the
end of each exposure, which was attributed
to lack of physical exercise, unfavorable
illumination, and monotonous noise from
fans
188 mg/m3 2 drowsiness with a very mild headache in 1
subject; no after effects
375 mg/m3 4 moderate fatigue and sleepiness (3), and a
slight headache on one occasion (1)
750 mg/m3 3 fatigue (3), muscular weakness (2),
confusion (2), impaired coordination (2),
paraesthesia of the skin (2), repeated
headache (1), and nausea (1) at the end
of the exposure; in several instances, the
pupils were dilated, pupillary light reflex
was impaired, and the fundus of the eye was
was engorged; after-effects included
fatigue, general confusion, moderate
insomnia, and restless sleep in all 3
subjects
1125 mg/m3 2 severe fatigue (3), headache (2), muscular
weakness and incoordination (1), and slight
pallor of the eyeground (2); after-effects
included fatigue (3) and insomnia (1)
1500 mg/m3 2 fatigue and mental confusion (3), headache,
paraesthesia of the skin, muscular
weakness, dilated pupils, and pale
eyeground (2); after effects were fatigue
(3), skin paraesthesia (1), headache (1),
and insomnia (2)
---------------------------------------------------------------------
Table 13. (contd.)
---------------------------------------------------------------------
Concentration Number of Effects
exposures
---------------------------------------------------------------------
2250 mg/m3 1 extreme fatigue, mental confusion,
exhilaration, nausea, headache, and dizziness
(3), and severe headache (2) after 3 h of
exposure; after 8 h exposure, the effects
included considerable incoordination and
staggering gait (3), and several instances of
dilated pupils, impaired pupillary light
reflex, and pale optic discs; after-effects
included fatigue and weakness, nausea,
nervousness, and some confusion (3), severe
headache (2), and insomnia (2); fatigue and
nervousness persisted on the following day
3000 mg/m3 1 rapid onset of severe fatigue and, after 3 h,
pronounced nausea, confusion, lack of self-
control, and considerable incoordination and
staggering gait in all 3 subjects; also,
pupillary light reflex was strongly impaired
(1), and optic discs were pale (2); all 3
subjects showed considerable after-effects,
lasting at least several days, which included
severe nervousness, muscular fatigue, and
insomnia
---------------------------------------------------------------------
a From: von Oettingen et al. (1942a,b).
b Exposures were twice weekly for 8 weeks. The number of subjects
affected is noted in parentheses.
9.2.2. Short- and long-term abuse in the general population
It is important to recognize that studies of intentional abuse
are generally concerned with exposures to complex mixtures in which
toluene is usually the principal constituent. Benzene is one of
the most important contaminants in commercial toluene.
Solvent abuse is a major problem throughout the world. As an
example, in Scotland alone, 1300 new cases of solvent abuse had
been reported to the police between 1977 and 1980 in a secondary
school population of almost half a million (King, 1982). In the
same period, 6 deaths following glue sniffing were recorded in
Scotland (King et al., 1981). King (1982) and King et al. (1981)
diagnosed a series of 20 cases of acute encephalopathy in children
aged 8 - 14 years following toluene abuse; 5 presenting in coma, 5
with ataxia and dysarthria, 3 with convulsions, and 2 with diplopia
and behaviour disturbance. In 6 of these subjects, the diagnosis
of solvent-induced encephalopathy was made solely by a blood-
toluene assay (0.8 - 8.0 mg/litre). Six of these children left
hospital with neurological impairment and one, seen 1 year later,
had persistent cerebellar signs. Thirteen children recovered
completely. The authors emphasized the importance of diagnosis, if
further damage due to continued abuse is to be prevented.
The extent of "sniffing" solvents containing toluene has been
extensively reviewed (Massengale, et al, 1963; Barman et al., 1964;
Press & Done, 1967a,b; Gellman, 1968; Wyse, 1973; Linder et al.,
1975; Faillace & Guynn, 1976; Oliver & Watson, 1977; Walter et al.,
1977; Watson, 1979). The concentrations of toluene inhaled under
these conditions can approach 112 500 mg/m3, i.e., saturation
concentration at 20 °C. Such severe exposures can result in gross
disorientation and unconsciousness (Hayden et al., 1977).
Episodes of toluene abuse are characterized by the progressive
development of CNS symptoms of dysfunction. Toluene sniffers
experience an initial excitatory stage that is typically
characterized by drunkenness, dizziness, euphoria, delusions,
nausea, and vomiting, and, less commonly, visual and auditory
hallucinations (Press & Done, 1967a,b; Wyse, 1973; Lewis &
Patterson, 1974; Hayden et al., 1977; Oliver & Watson, 1977; Tarsh,
1979; Streicher et al., 1981). As the duration of exposure
increases, symptoms indicative of CNS depression become evident
including confusion and disorientation, headache, blurred vision
and reduced speech, drowsiness, muscular incoordination, ataxia,
depressed reflexes, and nystagmus. In extreme cases, there is loss
of consciousness possibly associated with convulsions (Helliwell &
Murphy, 1979). The duration and severity of these effects vary
greatly, depending on the intensity of exposure; the duration may
range from 15 min to a few hours (Press & Done, 1967b). There are
reports of seizures including status epilepticus occurring as the
primary presentation of acute intoxication in toluene sniffers
(Helliwell & Murphy, 1979; King et al, 1981).
A case of permanent encephalopathy from repeated, prolonged
exposure (14 years) to pure toluene vapour was reported. A 33-
year-old man purchased approximately 4 litres of toluene from a
paint store every 4 - 6 weeks for 14 years to satisfy his addiction
to toluene vapour. The result of this addiction was permanent
cerebral atrophy. The clinical signs were ataxia, tremulousness,
unsteadiness, emotional lability, marked snout reflex (distorted
nostrils on subjection to sniff test), and positive Babinski sign
on the right side. The brain (cerebral hemispheres) damage was
confirmed by EEG and pneumoencephalography. This same individual
was the subject of a report published by Grabski (1961) who
reported cerebellar degeneration, hepatomegaly, and impaired liver
function after 6 years of toluene vapour inhalation (Knox & Nelson,
1966).
O'Brien et al. (1971) reported reversible hepatorenal damage,
confirmed by biochemical tests, in a 19-year-old male who sniffed
glue while employed as a sign painter. The blood-toluene level was
0.61 mg/litre.
These findings lead to the conclusion that should adverse
effects result from the abuse of toluene-based products, the
effects are likely to be transient and to follow closely on
intensive solvent exposure.
Schikler et al. (1982) reported the findings on 11 out of 42
cases of toluene abuse, who were examined by computed tomography
(CT) scan because of neurological abnormalities; 6 out of the 11
were found to have cerebellar cortical atrophy; 2 of the 6 had
cerebellar atrophy. The mean age of the patients was 22 years
(range 14 - 31 years) with a mean exposure of 10 years (range 4 -
16 years).
Fornazzari et al. (1983) noted a marked impairment of
neurological and neuropsychological test performance in 65% of 24
solvent abusers. Cerebellar symptoms were particularly prominent.
The impairment was significantly correlated with CT scan
measurements of cerebral and cerebellar atrophy.
Chronic neurological damage from solvent abuse (Table 14) has
been sporadically reported in patients who have abused toluene for
from 1.5 to 14 years and takes the form of dementia with cerebellar
ataxia (Satran & Dodson, 1963; Kelly, 1975; Hänninen et al., 1976;
Boor & Hurtig, 1977; Sasa et al., 1978; Malm & Lying-Tunell, 1980;
Lewis et al., 1981; Metrick & Brenner, 1982; Fornazzari et al.,
1983; Lazar et al., 1983).
Pathologically, in a post-mortem analysis of a 27-year-old man
addicted to a thinner containing approximately 40% toluene for 12
years, the most striking feature was diffuse cerebral and
cerebellar cortex atrophy. There was a 70% loss of cerebellar
Purkinje cells and giant axonal degeneration in the posterior and
lateral columns of the spinal cord (Escobar & Aruffo, 1980).
Other effects attributed to chronic glue sniffing (different
types of mixtures) besides cerebellar dysfunction include optic
atrophy with blindness (Keane, 1978; Ehyai & Freemon, 1983),
sensorineural hearing loss (Ehyai & Freemon, 1983), and convulsions
(Helliwell & Murphy, 1979; Allister et al., 1981). Evidence of
chronic neurological damage after a much shorter duration of glue
sniffing has appeared recently. Channer & Stanley (1983) reported
the case of a 16-year-old boy presenting with persistent visual
hallucinations after cessation of glue sniffing for several months,
who had evidence of a diffuse encephalopathy characterized by an
abnormal EEG and delayed visual evoked responses (VERs) to
checkerboard pattern reversal. In another study (Cooper et al.,
1985), VERs were studied in 12 young asymptomatic glue sniffers who
had abused glue for several months, but not on the day of the
recordings. The mean latencies of the VERs in the sniffers were
significantly prolonged in all compared with 27 controls and
outside the normal range in nine. In 2 subjects, the recordings
were repeated after abstinence for 6 months and remained abnormal.
The recovery process after damage has occurred seems to be slow if
the sniffing is stopped. The time scale is at least 6 months and
it may be that the damage is permanent.
Table 14. Summary of chronic toluene-abuse cases
--------------------------------------------------------------------------------------------------------------
Subject Inhala- Clinical and pathological manifestation Reference
(age) tion cerebel- mental abnormal brain visual liver others
period lar dys- retard- EEG atrophy impair- impair-
(years) function ation ment ment
--------------------------------------------------------------------------------------------------------------
Pure toluene
Male (25) 6 + + - + Grabski (1961)
(33) 14 + + + + - + Knox & Nelson
(1966)
Female (18) 6 + + + - + Takeuchi et al.
(1981b)
Male (21) 12 + + + - Lazar et al. (1983)
99% Toluene
Male (25) 10 + + - + - Boor & Hurtig
(1977)
Male (59) long + + - - - Boor & Hurtig
(1977)
Toluene
Male (30) 10 + + + - - Satran & Dodson
(1963)
Male (25) 0.3 + - - Escobar & Aruffo
(1980)
Male (11) < 1 + + + - - King (1982)
Male (25) 5 + - + + hearing Lazar et al. (1983)
loss
Male (18) 3 - - + - poly- Ehyai & Freemon
neuro- (1983)
pathy
Male (23) 7 + - - Ehyai & Freemon
(1983)
--------------------------------------------------------------------------------------------------------------
Table 14. (contd.)
--------------------------------------------------------------------------------------------------------------
Subject Inhala- Clinical and pathological manifestation Reference
(age) tion cerebel- mental abnormal brain visual liver others
period lar dys- retard- EEG atrophy impair- impair-
(years) function ation ment ment
--------------------------------------------------------------------------------------------------------------
68-30% Toluene
Male (19) 0.8 + + + - + + hallu- Suzuki et al.
cination, (1983)
aspermia
Male (23) 12 + + + + + - haematuria Metrick & Brenner
brainstem (1982)
disorder
Aromatic hydrocarbon
Female (30) 5 + + + + - Prockop (1977)
Thinner
Male (?) ? + + + - - Weisenberger (1977)
Male (28) 10 + - hearing Lazar et al. (1983)
loss
Paints
Female (19) 1.5 + - - - - Kelly (1975)
Male (20) 3 + + + Keane (1978)
Male (28) 16 + + + + ± haematuria Metrick & Brenner
brainstem (1982)
disorder
Glue or thinner
Male (27) 10 + + - + - Sasa et al. (1978)
Male (29) 12 + + + + - grand Allister et al.
mal (1981)
seizure
--------------------------------------------------------------------------------------------------------------
Table 14. (contd.)
--------------------------------------------------------------------------------------------------------------
Subject Inhala- Clinical and pathological manifestation Reference
(age) tion cerebel- mental abnormal brain visual liver others
period lar dys- retard- EEG atrophy impair- impair-
(years) function ation ment ment
--------------------------------------------------------------------------------------------------------------
Glue
Male (15) ? + ± - micro- Lazar et al. (1983)
scopic
haema-
turia
hearing
loss
Male (16) 0.25 + - - hearing Lazar et al. (1983)
loss
Male (27) 5 + - + + Ehyai & Freemon
(1983)
--------------------------------------------------------------------------------------------------------------
Haematological abnormalities have been occasionally reported in
sniffers of toluene-based glues. In a clinical survey of 89 glue
sniffers (aged 8 - 18 years), abnormalities of the blood were found
in 68 of the cases (Sokol & Robinson, 1963). An effect on the
white blood cells was indicated by findings of eosinophilia (25
subjects), leukocytosis (12 cases), and lymphopenia (4 subjects).
They also reported low haemoglobin values in 20 subjects and
basophilic stippling of erythrocytes in 42 of the patients, and
noted the frequent occurrence of poikilocytosis (25 cases),
anisocytosis (20 cases), hypochromia (14 cases), and polychromasia
(10 cases).
Examination of peripheral blood samples from 24 solvent
abusers, admitted to hospital, showed that 5 had lymphopenia, 3
lymphocytosis, and 3 normochromic normocytic anaemia (including 2
females) (Fornazzari et al., 1983).
In a total of 90 cases surveyed by 4 groups of investigators,
there were no instances of anaemia or lymphopenia, a single report
of neutropenia, and 6 cases characterized by an eosinophilia
greater than 5% were described (Christiansson & Karlsson, 1957;
Massengale et al., 1963; Barman et al., 1964; Press & Done, 1967b).
Powars (1965) diagnosed 1 fatal case of acute aplastic anaemia
associated with pancytopenia and 5 patients with homozygous sickle
cell anaemia that showed a reversible erythrocytic aplastic crisis
associated with glue sniffing.
Despite occasional reports to the contrary, Assennato et al.
(1977) and Trevisan & Chiesura (1978) came to the conclusion that
there appears to be a low incidence of hepatorenal injury in
persons who abuse toluene-based products. Litt et al. (1972) found
modest elevations in serum glutamic pyruvic transaminase (SGPT) (EC
2.6.1.2) levels in only 2% and increased alkaline phosphatase (EC
3.1.3.1) levels in 5% of a group of 982 glue sniffers. Press &
Done (1967b) observed slight but transient abnormalities in the
urinalysis of a small percentage of the glue sniffers they
examined. Liver function tests were normal. Weisenberger (1977)
observed some disturbances of aspartate aminotransferase (EC
2.6.1.1) and LDH in a toluene addict who was hospitalized in a
catatonic state. These abnormalities disappeared early in the
patient's hospital stay. Fornazzari et al. (1983) found transient
elevations of serum alkaline phosphatase in 13, and SGOT in 7,
solvent abusers. These changes returned to normal after 2 weeks'
abstinence.
Russ et al. (1981) reported irreversible renal failure in a
20-year-old male who had sniffed glue containing 16.5% toluene
twice a week for 9 months. Repeated renal biopsies showed
progressive tubular damage.
It appears that deliberate inhalation of glues and paint is
associated with renal tubular defects documented by the presence of
metabolic acidosis (Taher et al., 1974; Fischman & Oster, 1979;
Bennett & Forman, 1980; Kroeger et al., 1980; Moss et al., 1980;
Voigts & Kaufman, 1983). The cases of acidosis described by these
investigators are characterized by serious electrolyte
abnormalities (hypokalemia, hypophosphatemia, hyperchloremia), and
may be related to impaired hydrogen ion secretion in the distal
renal tubule (distal renal tubular acidosis). Other metabolic
abnormalities include pyuria, haematuria, and proteinuria (Voigts &
Kaufman, 1983). The role of toluene in the causation of renal
damage in these cases is unclear, since solvent mixtures were
abused.
Toutant & Lippman (1979) reported the outcome of pregnancy in a
woman addicted to solvents containing toluene for 14 years. In
addition to her heavy solvent abuse, she had a 3-year history of
alcohol intake (6 packs of beer/week). The male child born at term
was at the 10th percentile for weight and the 5th percentile for
head size. It had similar features to fetal alcohol syndrome
(microcephaly, flat nasal bridge, hypoplastic mandible, etc.). The
authors suggested that there might be an analogous "fetal solvents
syndrome" or that excessive solvent intake might enhance the
toxicity of alcohol. Recently, Streicher et al. (1981) reported
that of 3 women who continued to sniff paint throughout pregnancy,
one had a child with cerebellar dysfunction.
Reisin et al. (1975) published a report regarding the
development of severe myoglobinuria and non-oliguric acute renal
failure in a paint factory worker who was exposed to pure toluene
by skin contact and aspiration when a hose burst. The patient had
inhaled sufficient amounts of toluene to cause loss of
consciousness for 18 h and subsequent development of chemical
pneumonitis. He also sustained superficial burns on approximately
10% of his body surface area. Acute renal failure apparently
developed from the lack of fluid intake accompanied by heavy
myoglobinuria rather than from a direct effect of toluene. The
early administration of intravenous fluids and diuretics, and the
use of haemodialysis, led to complete recovery.
Askergren (1981) and Askergren et al. (1981a,b) observed that
exposure of rotogravure workers to toluene was associated with an
elevated excretion of erythrocytes and leukocytes in the urine.
Exposure levels in the work-place were reported to be below
300 mg/m3, though some subjects were exposed for short periods to
levels 2 - 3 times as high. Franchini et al. (1983) reported that
renal function impairment indicators such as total proteinuria,
albuminuria and urinary excretion of muramidase (EC 3.2.1.17) and
beta-glucuronidase (EC 3.2.1.31) provided some evidence of renal
damage due to occupational exposure to organic solvents and
suggested that the kidney lesions are tubular rather than
glomerular and mild.
9.2.3. Epidemiological studies
No epidemiological studies on populations exposed to toluene
are available.
9.3. Occupational Exposure
Using data obtained from a survey conducted in the USA by the
US Bureau of Occupational Safety and Health in 1977, US NIOSH
estimated that 1.6 million persons in the work force could have
potential exposure to toluene.
9.3.1. Skin and mucous membranes
Repeated or prolonged skin contact with liquid toluene will
remove natural lipids from skin, causing dryness, fissures, and
contact dermatitis (Gerarde, 1960; Browning, 1965) or an injury to
the epidermal stratum corneum (Malten et al., 1968).
Parmeggiani & Sassi (1954) reported irritation of the upper
respiratory tract and conjunctiva in male subjects who were exposed
to 750 - 3000 mg toluene/m3 for "many" years.
Transient epithelial injury to the eyes, which consisted of
moderate conjunctival irritation and corneal damage, with no loss
of vision, was observed in workers who were accidentally splashed
with toluene (McLaughlin, 1946; Grant, 1962). Complete recovery
generally occurred within 48 h. The results of opthalmological
examinations of 106 spray painters who were exposed to toluene in
mixtures at levels of 375 - 4125 mg/m3 for periods ranging from 2
weeks to more than 5 years were reported to be without clear
symptoms (Greenburg et al., 1942). Loss of visual acuity, optical
neuropathy, and nystagmus in toluene or solvents- and thinner-
sniffers have been reported by Prockop (1977), Keane (1978), Malm &
Lying-Tunell (1980), Takeuchi et al. (1981b), and Kimura et al.
(1982).
9.3.2. Central nervous system
Wilson (1943) described the effects of exposure to "commercial"
toluene vapour on 100 workers (out of a total of 1000 workers) who
showed symptoms severe enough to seek examination at a hospital.
The workers were exposed daily to toluene concentrations ranging
from 188 to 5625 mg/m3 for periods of 1 - 3 weeks. The
concentration of toluene was determined shortly after each exposed
person appeared at the hospital with symptoms, and the patients
were classified into groups according to extent of exposure. The
following effects were reported:
at 188 - 750 mg/m3 (approximately 60% of the patients):
headache, lassitude, and loss of appetite; these symptoms
were so mild that they were considered to be due primarily
to psychogenic and other factors rather than to toluene
fumes;
at 750 - 1875 mg/m3 (approximately 30% of the patients):
headache, nausea, bad taste in the mouth, anorexia,
lassitude, slight but definite impairment of coordination
and reaction time, and momentary loss of memory; and
at 1875 - 5625 mg/m3 (approximately 10% of the patients):
nausea, headache, dizziness, anorexia, palpitation, and
extreme weakness; loss of coordination was pronounced and
reaction time was definitely impaired.
No clear distinction has been made between the effects
attributable to the direct depressant action on the nervous system
of toluene present in the organism, and those that may be
persisting functional (or even morphological) sequelae of past
exposure. Psychological examinations, carried out 16 h after the
working shift, revealed some impairment in psychological
performance, which suggests the possibility that the functional
changes may persist for some time after the direct narcotic effect
(Hänninen et al., 1976). The impaired mental functions included
visual intelligence, sensory and vestibular function, memory
functions, and verbal intelligence (Lindstrom, 1973, 1982; de Rosa
et al., 1974; Rouskova, 1975; Hänninen et al., 1976; Seppäläinen et
al., 1978; Elofsson et al., 1980; Husman & Karli, 1980; Biscaldi et
al., 1981; Iregren, l982; Seppäläinen, 1982; Coscia et al., 1983).
Narcosis is the likely result of acute toluene exposure at high
concentrations. A number of accounts of workers who were rendered
unconscious by toluene vapour have been published (Lurie, 1949;
Browning, 1965; Longley et al., 1967; Reisin et al., 1975). Most
of these cases involved the exposure of workmen to high levels of
toluene during maintenance operations in confined areas with poor
ventilation.
9.3.3. Peripheral nervous system
There have been no reports of peripheral neuropathy occurring
in association with exposure to toluene alone. Most of the
reported cases have involved exposures to mixtures containing
either n-hexane or methyl ethylketone, which are known to cause
damage to peripheral nerves (Herskowitz et al., 1971; Goto et al.,
1974; Shirabe et al., 1974; Korobkin et al., 1975; Towfighi et al.,
1976; Alkenkirch et al., 1977; Boor & Hurtig, 1977).
Peripheral biopsy of radial cutaneous nerves showed distention
of axons, thinning of the myelin sheath, and widening of the nodes
of Ranvier (Korobkin et al., 1975); and axonal degeneration of
large diameter fibres in sural nerve (Shirabe et al., 1974;
Towfighi et al., 1976). Neurological examination revealed
autonomic vascular dysfunction in 28% (15% in control) and spinal
root syndrome in 9% (0.05% in control) (Syrovadko, 1977). The
author attributed the spinal root syndrome and also uterine
prolapse to the working posture; other changes (neurological,
haematological, and gynaecological) were considered to be due to
the action of toluene.
9.3.4. Blood and haematopoietic system
Early reports of occupational exposures (generally prior to the
1950s) ascribed myelotoxic effects to toluene exposure (Ferguson et
al., 1933; Greenburg et al., 1942; Wilson, 1943). However, most of
the recent evidence indicates that the chemical is not toxic to the
blood or bone marrow (Parmeggiani & Sassi, 1954; Capellini &
Alessio, 1971; Matsushita et al., 1975; Tähti et al., 1981). The
myelotoxic effects previously attributed to toluene are now
generally regarded to be the result of concurrent exposure to
benzene, present as a contaminant.
Banfer (1961) examined 112 rotogravure printers and helpers who
were exposed to the vapours of toluene-containing printing inks for
at least 3 years. Controls included 478 unexposed persons from 2
groups. The available commercial toluene used in these inks
reportedly contained only traces of benzene (< 0.3%). Analysis of
the room air for toluene by infrared spectroscopy was limited to
samples taken on a single day from 5 different locations in the
machine room (750 - 1500 mg/m3). Haematological examinations of
the workers and controls did not reveal any significant changes in
the total number of leukocytes, lymphocytes, granulocytes, or
erythrocytes, or in haemoglobin levels. Matsushita (1966)
investigated 97 painters exposed to toluene (up to 6750 mg/m3) and
xylene for an average of 6.2 years and 49 control workers. No
significant differences were found in the specific gravity of whole
blood, erythrocyte counts, haemoglobin concentration, and leukocyte
counts between the exposed workers and the controls, except for a
significant increase in Mommsen's toxic granules in the exposed
workers.
9.3.5. Liver and kidney
Liver enlargement (palpation) was reported in 61 aeroplane
painters exposed to 375 - 4125 mg toluene/m3 for up to 5 years.
Urinalysis and bilirubin in serum did not show any abnormalities
(Greenberg et al., 1942).
Waldron et al. (1982) examined liver function in 59 males, who
had been exposed to toluene for various periods, in comparison with
59 controls. At the time of the study, levels of exposure were
about 375 mg/m3; however, in previous years, the levels had been
considerably higher (up to 1875 mg/m3). Exposed males had
significantly lower levels of alanine aminotransferase (EC
2.6.1.2). There was no evidence of a trend towards higher levels
with increasing duration of exposure. None of the men had any
symptoms of liver dysfunction on clinical examination.
Szilard et al. (1978) reported the results of periodic
observation of 170 persons working in toluene-containing
atmospheres (duration of exposure 2 - 14 years at concentrations of
200 - 300 mg/m3 rising at times to 3000 mg/m3). They found
hepatomegaly and increased SGOT activity in 20 - 50% of workers.
Twenty-two of the 170 workers had liver biopsies. Routine
histology revealed no pathological changes. Electron microscopy
revealed changes in the shape of mitochondria and degranulation of
the RER.
Abnormalities in the glycoprotein, serum mucoid, and
haptoglobin patterns were reported among 53 women with histories of
occupational exposure to toluene (Kowal-Gierczak et al., 1969), and
51 showed changes in the serum levels of iron and copper, and
urinary excretion of porphyrin (Cieslinska et al., 1969), while
exposed to toluene at about 250 mg/m3 for 2 - 17 years.
In an examination of 94 rotogravure printers with a history of
exposure to 68 - 1875 mg toluene/m3 and of a reference group of 30
municipal clerks, Szadkowski et al. (1976) found a significant
reduction in bilirubin and alkaline phosphatase levels in the
exposed group, but no difference from controls in SGOT, SGPT,
leucine aminopeptidase (EC 2.6.1.6), or cholinesterase (EC 3.1.1.8)
levels.
9.3.6. Menstruation
Michon (1965), Matsushita et al. (1975), and Syrovadko (1977)
described studies concerning the complaints of women exposed to
toluene, mainly in combination with other aromatic hydrocarbons.
These complaints included menstrual disturbances such as prolonged
and intensive menstrual bleeding. From the available data, it was
emphasized that a specific effect of toluene could not be
determined.
9.3.7. Chromosome damage
General
There are discrepancies in findings related to chromosome
damage in peripheral lymphocytes among workers exposed to toluene.
An unequivocal evaluation of the genetic effects of occupational
toluene exposure, based on available studies, cannot be made
because of the relatively small number of subjects analysed,
variation in the extent of exposure between these studies, and
insufficient information on possible exposure to other chromosome-
damaging agents (benzene, tobacco smoke, etc.).
Conventional chromosome aberration analyses from 24 rotogravure
workers (exposed only to toluene after 1953) (Forni et al., 1971)
and SCEs and chromosome aberration analyses from 32 rotogravure
workers (average length of exposure = 14 years) (Mäki-Paakkanen et
al., 1980) revealed no increase in the rate of chromosome damage in
cultured blood lymphocytes compared with controls. In the former
study, the concentration of toluene, containing traces of xylene,
was generally below, but occasionally above, 750 mg/m3, in the
working zone. However, between the working machines, it was well
over 750 mg/m3. In the second study, individual exposures varied
from 26 - 420 mg toluene containing < 0.05% benzene/m3.
Haglund et al. (1980) reported negative findings from 17
workers in the paint industry exposed to a mixture of organic
solvents, mainly containing xylene and toluene. In the chromosome
aberration analyses, no differences were found between 5 workers
(employed from 0.8 to 44 years with the highest exposure to toluene
concentration > 100 mg/m3), and their matched controls.
Funes-Cravioto et al. (1977) presented data on 14 workers who
were exposed to toluene (possibly containing a low percentage of
benzene) in a rotogravure factory. Length of exposure ranged from
1.5 to 26 years and air measurements of toluene showed time-
weighted average values of 375 - 750 mg/m3 with occasional rises to
1875 and 2655 mg/m3. In most cases, the exposures were
sufficient to cause frequent headaches and fatigue, and occasional
vertigo, nausea, and feelings of drunkenness. Analyses of cultured
blood lymphocytes showed an excess of chromosome aberrations in the
14 toluene-exposed workers compared with a control group of 49
adults.
Bauchinger et al. (1982) reported a statistically-significant
increase in the mean number of SCEs and structural chromosomal
aberrations in cultured blood lymphocytes from a group of 20 male
rotogravure workers exposed to 750 - 1125 mg toluene/m3 (benzene
content < 0.3%) for more than 16 years, in comparison with 24
unexposed persons. Their results were similar to the observations
of Funes-Cravioto et al. (1977). For the statistical evaluation of
SCEs data, the subjects of both groups were subdivided into smokers
and non-smokers. Such an analysis revealed significantly higher
SCE values for non-smoking rotogravure workers than for non-smoking
controls. This was also true for smoking rotogravure workers
compared with smoking controls. In both groups, smokers had
significantly higher SCE values than non-smokers. Later, Schmid &
Bauchinger (1984) repeated the chromosome aberration and SCEs
analyses from 27 workers of the same plant with earlier exposure to
toluene. The workers had not been exposed for between 4 months and
5 years. In a subgroup of 13 workers without toluene exposure for
up to two years, a significantly higher number of cells with
aberrations was found (mainly chromatid types) compared with
controls, whereas the frequency of gaps was not elevated. A
subgroup of 14 workers without toluene exposure for between 2.5 and
5 years did not show any increase in the number of cells with
structural chromosome aberrations. In both subgroups, the SCE
values for smoking and non-smoking workers were unchanged compared
with the corresponding controls. The authors concluded that
structural chromosome changes induced by toluene exposure could
persist for up to 2 years after exposure, but that after this time,
the number of gaps and SCEs dropped to the control level.
According to Bauchinger et al. (1982), a weak clastogenic
effect of toluene can only be detected if there is a sufficiently
large number of subjects exposed to high toluene concentrations
(> 750 mg/m3) and a large number of cells are scored. The authors
state that in the previously published studies too few metaphases
(100 cells per individual) were analysed and that the negative
result of Forni et al. (1971) and Mäki-Paakkanen et al. (1980) may
be explained by the lower toluene exposure of the workers.
The work of Vijayalaxmi & Evans (1982) and that of Obe et al.
(1982) quite clearly showed that the frequency of chromosome
aberrations (and also of SCEs) is increased in cultured blood
lymphocytes of smokers as compared with non-smokers. Moreover,
Mäki-Paakkanen et al. (1984) have found that smoking causes the
same type of damage (chromatid-type) observed by Bauchinger et al.
(1982) and Schmid & Bauchinger (1984).
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of Human Health Risks
The major route of human exposure is through inhalation.
Toluene is readily absorbed from the respiratory tract with an
uptake of approximately 40 - 60% in human beings. Smaller amounts
are rapidly absorbed via the skin and complete absorption occurs in
the gastrointestinal tract, but at a slower rate. However, the
presence of small amounts of toluene in drinking-water and food
adds only minor quantities to man's total daily uptake. Once
absorbed, toluene is rapidly metabolized to benzoic acid and
excreted in the urine as hippuric acid and its conjugates. In the
case of daily exposure to high concentrations, for instance, under
occupational conditions, significant uptake of toluene into lipid-
rich tissues, such as adipose tissue and the central nervous
system, occurs.
10.2. Acute and Short-Term Effects on Man
Based on the available studies, the odour threshold for toluene
in human beings is estimated to be 9.4 mg/m3 (2.5 ppm). The acute
and short-term effects of toluene can be summarized as follows:
- levels up to 375 mg/m3 for a few hours showed subjective
complaints of fatigue and drowsiness, but no observable
impairment of reaction time or coordination;
- up to 750 mg/m3 for 8 h resulted in mild throat and
eye irritation, some impairment of cognitive function,
headache, dizziness, and sensation of intoxication;
- up to 1500 mg/m3 for 8 h, besides the symptoms already
mentioned, caused lachrymation, skin paraesthesia, gross
signs of incoordination, and mental confusion.
These effects are reversible on cessation of exposure, but become
increasingly severe and persistent with increasing concentration
and/or duration of exposure. No toxicity was observed in human
beings repeatedly exposed to toluene levels of less than 188 mg/m3
for short periods of time or exposed once to a level of 375 mg/m3
for a few hours.
The critical target organs for toluene are the central nervous
system, probably because of the accumulation of toluene in the
lipid-rich tissues, from which it is slowly released (toluene
concentrations are higher in brain and adipose tissues than in the
blood).
Effects on the central nervous system begin to appear with an
inhalation exposure of 375 mg/m3, for 6 h/day, over 4 days. Gross
signs of incoordination, depression of the central nervous system,
and mental confusion are produced with exposure to a toluene
concentration of approximately 1500 mg/m3 for more than 8 h.
Convulsions, nausea, and coma have been noted in human beings at
concentrations of 2250 mg/m3 and higher. Exposure to very high
concentrations (above 15 000 mg/m3) leads to narcosis and death.
The toxic effects of toluene in human beings after long-term
exposure are, in principal, the same. The CNS effects may be
depressant or excitatory, with euphoria preceeding disorientation,
tremulousness, hallucinations, ataxia, and coma. Human beings are
more sensitive than certain animal species. Effects induced in
human beings at 750 mg/m3 were seen in rats only after exposure to
1875 mg/m3. Animal studies showed that sensitivity to toluene
varies with species. Differences were also found according to the
sex and age of the animals. The acute LC50 for mice and rats has
been reported to be higher than 20 000 mg/m3.
A proper multiple generation reproduction study is not
available. From the teratogenicity studies on mice, rats, and
rabbits, toluene can be considered negative after inhalation
exposure. In rats, given high doses of 1000 - 1500 mg/m3, for
8 h/day, during the period of organogenesis, no maternal toxicity
was noted, but an influence on fetal weight and delayed
ossification was observed. An embryotoxic effect cannot be
excluded. No adverse effects were noted in mice at 375 mg/m3.
Toluene caused spontaneous abortions in rabbits at 1000 mg/m3 and
embryolethality and fetotoxicity in rats administered a dose level
of 6000 mg/m3 for 24 h/day, on days 4 - 21 of gestation.
A significantly increased incidence of cleft palate was induced
in mice after oral administration of 870 mg toluene/kg body weight
on days 6 - 15 of gestation, but not with a dose level of 430 mg/kg
body weight.
The effects of toluene on human male reproduction have not been
examined; however, degeneration of germinal cells in the rat testes
has been observed in one study after exposure to 750 mg/m3 for
8 h/day, 6 days/week, for one year. This finding was not confirmed
in other studies at much higher dose levels.
Numerous studies on experimental animals and studies of groups
of workers exposed to different concentrations of toluene,
sometimes for more than 10 years failed to demonstrate effects on
the haematopoietic system. At exposure levels exceeding 4000
mg/m3, cardiac arrhythmia was seen in rats and, at a dose level of
7500 mg/m3, kidney damage was found in dogs. Renal function
impairment was also seen in workers exposed to levels exceeding
300 mg toluene (mixtures)/m3 air. Indicators studied were
proteinuria, albuminuria, and excretion of muramides and beta-
glucuronidase. Effects on the liver were seen only at very high
levels.
In long-term carcinogenicity studies on rats, inhalation of
concentrations of 112.5, 375, and 1125 mg/m3 did not show clear
effects, with the exception of a reduction in haematocrite and
increase in mean corpuscular haemoglobin concentration at the
highest dose level. No increase in tumour incidence was observed.
Two long-term studies concerning the oral administration of toluene
to rats and mice are in progress.
Pure toluene does not seem to have any, or only negligible,
mutagenic effects in different test systems. However, the
potential mutagenic effects of mixtures cannot be assessed at this
time.
No epidemiological studies have been carried out following
exposure to toluene.
Assessment of the toxicity of toluene in the workplace is
frequently complicated by the impurity of the technical toluene
used and/or the presence of other solvents that may themselves be
toxic. A similar situation exists in relation to solvent abuse.
Other solvents that complicate the evaluation are benzene and
n-hexane.
Although data are fairly conclusive for the evaluation of human
health risks from pure toluene, no evaluation can be made for
exposure to solvent mixtures containing toluene. Data on persons
exposed to high levels of mixtures are available and indicate a
difference in target organs; an increased risk of liver damage or
toxic effects on the haemopoietic tissue, the immune system and
endocrine system. However, no quantitative risk evaluation can be
made at present.
Persons involved in long-term abuse routinely exceed
concentrations of 3750 mg/m3, which causes a significant incidence
of solvent-induced morbidity or permanent neurological deficit.
Irreversible neurological sequelae may present as encephalopathy,
optic atrophy, equilibrium disorders, diencephalic syndrome, and
cerebellar ataxia. These have been described in adults, as well as
in children of 8 - 14 years of age.
10.3. Evaluation of Environmental Hazards of Toluene
In areas without wind, toluene vapour can concentrate in
depressions. A potentially serious safety hazard can result where
the explosive limits (1.17 - 7.10% volume in air) are exceeded.
Present evidence indicates that toluene concentrations in
natural waters seldom exceed 0.1 mg/litre, though higher
concentrations may be found near spills. Toluene is non-persistent
and is rapidly volatilized or biodegraded. It is unlikely that
toluene is bioaccumulated in fish and the food chain.
Toluene is of moderate to low toxicity for water organisms.
The LC50 ranges from 3.7 to 1180 mg/litre. The LC50s for most of
the fish and invertebrates studied have been of the order of 15 -
30 mg/litre. Photosynthesis and respiration by marine plankton
communities are inhibited at concentrations of 30 mg/litre. The
first effects on aquatic communities including inhibition of
reproduction and growth may be experienced at concentrations of
toluene in water of 2 mg/litre.
Toluene probably exists in soils in the adsorbed state and may
participate in chemical reactions and biological degradation and
transformation. Volatilization takes place and is dependent on the
nature of the soil. Transfer of toluene from soil to groundwater
takes place and this will result in contamination of sources of
drinking-water.
Toluene is easily degraded by activated sludge in sewage and
biodegraded by a variety of soil microorganisms.
11. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
The average daily maximum allowable concentration (MACad) and
the highest momentary (single-occasion MAChm) for toluene in the
ambient air of residential areas in the USSR is 0.6 mg/m3, and the
maximum acceptable limits of toluene in bodies of water for
sanitary-domestic uses is 0.5 mg/litre (IRPTC, 1982).
Examples of occupational exposure limits as time-weighted
averages (TWA) for an 8-h day and a 40-h week include: 200 mg/m3
in Czechoslovakia and the German Democratic Republic; 375 mg/m3 in
Ireland, Japan, and the USA (NIOSH); 750 mg/m3 in the Federal
Republic of Germany and the USA (OSHA); and 300 mg/m3 in Sweden.
Other limits include: 100 mg/m3 as a ceiling concentration in
Hungary; and 50 mg/m3 as the maximum allowable concentration in the
USSR.
REFERENCES
ABOU-EL-MARKAREM, M.M., MILLBURN, P., SMITH, R.L., & WILLIAMS,
R.T. (1967) Biliary excretion of foreign compounds. Benzene
and its derivatives in the rat. Biochem. J., 105: 1269-1274.
AIKAWA, H., MISAWA, T., & SHIGETA, S. (1982) [A study of
direct injection method using glass-insert in gas
chromatographic determination of toluene in whole blood.] Jpn
J. ind. Health, 24: 92-93 (in Japanese).
AL-GAILANY, K.A.S., HOUSTON, J.B., & BRIDGES, J.W. (1978)
The role of substrate lipophilicity in determining Type 1
microsomal P-450 binding characteristics. Biochem. Pharmacol.,
27(5): 783-788.
ALKENKIRCH, J., MAGER, J., STOLTENBURG, G., & HELMBRECHT, J.
(1977) Toxic polyneuropathies after sniffing a glue thinner.
J. Neurol., 214(2): 137-152.
ALLISTER, C., LUSH, M., OLIVER, J.S., & WATSON, J.M. (1981)
Status epilepticus caused by solvent abuse. Br. med. J., 283:
1156.
ALTSHULLER, A.P., LONNEMAN, W.A., SUTTERFIELD, F.D., &
KOPCZYNSKI, S.L. (1971) Hydrocarbon composition of the
atmosphere of the Los Angeles Basin - 1967. Environ. Sci.
Technol., 5(10): 1009-1016.
AMSEL, L.P. & LEVY, G. (1969) Drug biotransformation
interactions in man. II. A pharmacokinetic study of the
simultaneous conjugation of benzoic and salicylic acids with
glycine. J. pharm. Sci., 58(3): 321-326.
ANDERSEN, I., LUNDQUIST, G.R., MOLHAVE, L., PEDERSEN, O.F.,
PROCTOR, D.F., VAETH, M., & WYON, D.P. (1983) Human response
to controlled levels of toluene in six-hour exposures. Scand.
J. Work environ. Health, 9: 405-418.
ANDERSON, G.E., LIU, C.S., HOLMAN, H.Y., & KILLUS, J.P.
(1980) Human exposure to atmospheric concentrations of
selected chemicals, Research Triangle Park, North Carolina, US
Environmental Protection Agency (Prepared by Systems
Applications, Inc., San Rafael, California, Contract No.
EPA 68-02-3066).
ANDERSSON, K., FUXE, K., TOFTGARD, R., NILSEN, O.G., ENEROTH,
P., & GUSTAFSSON, J.A. (1980) Toluene-induced activation of
certain hypothalamic and media-eminence catecholamine nerve-
terminal systems of the male-rat and its effects on anterior
pituitary hormone secretion. Toxicol. Lett., 5(6): 393-398.
ANDREWS, L.S., LEE, E.W., WITMER, C.M., KOCSIS, J.J., &
SNYDER, R. (1977) Effects of toluene on the metabolism,
disposition, and hemopoietic toxicity of (3H)benzene. Biochem.
Pharmacol., 26: 293-300.
ANGERER, J. (1976) [Chronic exposure to solvents at the
work-place. IV. Thin-layer chromatographic-densimetric method
for measuring hippuric acid in urine.] Int. Arch. occup.
environ. Health, 36: 287-297 (in German).
ANGERER, J. (1979) Occupational chronic exposure to organic
solvents. VII. Metabolism of toluene in man. Int. Arch. occup.
environ. Health, 43(1): 63-67.
ANTHONY, R.M., BOST, R.O., THOMPSON, W.L., & SUNSHINE, I.
(1978) Paraldehyde, toluene, and methylene chloride analysis
by headspace gas chromatography. J. anal. Toxicol., 2: 262-264.
APOSTOLI, P., BRUGNONE, F., PERBELLINI, L., COCHEO, V.,
BELLOMO, M.L., & SILVESTRI, R. (1982) Biomonitoring of
occupational toluene exposure. Int. Arch. occup. environ.
Health, 50: 153-168.
ARNTS, R.R. & MEEKS, S.A. (1981) Biogenic hydrocarbon
contribution to the ambient air of selected areas. Atmos.
Environ., 15(9): 1643-1651.
ASKERGREN, A. (1981) Studies on kidney function in subjects
exposed to organic solvents. III. Excretion of cells in the
urine. Acta med. Scand., 210: 103-106.
ASKERGREN, A., ALLGEN, L.G., KARLSSON, C., LUNDBERG, I., &
NYBERG, E. (1981a) Studies on kidney function in subjects
exposed to organic solvents. I. Excretion of albumin and
B-2-microglobulin in the urine. Acta med. Scand., 209: 479-483.
ASKERGREN, A., ALLGEN, L.G., & BERGSTROM, J. (1981b) Studies
on kidney function in subjects exposed to organic solvents.
II. The effect of desmopressin in a concentration test and the
effect of exposure to organic solvents on renal concentrating
ability. Acta med. Scand., 209: 485-488.
ASSENNATO, G., MARTINO, M., & L'ABBATE, N. (1977) [Activity
of serum ornithincarbamyl transferase in subjects exposed to
benzene and toluene.] Terapia, 62: 82-87 (in Italian).
ASTRAND, I. (1975) Uptake of solvents in the blood and
tissues of man. A review. Scand. J. Work environ. Health,
1(4): 199-218.
ASTRAND, I. (1983) Effect of physical exercise on uptake,
distribution, and elimination of vapours in man. V. In: Vern
Fiserova - Bergerova, ed. Modeling of inhalation exposure to
vapors: uptake, distribution, and elimination, Boca Raton, CRC
Press, Vol II (Chapter 5).
ASTRAND, I., EHRNER-SAMUEL, H., KILBOM, A., & OVRUM, P. (1972)
Toluene exposure. I. Concentration in alveolar air and blood
at rest and during exercise. Work environ. Health, 9: 119-130.
BAKKE, O.M. & SCHELINE, R.R. (1970) Hydroxylation of
aromatic hydrocarbons in the rat. Toxicol. appl. Pharmacol.,
16: 691-700.
BAKKE, T. & SKJOLDAL, H.R. (1979) Effects of toluene on the
survival, respiration, and adenylate system of a marine
isopod. Mar. Pollut. Bull., 10(4): 111-115.
BANFER, W. (1961) [Studies on the effect of pure toluene on
the blood picture of photogravure printers and helper
workers.] Zentralbl. Arbeitsmed., 11: 35-40 (in German).
BARMAN, M.L., SIEGEL, N.B., BEEDLE, D.B., & LARSON, R.K.
(1964) Acute and chronic effects of glue sniffing. Calif.
Med., 100(1): 19-22.
BATCHELOR, J.J. (1927) The relation toxicity of benzol and
its higher homologues. Am. J. Hyg., 7: 276-298.
BATTIG, K. & GRANDJEAN, E. (1964) Industrial solvents and
avoidance conditioning in rats. Arch. environ. Health, 9:
475-749.
BAUCHINGER, M., SCHMID, E., DRESP, J., KOLIN-GERRESHEIM, J.,
HAUF, R., & SUHR, E. (1982) Chromosome changes in lymphcytes
after occupational exposure to toluene. Mutat. Res., 102: 439-445.
BELLANCA, J.A., DAVIS, P.L., DONNELLY, B., DAL CORTIVO, L.A.,
& WEINBERG, S.B. (1982) Detection and quantitation of
multiple volatile compounds in tissues by GC and GC/MS.
J. anal. Toxicol., 6: 238-240.
BELLAR, T.A. & LICHTENBERG, J.J. (1979) Semiautomated
headspace analysis of drinking-water and industrial waters for
purgeable volatile organic compounds. In: Van Hall, C.E., ed.
Measurement of organic pollutants in water and wastewater,
Philadelphia, Pennsylvania, American Society for Testing and
Materials, pp. 108-129 (ASTM STP 686).
BENIGNUS, V.A., MULLER, K.E., BARTON, C.N., & BITTIKOFER,
J.A. (1981) Toluene levels in blood and brain of rats during
and after respiratory exposure. Toxicol. appl. Pharmacol., 61:
326-334.
BENIGNUS, V.A., MULLER, K.E., GRAHAM, J.A., & BARTON, C.N.
(1984a) Toluene levels in blood and brain of rats as a
function of toluene level in inspired air. Environ. Res., 33:
39-46.
BENIGNUS, V.A., MULLER, K.E., BARTON, C.N., & BITTIKOFER,
J.A. (1984b) Toluene blood level following subcutaneous
injection of toluene in the rat. Environ. Res., 33: 441-453.
BENNETT, R.H. & FORMAN, H.R. (1980) Hypokalemic periodic paralysis
in chronic toluene exposure. Arch. Neurol., 37(10): 673.
BENVILLE, P.E., Jr & KORN, S. (1977) The acute toxicity of
six monocyclic aromatic crude oil components to striped bass
(Morone saxatilis) and bay shrimp (Crago franciscorum). Calif.
Fish Game, 63(4): 204-209.
BERGMAN, K. (1978) Application of whole-body autoradiography
to distribution studies of organic solvents. In: Proceedings
of the International Symposium on the Control of Air Pollution
in the Work Environment, Part 2, pp. 128-139.
BERGMAN, K. (1979) Whole-body autoradiography and allied
tracer techniques in distribution and elimination studies of
some organic solvents. Scand. J. Work environ. Health,
5(Suppl. 1): 263 pp.
BERGMAN, K. (1983) Application and results of whole-body
autoradiography in distribution studies of organic solvents.
Crit. Rev. Toxicol., 12: 59-118.
BERTSCH, W., ANDERSON, E., & HOLZER, G. (1975) Trace
analysis of organic volatiles in water by gas
chromatography-mass spectrometry with glass capillary columns.
J. Chromatogr., 112: 701-718.
BERRY, W.O. (1980) A comparative study of the uptake of
toluene by bluegill, sunfish Lepomis macrochirus, and
Orconectes rusticus. Environ. Pollut., 80: 109-119.
BERRY, W.O. & BRAMMER, J.D. (1977) Toxicity of water-soluble
gasoline fractions to fourth-instar larvae of the mosquito
Aedes aegypti L. Environ. Pollut., 13(3): 229-234.
BIENIEK, G. & WILCZOK, T. (1981) Thin-layer chromatography
of hippuric and m-methylhippuric acid in urine after mixed
exposure to toluene and xylene. Br. J. ind. Med., 38: 304-306.
BIENIEK, G., PALYS, E. & WILCZOK, T. (1982) TLC separation
of hippuric, mandelic, and phenylglyoxylic acids from urine
after mixed exposure to toluene and styrene. Br. J. ind. Med.,
39: 187-190.
BISCALDI, G.P., MINGARDI, M., POLLINI, G., MOGLIA, A., &
BOSSI, M.C. (1981) Acute toluene poisoning. Electroneuro-
physiological and vestibular investigations. Toxicol. Eur.
Res., 3(6): 271-273.
BONNET, P., RAOULT, G., & GRADISKI, D. (1979) Concentrations
léthales 50 des principaux hydrocarbures aromatiques. Arch.
Mal. Med. Trav. Sécur. soc., 40(8-9): 805-810.
BOOR, J.W. & HURTIG, H.I. (1977) Persistent cerebellar
ataxia after exposure to toluene. Ann Neurol., 2(5): 440-442.
BOS, R.P., BROUNS, R.M.E., VAN DOORN, R., THEUWS, J.L.G., &
HENDERSON, P.T. (1981) Non-mutagenicity of toluene, o-, m-,
and p-xylene, o-methylbenzyl alcohol, and o-methylbenzyl
sulfate in the Ames assay. Mutat. Res., 88(3): 273-279.
BRAIER, L. (1973) A comparative study of isocylic
hydrocarbons in animals and in man. Haematologica, 58(7-8):
491-500.
BRENNIMAN, G., HARTUNG, R., & WEBER, W.J., Jr (1976) A
continuous-flow bioassay method to evaluate the effects of
outboard motor exhausts and selected aromatic toxicants on
fish. Water Res., 10(2): 165-169.
BRIDIE, A.L., WOLFF, C.J.M., & WINTER, M. (1979) BOD and COD
of some petrochemicals. Water Res., 13: 627-630.
BRODZINSKY, R. & SINGH, H.B. (1982) Volatile organic
chemicals in the atmosphere: an assessment of available data,
Menlo Park, California, Stanford Research Institute (Final
Report Prepared for the US Environmental Protection Agency).
BROWN, S.L., CHAN, F.Y., JONES, J.L., LIU, D.H., MCCALEB,
K.E., MILL, T., KAPIOS, K.M., & SCHENDEL, D.E. (1975)
Research program on hazard priority ranking of manufactured
chemicals. Phase II: chemicals 1-20, Menlo Park, California,
Stanford Research Institute (Final Report Prepared by SRI)
National Science Foundation, Washington DC. Available from:
National Technical Information Service, Springfield, Virginia
(NTIS PB 263 161).
BROWNING, E. (1965) Toxicity and metabolism of industrial
solvents, Amsterdam, London, New York, Elsevier Publishing
Co., pp. 66-76.
BRUCKNER, J.V. & PETERSON, R.G. (1976) Evaluation of toluene
toxicity utilizing the mouse as an animal model of human
solvent abuse. Pharmacology, 18(2): 244.
BRUCKNER, J.V. & PETERSON, R.G. (1981a) Evaluation of
toluene and acetone inhalant abuse. I. Pharmacology and
pharmacodynamics. Toxicol. appl. Pharmacol., 61: 27-38.
BRUCKNER, J.V. & PETERSON, R.G. (1981b) Evaluation of
toluene and acetone inhalant abuse. II. Model development and
toxicology. Toxicol. appl. Pharmacol., 61: 302-312.
BRUGNONE, F., PERBELLINI, L., GRIGOLINI, L., CAZZADORI, A., &
GAFFURI, E. (1976) Alveolar air and blood toluene
concentration in rotogravure workers. Int. Arch. occup.
environ. Health, 38: 45-54.
BRUGNONE, F., PERBELLINI, L., GARUFFI, E., & APOSTOLI, P.
(1980) Biomonitoring of industrial solvent exposures in
workers' alveolar air. Int. Arch. occup. environ. Health, 47:
245-250.
BRUGNONE, F., PERBELLINI, L., APOSTOLI, P., LOCATELLI, M., &
MARIOTTO, P. (1983) Decline of blood and alveolar toluene
concentration following two accidental human poisonings.
Int. Arch. occup. environ. Health, 53: 157-165.
CALDWELL, R.S., CALDARONE, E.M., & MALLON, M.H. (1976)
Effects of a seawater-soluble fraction of cook inlet crude oil
and its major aromatic components on larval stages of the
dungeness crab, Cancer magister dana. In: Fate and effects of
petroleum hydrocarbon in marine organisms and ecosystems,
New York, Pergamon Press, pp. 210-220.
CAMERON, G.R., PATERSON, J.L.H., DE SARAM, G.S.W., & THOMAS,
J.C. (1938) The toxicity of some methyl derivatives of
benzene with special reference to pseudocumene and heavy
coal-tar naphtha. J. Path. Bact., 46: 95-107.
CANADY, W.J., ROBINSON, D.A., & COLBY, H.D. (1974) A
partition model for hepatic cytochrome P-450-hydrocarbon
complex formation. Biochem. Pharmacol., 23(21): 3075-3078.
CAPELLINI, A. & ALESSIO, L. (1971) [The urinary excretion of
hippuric acid in workers exposed to toluene.] Med. Lav.,
62(4): 196-201 (in Italian).
CAPEROS, J.R. & FERNANDEZ, J.G. (1977) Simultaneous
determination of toluene and xylene metabolites in urine by
gas chromatography. Br. J. ind. Med., 34: 229-233.
CARLSON, R.M., CARLSON, R.E., KOPPERMAN, H.L., & CAPLE, R.
(1975) Facile incorporation of chlorine into aromatic systems
during aqueous chlorination processes. Environ. Sci. Technol.,
9(7): 674-675.
CARLSSON, A. (1982a) Exposure to toluene. Uptake,
distribution, and elimination in man. Scand. J. Work environ.
Health, 8(1): 43-55.
CARLSSON, A. (1982b) Uptake, distribution, and elimination
of methylene chloride and toluene. Arbete Och Halsa, 3: 1-44.
CARLSSON, A. & LINDQVIST, T. (1977) Exposure of animals and
man to toluene. Scand. J. Work environ. Health, 3(3): 135-143.
CARLSSON, A. & LJUNGQUIST, E. (1982) Exposure to toluene.
Concentration in subcutaneous adipose tissue. Scand. J. Work
environ. Health, 8: 56-62.
CARPENTER, C.P. & SMYTH, H.F. (1946) Chemical burns of the
rabbit cornea. Am. J. Opthalmol., 29: 1363-1372.
CARPENTER, C.P., SHAFFER, C.B., WEIL, C.S., & SMYTH, H.F., Jr
(1944) Studies on the inhalation of 1,3-butadiene with a
comparison of its narcotic effect with benzol, toluol, and
styrene, and a note on the elimination of styrene by the
human. J. ind. Hyg. Toxicol., 26(3): 69-78.
CARPENTER, C.P., GEARY, D.L., Jr, & MYERS, R.C. (1976a)
Petroleum hydrocarbon toxicity studies. X. Animal and human
response to vapors of '50 Thinner'. Toxicol. appl. Pharmacol.,
36(3): 427-442.
CARPENTER, C.P., GEARY, D.L., Jr, MYERS, R.C., NACHREINER,
D.J., SULLIVAN, L.J., & KING, J.M. (1976b) Petroleum
hydrocarbon toxicity studies. XIII. Animal and human response
to vapors of toluene concentrate. Toxicol. appl. Pharmacol.,
36: 473-490.
CHAMBERS, C.W., TABAK, H.H., & KABLER, P.W. (1963)
Degradation of aromatic compounds by phenol-adapted bacteria.
J. Water Pollut. Contr. Fed., 35(12): 1517-1528.
CHAND, P. & CLAUSEN, J. (1982) Effects of toluene on
cytochrome P-450 mixed-function oxygenase and
glutathione- S-transferase activities in rat brain and liver.
Bull. environ. Contam. Toxicol., 28: 542-545.
CHANNER, K.S. & STANLEY, S. (1983) Persistent visual
hallucinations secondary to chronic solvent encephalopathy:
case report and review of the literature. J. Neurol.
Neurosurg. Psychiatr., 46: 83-86.
CHRISTIANSSON, G. & KARLSSON, B. (1957) ["Sniffing" - Method
of intoxication among children.] Svensk Lakartidn., 54: 33-44
(in Swedish).
CIER, H.E. (1969) Toluene. In: Standen, A., ed. Kirk-Othmer
encycopedia of chemical technology, 2nd ed., New York, John
Wiley and Sons, Vol. 20, 528 pp.
CIESLINSKA, A., KOWAL-GIERCZAK, B., KUCZYNSKA-SEKIETA, K.,
MALOLEPSZY, J., & WRZYSZCZ, M. (1969) [Serum iron and copper
levels in subjects with chronic toluene exposure.] Pol. Tyg.
Lek., 24: 1848-1850 (in Polish).
COCHEO, V., SILVESTRI, R., BOMBI, G.G., & PERBELLINI, L.
(1982) Purge and trap analysis of toluene in blood:
comparison with the headspace method. Am. Ind. Hyg. Assoc. J.,
43(12): 938-941.
CONTRERAS, C.M., GONZALEZ-ESTRADA, T., ZARABOZO, D., &
FERNANDEZ-GUARDIOLA, A. (1979) Petit mal and grand mal
seizures produced by toluene or benzene intoxication in the
cat. Electroencephalogr. clin. Neurophysiol., 46(3): 290-301.
COOMBS, M.M., SHATT, T.S., & CROFT, C.J. (1973) Correlation
between carcinogenicity and chemical structure in
cyclopenta[ a]phenanthrenes. Cancer Res., 33: 832-837.
COOPER, R., NEWTON, P., & REED, M. (1985) Neurophysiological
signs of brain damage due to glue sniffing. Electro-
encephalogr. clin. Neurophysiol., 60: 23-26.
COSCIA, G.C., TABARO, G., ALBERA, C., TUBINO, L., MORRA, B.,
DISCALZI, G., & TURCO, L. (1983) [Vestibular alterations
through exposure to toluene.] Med. Lav., 74: 23-29 (in
Italian).
DALHAMN, T., EDFORS, M.L., & RYLANDER, R. (1968a) Mouth
absorption of various compounds in cigarette smoke. Arch.
environ. Health, 16(6): 831-835.
DALHAMN, T., EDFORS, M.L., & RYLANDER, R. (1968b) Retention
of cigarette smoke components in human lungs. Arch. environ.
Health, 17: 746-748.
DALY, J., JERINA, D., & WITKOP, B. (1968) Migration of
deuterium during hydroxylation of aromatic substrates by liver
microsomes. I. Influence of ring substituents. Arch. Biochem.
Biophys., 128: 517-527.
DAMBRAUSKAS, T. & COOK, W.A. (1963) Methanol as the
absorbing reagent in the determination of benzene, toluene,
xylene, and their mixtures in air. Am. Ind. Hyg. Assoc. J.,
24: 568-575.
DAVIS, E.M., MURRAY, H.E., LIEHR, J.G., & POWERS, E.L.
(1981) Basic microbial degradation rates and chemical
byproducts of selected organic compounds. Water Res., 15:
1125-1127.
DECHEV, G.D. & DAMYANOVA, A.A. (1977) [Functional
investigation of bacterial composition of active sludge.]
Bulgar. Akad. Nauk. Dokl. Bolgar. Akad. Nauk., 30(10):
1475-1478 (in Bulgarian) (Chemical Abstract 89, pp. 344, No.
135021r. 1978).
DELAUNAY, A., LEBRUN, J., FOUCQUIER, E., & WANG, H.S. (1950)
Etudes sur la perméabilité capillaire. Action et mécanisme
d'action du toluène et des corps voisins sur la perméabilité
des capillaires sanguins. Compte Rendu Soc. Biol., 144: 58-59.
DE ROSA, E., SARTO, F., MAZZOTTA, M., & ZOLLI, M. (1974)
[Newer patterns of toluene toxicity.] Lav. Umano, 26: 144-151
(in Italian).
DEVLIN, E.W., BRAMMER, J.D., & PUYEAR, R.L. (1982) Acute
toxicity of toluene to three age groups of fathead minnows
(Pimephales promelas). Bull. environ. Contam. Toxicol., 29:
12-17.
DIVINCENZO, G.D. & KRASAVAGE, W.J. (1974) Serum ornithine
carbamyl transferase as a liver response test for exposure to
organic solvents. Am. Ind. Hyg. Assoc. J., 35: 21-29.
DOAK, S.M.A., SIMPSON, B.J.E., HUNT, P.F., & STEVENSON, D.E.
(1976) The carcinogenic response in mice to the topical
application of propane sultone to the skin. Toxicology, 6:
139-154.
DOBROKHOTOV, V.B. (1972) [The mutagenic influence of benzene
and toluene under experimental conditions.] Gig. i Sanit., 37:
36-39 (in Russian).
DOBROKHOTOV, V.B. & ENIKEEV, M.I. (1976) [Mutagenic effect
of benzene, toluene, and a mixture of these hydrocarbons in a
chronic experiment.] Gig. i Sanit., 2(1): 32-34 (in Russian).
DONNER, M., HUSGAFVEL-PURSIAINEN, K., MAKI-PAAKKANEN, J.,
SORSA, M., & VAINIO, H. (1981) Genetic effects of in vivo
exposure to toluene. Mutat. Res., 85: 293-294.
DOWTY, B.J., ANTOINE, S.R., & LASETER, J.L. (1979)
Quantitative and qualitative analysis of purgeable organics by
high-resolution gas chromatography and flame ionization
detection. In: Van Hall, C.E., ed. Measurement of organic
pollutants in water and wastewater, Philadelphia,
Pennsylvania, American Society for Testing and Materials, pp.
24-35 (ASTM STP 686).
DROZD, J., NOVAK, J., & RIJKS, J.A. (1978) Quantitative and
qualitative headspace gas analysis of parts per billion
amounts of hydrocarbons in water. A study of model systems by
capillary-column gas chromatography with splitless sample
injection. J. Chromatogr., 158: 471-482.
DUTKIEWICZ, T. & TYRAS, H. (1968a) The quantitative
estimation of toluene skin absorption in man. Arch.
Gewerbepath Gewerbehyg., 24: 253-257.
DUTKIEWICZ, T. & TYRAS, H. (1968b) Skin absorption of
toluene, styrene, and xylene by man. Br. J. ind. Med., 25(3):
243.
EGLE, J.L. & GOCHBERG, B.J. (1976) Respiratory retention of
inhaled toluene and benzene in the dog. J. Toxicol. environ.
Health, 1(3): 531-538.
EHYAI, A. & FREEMON, F.R. (1983) Progressive optic
neuropathy and sensorineural hearing loss due to chronic glue
sniffing. J. Neurol. Neurosurg. Psychiatr., 46: 349-351.
EL-DIB, M.A., MOURSY, A.S., & BADAWY, M.I. (1978) Role of
absorbents in the removal of soluble aromatic hydrocarbons
from drinking-water. Water Res., 12: 1131-1137.
EL MASRY, A.M., SMITH, J.N., & WILLIAMS, R.T. (1956) Studies
in detoxication. The metabolism of alkylbenzenes,
n-propylbenzene, and n-butylbenzene with further observations
on ethylbenzene. Biochem. J., 64: 50-56.
ELOFSSON, S.A., GAMBERALE, F., HINDMARSH, T., IREGREN, A.,
ISAKSSON, A., JOHNSSON, I., KNAVE, B., LYDAHL, E., MINDUS, P.,
PERSSON, H.E., PHILIPSON, B., STEBY, M., STRUWE, G., SODERMAN,
E., WENNBERG, A., & WIDEN, L. (1980) Exposure to organic
solvents. A cross-sectional epidemiologic investigation on
occupationally-exposed car and industrial spray painters with
special reference to the nervous system. Scand. J. Work
environ. Health, 6: 239-273.
ELOVAARA, E., HEMMINKI, K., & VAINIO, H. (1979) Effects of
methylene chloride, trichoroethane, trichloroethylene,
tetrachloroethylene, and toluene on the development of chick
embryos. Toxicology, 12(2): 111-119.
ESCOBAR, A. & ARUFFO, C. (1980) Chronic thinner
intoxication: clinico-pathological report of a human case.
J. Neurol. Neurosurg. Psychiatr., 43: 986-994.
ESPOSITO, G.G. & JACOBB, B.W. (1977) Chromatographic
determination of aromatic hydrocarbons in ambient air.
Am. Ind. Hyg. Assoc. J., 38: 401-407.
EULER, H.H. (1967) [Animal experiments to investigate a
harmful industrial substance.] Arch. Gynaekol., 204: 258-259
(in German).
EVANS, E.L. & MITCHELL, A.D. (1980) An evaluation of the
effect of toluene on sister chromatid exchange frequencies in
cultured Chinese hamster ovary cells, Research Triangle Park,
North Carolina, US Environmental Protection Agency (Prepared
by SRI International, Menlo Park, California, Contract No.
68-02-2947).
FABRE, R., TRUHAUT, R., LAHAM, S., & PERON, M. (1955)
Recherches toxicologiques sur les solvants de remplacement du
benzène. II. Etude du toluène. Arch. Mal. prof. Méd. Trav.
Séc. soc., 16: 197-215.
FAILLACE, L.A. & GUYNN, R.W. (1976) Abuse of organic
solvents. Phychosomatics, 17(4): 188-189.
FEDERAL REGISTER (1979) Purgeable aromatics. Method 602.
Fed. Reg., 44(233): 69474-69478.
FELDT, E.G. & ZHURKOV, V.S. (1984) Study of the mutagenic
effects of benzene and toluene in the mammalian somatic and
germ cells. In: The 14th Annual Meeting of EEMS, Moscow, 1984,
pp. 163-164.
FERGUSON, T., HARVEY, W.F., & HAMILTON, T.D. (1933) An
enquiry into the relative toxicity of benzene and toluene.
Ind. Hyg., 33: 547-575.
FETT, E.R., CHRISTOFFERSEN, D.J., & SNYDER, L.R. (1968)
Routine determination of benzene, toluene, ethylbenzene and
total aromatics in hydrocarbon solvents by a combination of
liquid and gas chromatography. J. Gas Chromatogr., 6: 572-576.
FISCHMAN, C.M. & OSTER, J.R. (1979) Toxic effects of
toluene. A new cause of high anion gap metabolic acidosis.
J. Am. Med. Assoc., 241(16): 1713-1715.
FLUCK, E.R., POIRIER, L.A., & RUELIUS, H.W. (1976) Evalua-
tion of a DNA polymerase-deficient mutant of E. coli for the
rapid detection of carcinogens. Chem.-biol. Interact., 15:
219-231.
FODOR, G.C., SCHLIPKOETER, H.W., & ZIMMERMANN, M. (1973) The
objective study of sleeping behaviour in animals as a test of
behavioural toxicity. In: Adverse effects of environmental
chemicals and psychotropic drugs. Quantitative interpretation
of functional tests, Germany, Elsevier Scientific Publishers,
Vol. 1, pp. 115-123.
FORNAZZARI, L., WILKINSON, D.A., KAPUR, B.M., & CARLEN, P.L.
(1983) Cerebellar, cortical, and functional impairment in
toluene abusers. Acta neurol. Scand., 67: 319-329.
FORNI, A., PACIFICO, E., & LIMONTA, A. (1971) Chromosome
studies in workers exposed to benzene or toluene or both.
Arch. environ. Health, 22(3): 373-378.
FRACCHIA, M., PIERCE, L., GRAUL, R., & STANLEY, R. (1977)
Desorption of organic solvents from charcoal collection tubes.
Am. Ind. Hyg. Assoc. J., 38: 144-146.
FRANCHINI, I., CAVATORTA, A., FALZOI, M., LUCERTINI, S., &
MUTTI, A. (1983) Early indicators of renal damage in workers
exposed to organic solvents. Int. Arch. occup. environ.
Health, 52: 1-9.
FRASER, D.A. & RAPPAPORT, S. (1976) Health aspects of the
curing of synthetic rubbers. Environ. Health Perspect., 17:
45-53.
FREI, J.V. & KINGSLEY, W.F. (1968) Observations on
chemically-induced regressing tumours of mouse epidermis.
J. Natl Cancer Inst., 41(6): 1307-1313.
FREI, J.V. & STEPHENS, P. (1968) The correlation of
promotion of tumour growth and of induction of hyperplasia in
epidermal two-stage carcinogenesis. Br. J. Cancer, 22: 83-92.
FUNES-CRAVIOTO, F., ZAPATA-GAYON, C., KOLMODIN-HEDMAN, B.,
LAMBERT, B., LINDSTEN, J., NORBERG, E., NORDENSKJOLD, M.,
OLIN, R., & SWENSSON, A. (1977) Chromosome aberrations and
sister-chromatid exchange in workers in chemical laboratories
and a rotoprinting factory and in children of women laboratory
workers. Lancet, 13 August: 322-325.
FURNAS, D.W. & HINE, C.H. (1958) Neurotoxicity of some
selected hydrocarbons. Am. Med. Assoc. Arch. Ind. Health, 18:
9-15.
FUXE, K., LOFSTROM, A., HOKFELT, T., FERLAND, L., ANDERSSON,
K., AGNATI, L.F., ENEROTH, P., GUSTAFFSSON, J.A., & SKETT, P.
(1978) Influence of central catecholamines on LHRH-containing
pathways. Clin. Obstet. Gynaecol., 5(2): 251-256.
FUXE, K., ANDERSSON, K., NILSEN, O.G., TOFTGARD, R., ENEROTH,
P., & GUSTAFSSON, J.A. (1982) Toluene and telencephalic
dopamine: selective reduction of amine turnover in discrete DA
nerve terminal systems of the anterior caudate nucleus by low
concentrations of toluene. Toxicol. Lett., 12: 115-123.
GAD-EL-KARIM, M.M., HARPER, B.L., & LEGATOR, M.S. (1984)
Modifications in the myeloclastogenic effect of benzene in
mice with toluene, phenobarbital, 3-methylcholanthrene,
Aroclor 1254, and SKF-525A. Mutat. Res., 135: 225-243.
GAMBERALE, F. & HULTENGREN, M. (1972) Toluene exposure. II.
Psychophysiological functions. Work environ. Health, 9(3):
131-139.
GELLER, I., HARTMANN, R.J., RANDLE, S.R., & GAUSE, E.M.
(1979) Effects of acetone and toluene vapours on multiple
schedule performance of rats. Pharmacol. Biochem. Behav., 11:
395-399.
GELLMANN, V. (1968) Glue sniffing among Winnipeg School
children. Can. Med. Assoc. J., 98: 411-413.
GERARDE, H.W. (1960) Toxicology and biochemistry of aromatic
hydrocarbons, New York, Elsevier Publishing Co., pp. 141-150.
GIBSON, D.T. (1971) Microbial oxidation of aromatic
hydrocarbons. Crit. Rev. Microbiol., 1(2): 199-223.
GIBSON, J.E. & HARDISTY, J.F. (1983) Chronic toxicity and
oncogenicity bioassay of inhaled toluene in Fischer-344 rats.
Fundam. appl. Toxicol., 3: 315-319.
GOTO, I., MATSUMURA, M., INOUE, N., MURAI, Y., SHIDA, K.,
SANTA, T., & KUROIWA, Y. (1974) Toxic polyneuropathy due to
glue sniffing. J. Neurol. Neurosurg. Psychiatr., 37(7):
848-853.
GRABSKI, D.A. (1961) Toluene sniffing producing cerebellar
degeneration. Am. J. Psychiatr., 118: 461-462.
GRANT, W.M. (1962) Toxicology of the eye, Springfield,
Illinois, Charles C. Thomas, pp. 544-545.
GREENBURG, L., MAYERS, M.R., HEIMANN, H., & MOSKOWITZ, S.
(1942) The effects of exposure to toluene in industry.
J. Am. Med. Assoc., 118: 573-578.
GRIZZLE, P.L. & THOMSON, J.S. (1982) Liquid chromatographic
separation of aromatic hydrocarbons with chemically-bonded
(2,4-dinitroanilinopropyl) silica. Anal. Chem., 54: 1071-1078.
GROB, K. & GROB, G. (1971) Gas-liquid chromatographic/mass
spectrometric investigation of C6-C20 organic compounds in an
urban atmosphere. J. Chromatogr., 62: 1-13.
GROB, K. & ZURCHER, F. (1976) Stripping of trace organic
substances from water: equipment and procedure.
J. Chromatogr., 117: 285-294.
GUILLEMIN, M., MURSET, J.C., LOB, M., & RIQUEZ, J. (1974)
Simple method to determine the efficiency of a cream used for
skin protection against solvents. Br. J. ind. Med., 31(4):
310-316.
GUT, I. (1971) [The influence of toluene inhalation on the
metabolism of toluene, benzene, and hexobarbital in the rat
liver.] Cesk. Hyg., 16(6): 183-187 (in Czech).
GUT, I. (1983) Influence of frequently-used industrial
solvents and monomers of plastics on xenobiotic matabolism.
Zbl. Pharm., 122(11): 1139-1162.
GUT, I., KOPECKY, J., NERUDOVA, J., KRIVUCOVA, M., & PELECH,
L. (1981) Metabolic and toxic interactions of benzene and
acrylonitrile with organic solvents. In: Gut, I., Cikrt, M.,
& Plaa, G.L., ed. Industrial and environmental xenobiotics,
Berlin, New York, Springer-Verlag.
HAGLUND, U., LUNDBERG, I., & ZECH, L. (1980) Chromosome
aberrations and sister chromatid exchanges in Swedish paint
industry workers. Scand. J. Work environ. Health, 6: 291-298.
HANNINEN, H., ESKELINEN, L., HUSMAN, K., & NURMINEN, M.
(1976) Behavioral effects of long-term exposure to a mixture
of organic solvents. Scand. J. Work environ. Health, 4:
240-255.
HANSEN, N., JENSEN, V.B., APPELQUIST, J., & MORCH, E. (1978)
The uptake and release of petroleum hydrocarbons by the marine
mussel Mytilus edulis. Prog. Water Technol., 10(5-6): 351-359.
HANSEN, S.H. & DOSSING, M. (1982) Determination of urinary
hippuric acid and o-cresol, as indices of toluene exposure, by
liquid chromatography on dynamically-modified silica.
J. Chromatogr., 229: 141-148.
HASANEN, E., KARLSSON, V., LEPPAMAKI, E., & JUHALA, M.
(1981) Benzene, toluene, and xylene concentrations in car
exhausts and in city air. Atmos. Environ., 15(9): 1755-1757.
HAYDEN, J.W., PETERSON, R.G., & BRUCKNER, J.V. (1977)
Toxicology of toluene (methylbenzene): review of current
literature. Clin. Toxicol., 11(5): 549-559.
HELLIWELL, M. & MURPHY, M. (1979) Drug-induced neurological
disease (letter). Br. med. J., 1: 1283-1284.
HERSKOWITZ, A., ISHII, W., & SCHAUNBERG, H. (1971) n-hexane
neuropathy: a syndrome occurring as a result of industrial
exposure. N. Engl. J. Med., 285: 82-85.
HESTER, N.E. & MEYER, R.A. (1979) A sensitive technique for
measurement of benzene and alkylbenzenes in air. Environ. Sci.
Technol., 13(1): 107-109.
HISANAGA, N. & TAKEUCHI, Y. (1983) Changes in sleep cycle
and EEG of rats exposed to 4000 ppm toluene for four weeks.
Ind. Health, 21(3): 153-164.
HOFF, M.C. (1983) Toluene. In: Kirk-Othmer encyclopedia of
chemical technology, 3rd ed., New York, Chichester, John Wiley
& Sons, The Wiley Interscience Publication, Vol. 23,
pp. 246-273.
HOLLIFIELD, H.C., BREDER, C.V., DENNISON, J.L., ROACH, J.A., &
ADAMS, W.S. (1980) Container-derived contamination of maple
syrup with methyl methacrylate, toluene, and styrene as
determined by headspace gas-liquid chromatography. J. Assoc.
Off. Anal. Chem., 63: 173-177.
HOLMBERG, P.C. (1979) Central nervous system defects in
children born to mothers exposed to organic solvents during
pregnancy. Lancet, 8135: 177-179.
HOLZER, G., SHANFIELD, H., ZLATKIS, A., BERTSCH, W., JUAREZ,
P., MAYFIELD, H., & LIEBICH, H.M. (1977) Collection and
analysis of trace organic emissions from natural sources.
J. Chromatogr., 142: 755-764.
HONMA, T. (1983) Changes in acetylcholine metabolism in rat
brain after a short-term exposure to toluene and n-hexane.
Toxicol. Lett., 16: 17-22.
HONMA, T., MIYAGAWA, M., SATO, M., & HASEGAWA, H. (1982)
Increase in glutamine content of rat midbrain induced by
short-term exposure to toluene and hexane. Ind. Health, 20:
109-115.
HONMA, T., SUDO, A., MIYAGAWA, M., SATO, M., & HASEGAWA, H.
(1983) Significant changes in the amounts of neurotransmitter
and related substances in rat brain induced by subacute
exposure to low levels of toluene and xylene. Ind. Health, 21:
143-151.
HORIGUCHI, S. & INOUE, K. (1977) Effects of toluene on the
wheel-turning activity and peripheral blood findings in mice:
an approach to the maximun allowable concentration of toluene.
J. toxicol. Sci., 2(4): 363-372.
HUDAK, A. & UNGVARY, GY. (1978) Embryotoxic effects of
benzene and its methyl derivatives: toluene and xylene.
Toxicology, 11: 55-63.
HUDAK, A., BORS, Z., & UNGVARY, GY. (1975) Experimental
investigation of the hepatoxic effect of toluol. I. A
histological and histochemical study. Orsz. Munka - es
Uzemegeszs. Intez. exp. Pathol. Osztal., 15(3): 209-217.
HUDAK, A., RODICS, K., STUBER, I., & UNGVARY, GY. (1977) The
effects of toluene inhalation on pregnant CFY rats and their
offspring. Munkavedelem, 23(Suppl. 1-3): 25-30 (Report No.
TR-83-0061).
HUSMAN, K. & KARLI, P. (1980) Clinical neurological findings
among car painters exposed to a mixture of organic solvents.
Scand. J. Work environ. Health, 6: 33-39.
IKEDA, M. (1974) Reciprocal metabolic inhibition of toluene
and trichloroethylene in vivo and in vitro. Int. Arch.
Arbeitsmed., 33(2): 125-130.
IKEDA, T. & MIYAKE, H. (1978) Decreased learning in rats
following repeated exposure to toluene: preliminary report.
Toxicol. Lett., 1(4): 235-239.
IKEDA, M. & OHTSUJI, H. (1969) Significance of urinary
hippuric acid determination as an index of toluene exposure.
Br. J. ind. Med., 26(3): 244-246.
IKEDA, M. & OHTSUJI, H. (1971) Phenobarbital-induced
protection against toxicity of toluene and benzene in the rat.
Toxicol. appl. Pharmacol., 20(1): 30-43.
IKEDA, M., OHTSUJI, H., & IMAMURA, T. (1972) In vivo
supression of benzene and styrene oxidation by coadministered
toluene in rats and effects of phenobarbital. Xenobiotica,
2(2): 101-106.
IKEDA, T., MAEHARA, N., SADMOTO, T., HARABUCHI, I., YAMAMURA,
K., & MIYAKE, H. (1981) Effects of toluene exposure on the
rest-activity cycle of rats. Toxicol. Lett., 9(3): 255-266.
INOUE, T., TAKEUCHI, Y., HISANAGA, N., ONO, Y., IWATA, M.,
OGATA, M., SAITO, K., SAKURAI, H., HARA, I., MATSUSHITA, T., &
IKEDA, M. (1983) A nationwide survey on organic solvent
components in various solvent products. Part 1. Homogeneous
products such as thinners, degreasers, and reagents.
Ind. Health, 21: 175-183.
IREGREN, A. (1982) Effects on psychological test performance
of workers exposed to a single solvent (toluene): a comparison
with effects of exposure to a mixture of organic solvents.
Neurobehav. Toxicol. Teratol., 4: 695-701.
IRPTC (1982) In: Izmerov, N.F., Sanotsky, I.V., & Sidorov,
K.K., ed. Toxicometric parameters of industrial toxic
chemicals under single exposure, Moscow, GRNT, United Nations
Environment Programme Centre of International Projects,
pp. 111.
ISHIKAWA, T.T. & SCHMIDT, H., Jr (1973) Forced turning
induced by toluene. Pharmacol. Biochem. Behav., 1(5): 593-595.
IWATA, M., TAKEUCHI, Y., HISANAGA, N., & ONO, Y. (1983)
Changes of n-hexane metabolites in urine of rats exposed to
various concentrations of n-hexane and to its mixture with
toluene or MEK. Int. Arch. occup. environ. Health, 53: 1-8.
JAKOBSON, I., WAHLBERG, J.E., HOLMBERG, B., & JOHANSSON, G.
(1982) Uptake via the blood and elimination of 10 organic
solvents following epicutaneous exposure of anesthetized
guinea-pigs. Toxicol. appl. Pharmacol., 63: 181-187.
JENKINS, L.J., Jr, JONES, R.A., & SIEGEL, J. (1970)
Long-term inhalation screening studies of benzene, toluene,
o-xylene, and cumene on experimental animals. Toxicol. appl.
Pharmacol., 16: 818-823.
JERMINI, C., WEBER, A., & GRANDJEAN, E. (1976) Quantitative
determination of various gas-phase components of the
side-stream smoke of cigarettes in the room air as a
contribution to the problem of passive smoking. Int. Arch.
occup. environ. Health, 36: 169-181.
JOHANSSON, I. (1978) Determination of organic compounds in
indoor air with potential reference to air quality. Atmos.
Environ., 12: 1371-1377.
JUNGCLAUS, G.A., GAMES, L.M., & HITES, R.A. (1976)
Identification of trace organic compounds in tire
manufacturing plant wastewaters. Anal. Chem., 48(13):
1894-1896.
JUNGCLAUS, G.A., LOPEZ-AVILA, V., & HITES, R.A. (1978)
Organic compounds in an industrial wastewater: a case study of
their environmental impact. Environ. Sci. Technol., 12(1):
88-96.
KAPLAN, D.L. & HARTENSTEIN, R. (1979) Problems with toluene
and the determination of extracellular enzyme activity in
soils. Soil Biol. Biochem., 11: 335-338.
KATZ, M. (1969) Measurement of air pollutants. Guide to the
selection of methods, Geneva, World Health Organization.
KAUBISCH, N., DALY, J.W., & JERINA, D.M. (1972) Arene oxides
as intermediates in the oxidative metabolism of aromatic
compounds. Isomerization of methyl-substituted arene oxides.
Biochemistry, 11(16): 3080-3088.
KAWAI, T., HORIGUCHI, S., & TERAMOTO, K. (1984) Toluene
exposure and urine hippuric acid, cresol, and phenol levels in
workers of vinyl shoe factories. J. Sci. Lab., 60(3; Part 2):
23-29.
KEANE, J.R. (1978) Toluene optic neuropathy. Ann. Neurol.,
4(4): 390.
KELLY, C.T.W. (1975) Prolonged cerebellar dysfunction
associated with paint sniffing. Pediatrics, 56: 605-606.
KEPLINGER, M.L., LANIER, G.E., & DEICHMANN, W.B. (1959)
Effects of environmental temperature on the acute toxicity of
a number of compounds in rats. Toxicol. appl. Pharmacol., 1:
156-161.
KIMURA, E.T., EBERT, D.M., & DODGE, P.W. (1971) Acute
toxicity and limits of solvent residue for sixteen organic
solvents. Toxicol. appl. Pharmacol., 19(4): 699-704.
KIMURA, T., SUZUKI, T., TANAKA, M., & TAKASU, K. (1982) [A
case of cerebellar ataxia with optic neuropathy from toluene
sniffing.] Clin. Neurol. (Rinsho Shinkei), 16: 79-81 (in
Japanese).
KING, M.D. (1982) Neurological sequelae of toluene abuse.
Human Toxicol., 1: 281-287.
KING, M.D., DAY, R.E., OLIVER, J.S., LUSH, M., & WATSON, J.M.
(1981) Solvent encephalopathy. Br. Med. J., 283: 663-665.
KIRKHART, B. (1980) Micronucleus test on toluene, Research
Triangle Park, North Carolina, US Environmental Protection
Agency (Prepared by SRI International, Menlo Park, California,
Contract No. 68-02-2947).
KNOX, J.W. & NELSON, J.R. (1966) Permanent encephalopathy
from toluene inhalation. N. Engl. J. Med., 275: 1494-1496.
KOLEKOVSKY, P. (1967) [A new colour reaction for the vapour
of some aromatic hydrocarbons.] Soviet J. anal. Chem., 22:
403-404 (in Russian).
KORN, S., MOLES, D.A., & RICE, S.D. (1979) Effects of
temperature on the median tolerance limit of pink salmon and
shrimp exposed to toluene, naphthalene, and Cook Inlet crude
oil. Bull. environ. Contam. Toxicol., 21(4-5): 521-525.
KOROBKIN, R., ASBURY, A.K., SUMNER, A.J., & NIELSEN, S.L.
(1975) Glue sniffing neuropathy. Arch. Neurol., 32: 158-162.
KORPELA, M., VAPAATALO, H., & TAHTI, H. (1983) Effect of
toluene on the hemolytic resistance of rat erythrocytes.
Toxicol. Lett., 17: 253-257.
KOSTAS, J. & HOTCHIN, J. (1981) Behavioral effects of
low-level perinatal exposure to toluene in mice. Neurobehav.
Toxicol. Teratol., 3(4): 467-469.
KOWAL-GIERCZAK, B., KUCZYNSKA-SEKIETA, K., CIESLINSKA, A.,
WRZYSZCZ, M., & MALOLEPSZY, J. (1969) [Some biochemical
tests in subjects occupationally exposed to toluene.]
Pol. Tyg. Lek., 24: 1682-1685 (in Polish).
KRIVANEK, N. & MULLIN, L.S. (1978) Comparison of conditioned
avoidance and unconditioned reflex tests in rats exposed by
inhalation to carbon monoxide, 1,1,1-trichloroethane, toluene,
or ethanol. Toxicol. appl. Pharmacol., 45(1): 357-358.
KROEGER, R.M., MOORE, R.J., LEHMAN, T.H., GIESY, J.D., &
SKEETERS, C.E. (1980) Recurrent urinary calculi associated
with toluene sniffing. J. Urol., 123(1): 89-91.
KRONEVI, T., WAHLBERG, J., & HOLMBERG, B. (1979)
Histopathology of skin, liver, and kidney after epicutaneous
administration of five industrial solvents to guinea-pigs.
Environ. Res., 19(1): 56-69.
KROST, K.J., PELLIZZARI, E.D., WALBURN, S.G., & HUBBARD, S.A.
(1982) Collection and analysis of hazardous organic
emissions. Anal. Chem., 54: 810-817.
KUMAI, M., KOIZUMI, A., SAITO, K., SAKURAI, H., INOUE, T.,
TAKEUCHI, Y., HARA, I., OGATA, M., MATSUSHITA, T., & IKEDA,
M. (1983) A nationwide survey on organic solvent components
in various solvent products. Part 2. Heterogeneous products
such as paints, inks and adhesives. Ind. Health, 21: 185-197.
LAHMANN, E., SEIFERT, B., & ULLRICH, D. (1977) The pollution
of ambient air and rain water by organic components of motor
vehicle exhaust-gases. In: Proceedings of the 4th
International Clean Air Congress, pp. 595-597.
LAZAR, R.B., HO, S.U., MELEN, O., & DAGHESTANI, A.N. (1983)
Multifocal central nervous system damage caused by toluene
abuse. Neurology, 33: 1337-1340.
LEONARD, M.J., FISHER, E.L., BRUNELLE, M.F., & DICKINSON, J.E.
(1976) Effects of the motor vehicle control program on
hydrocarbons in the central Los Angeles atmosphere. J. Air
Pollut. Contr. Assoc., 26(4): 359-363.
LEWIS, P.W. & PATTERSON, D.W. (1974) Acute and chronic
effects of the voluntary inhalation of certain commercial
volatile solvents by juveniles. J. Drug Issues, 4(2): 162-175.
LEWIS, J.D., MORITZ, D., & MELLIS, L.P. (1981) Long-term
toluene abuse. Am. J. Psychiatr., 138(3): 368-370.
LIJINSKY, W. & GARCIA, H. (1972) Skin carcinogenesis tests
of hydrogenated derivatives of anthanthrene and other
polynuclear hydrocarbons. Z. Krebsforsch., 77: 226-230.
LINDER, R.L., LERNER, S.E., & WESSON, D.R. (1975) Solvent
sniffing: a continuing problem among youth. Proc. West
Pharmacol. Soc., 18: 371-374.
LINDSTROM, K. (1973) Psychological performance of workers
exposed to various solvents. Work Environ., 10(3): 151-155.
LINDSTROM, K. (1982) Behavioral effects of long-term
exposure to organic solvents. Occup. Neurol. Acta neurol.
Scand., 66(suppl. 92): 131-141.
LINGG, R.D., MELTON, R.G., KOPFLER, F.C., COLEMAN, W.E., &
MITCHELL, D.E. (1977) Quantitative analysis of volatile
organic compounds by GC-MS. J. Am. Water Works Assoc., 69(11):
605-612.
LITT, I.F., COHEN, M.I., SCHONBERG, S.K., & SPIGLAND, I.
(1972) Liver disease in the drug-using adolescent.
J. Pediatr., 81: 238-242.
LITTON BIONETICS, INC. (1978a) Mutagenicity evaluation of
toluene, Kensington, Maryland, Litton Bionetics, Inc, 150 pp
(Final Report submitted to the American Petroleum Institute,
Washington DC, May 1978) (LBI Project No. 29847).
LITTON BIONETICS, INC. (1978b) Teratology study in rats.
Toluene, Kensington, Maryland, Litton Bionetics, Inc, 17 pp
(Final Report submitted to the American Petroleum Institute,
Washington DC, January 1978) (LBI Project No. 20698-4).
LITTON BIONETICS, INC. (1981) Mutagenicity evaluation of
toluene. Mouse dominant lethal assay, Kensington, Maryland,
Litton Bionetics, Inc, 15 pp (Final Report submitted to the
American Petroleum Institute, Washington DC, January 1981)
(LBI Project No. 21141-05).
LONGLEY, E.O., JONES, A.T., WELCH, R., & LOMAEV, O. (1967)
Two acute toluene episodes in merchant ships. Arch. environ.
Health, 14: 481-487.
LONNEMAN, W.A., BELLAR, T.A., & ALTSHULLER, A.P. (1968)
Aromatic hydrocarbons in the atmosphere of the Los Angeles
Basin. Environ. Sci. Technol., 2(11): 1017-1020.
LURIE, J.B. (1949) Acute toluene poisoning. S. Afr. med. J.,
23: 233-236.
LYAPKALO, A.A. (1973) [Genetic activity of benzene and
toluene.] Gig. Tr. Prof. Zabol., 17(3): 24-28 (in Russian).
MACKAY, D. & LEINONEN, P.J. (1975) Rate of evaporation of
low-solubility contaminants from water bodies to atmosphere.
Environ. Sci. Technol., 9: 1178-1180.
MACKAY, D. & WOLKOFF, A.W. (1973) Rate of evaporation of
low-solubility contaminants from water bodies to atmosphere.
Environ. Sci. Technol., 7(7): 611-614.
MCLAUGHLIN, R.S. (1946) Chemical burns of the human cornea.
Am. J. Ophthalmol., 29(11): 1355-1362.
MCLAUGHLIN, J., MARLIAC, J.P., VERRETT, M.J., MUTCHLER, M.K.,
& FITZHUGH, O.G. (1964) Toxicity of fourteen volatile
chemical as measured by the chick embryo method. Am. Ind. Hyg.
Assoc. J., 25: 282-284.
MAEDA, K. (1970) Effects of toluene on higher nervous
functions of rats. I. Effects of toluene exposure on
conditioned behaviour of rats. Jpn J. ind. Health, 12: 517-523.
MAFFETT, P.A., DOHERT, T.F., & MONKMAN, J.L. (1956) A direct
method for the collection and determination of micro amounts
of benzene or toluene in air. Am. Ind. Hyg. Assoc. Q, 17:
186-188.
MAKI-PAAKKANEN, J., HUSGAFVEL-PURSIAINEN, K., KALLIOMAKI,
P.-L., TUOMINEN, J., & SORSA, M. (1980) Toluene-exposed
workers and chromosome aberrations. J. Toxicol. environ.
Health, 6: 775-781.
MAKI-PAAKKANEN, J., SORSA, M. & VAINIO, H. (1984) Sister
chromatid exchanges and chromosome aberrations in rubber
workers. Teratog. Carcinog. Mutag., 4: 189-200.
MALM, G. & LYING-TUNELL, U. (1980) Cerebellar dysfunction
related to toluene sniffing. Acta. neurol. Scand., 62: 188-190.
MALTEN, K.E., SPRUIT, D., & DeKEIZER, M.J.M. (1968) Horny
layer injury by solvents. Berufsdermatosen, 16(3): 135-147.
MALTONI, C., CONTI, B., & COTTI, G. (1983) Benzene: a
multipotential carcinogen. Results of long-term bioassays
performed at the Bologna Institute of Oncology. Am. J. ind.
Med., 4: 589-630.
MASSENGALE, O.N., GLASER, H.H., LELIEVRE, R.E., DODDS, J.B., &
KLOCK, M.E. (1963) Physical and psychological factors in
glue sniffing. N. Engl. J. Med., 269(25): 1340-1344.
MATSUMOTO, T., TAKEUCHI, Y., TANAKA, T., & MAEDA, K. (1971)
[Experimental studies on the chronic toluene poisoning. III.
Effects of toluene exposure on blood and organs in the rats.]
Sangyo Igaku. Jpn J. ind. Health, 13: 501-506 (in Japanese
with English summary).
MATSUSHITA, T. (1966) A study on the blood findings in toluel
poisoning: appearance of Mommsen's toxic granules in
neutrophile leucocytes. Jpn J. ind. Health, 8: 239-248.
MATSUSHITA, T., WHITE, K.P., & SNEOKA, N. (1971) Chromosome
replication in coluenized Bacillus subtilis cells. Nature (New
Biol.), 232: 111-114.
MATSUSHITA, T., ARIMATSU, Y., UEDA, A., SATOH, K., & NOMURA,
S. (1975) Hematological and neuromuscular response of
workers exposed to low concentration of toluene vapor.
Ind. Health, 13: 115-121.
MAY, J. (1966) Odour thresholds of solvents for assessment
of solvent odors in the air. Staub., 26(9): 24-28.
MAYNARD, D.J. & WEBER, D.D. (1981) Avoidance reactions of
juvenile coho salmon (Oncorhynchus kisutch) to monocyclic
aromatics. Can. J. Fish aquat. Sci., 38(7): 772-778.
MAYRSOHN, H., KURAMOTO, M., CRABTREE, J.H., SOLTERM, R.D., &
MANO, S.H. (1976) Atmospheric hydrocarbon concentrations,
June-September 1975, State of California Air Resources Board,
January 1976.
METRICK, S.A. & BRENNER, R.P. (1982) Abnormal brainstem
auditory evoked potentials in chronic pain sniffers.
Ann. Neurol., 12(6): 553-556.
MICHON, S. (1965) [Disturbance of menstruation in women
working in an atmosphere polluted with aromatic hydrocarbons.]
Pol. Tyg. Lek., 20: 1547-1649 (in Polish).
MOLES, A., BATES, S., RICE, S.D., & KORN, S. (1981) Reduced
growth of Coho salmon fry exposed to two petroleum components,
toluene and naphthalene in fresh water. Trans. Am. Fish. Soc.,
110(3): 430-436.
MORTELMANS, K.E. & RICCIO, E.S. (1980) In vitro
microbiological genotoxicity assays of toluene, Research
Triangle Park, North Carolina, US Environmental Protection
Agency (Prepared by SRI International, Menlo Park, California,
Contract No. 68-02-2947).
MORVAI, V. & UNGVARY, GY. (1979) Effects of simultaneous
alcohol and toluene poisoning on the cardiovascular system of
rats. Toxicol. appl. Pharmacol., 50(3): 381-389.
MORVAI, V., HUDAK, A., UNGVARY, GY., & VARGA, U.B. (1976)
ECG changes in benzene-, toluene-, and xylene-poisoned rats.
Acta med. Acad. Scientiarum Hung. tomus., 33(3): 275-286.
MOSER, V.C. & BALSTER, R.L. (1981) The effects of acute and
repeated toluene exposure on operant behavior in mice.
Neurobehav. Toxicol. Teratol., 3(4): 471-475.
MOSS, A.H., GABOW, P.A., KAEHNY, W.D., GOODMAN, S.I., & HAUT,
L.L. (1980) Fanconi's syndrome and distal renal tubular
acidosis after glue sniffing. Ann. intern. Med., 92(1): 69-70.
MULLIN, L.S. & KRIVANEK, N.D. (1982) Comparison of
unconditioned reflex and conditioned avoidance tests in rats
exposed by inhalation to carbon monoxide, 1,1,1-trichloro-
ethane, toluene, or ethanol. Neurotoxicology, 3: 126-137.
MUNGIKAR, A.M. & PAWAR, S.S. (1976a) Hepatic microsomal
mixed-function oxidase system during toluene treatment and the
effect of pretreatment of phenobarbital in adult rats. Bull.
environ. Contam. Toxicol., 15(2): 198-204.
MUNGIKAR, A.M. & PAWAR, S.S. (1976b) The effect of toluene,
phenobarbital, and 3-methylcholanthrene on hepatic microsomal
lipid peroxidation. Curr. Sci., 45(1): 22-24.
NAKAGAKI, K., ARITO, H., & TSURUTA, H. (1983) Changes in
sleep-waking rhythms of rats following a single injection of
toluene. Ind. Health, 21: 165-174.
NAWROT, P.S. & STAPLES, R.E. (1979) Embryo-fetal toxicity
and teratogenicity of benzene and toluene in the mouse.
Teratology, 19: 41A (abstract).
NELIGAN, R.E., LEONARD, M.J., & BRYAN, R.J. (1965) The gas
chromatographic determination of aromatic hydrocarbons in the
atmosphere. Presented to the Division of Water, Air, and Waste
Chemistry, Atlantic City, New Jersey, American Chemical
Society, September 12-17, 1965.
NESTMANN, E.R., LEE, E.G.-H., MATULA, T.I., DOUGLAS, G.R., &
MUELLER, J.C. (1980) Mutagenicity of constituents identified
in pulp and paper mill effluent using the Salmonella/
mammalian microsome assay. Mutat. Res., 79: 203-212.
NOMIYAMA, K. & NOMIYAMA H. (1974a) Respiratory retention,
uptake, and excretion of organic solvents in man. Benzene,
toluene, n-hexane, trichloroethylene, acetone, ethyl acetate,
and ethyl alcohol. Int. Arch. Arbeitsmed., 32(1-2): 75-83.
NOMIYAMA, K., & NOMIYAMA, H. (1974b) Respiratory elimination
of organic solvents in man. Benzene, toluene, n-hexane,
trichloroethylene, acetone, ethyl acetate, and ethyl alcohol.
Int. Arch. Arbeitsmed., 32(1-2): 85-91.
NOMIYAMA, K. & NOMIYAMA, H. (1978) Three fatal cases of
thinner-sniffing, and experimental exposure to toluene in
humans and animals. Int. Arch. occup. environ. Health, 41(1):
55-64.
OBE, G., VOGT, H-J., MADLE, S., FAHNING, A., & HELLER, W.D.
(1982) Double-blind study on the effect of cigarette smoking
on the chromosomes of human peripheral blood lymphocytes in
vivo. Mutat. Res., 92: 309-319.
O'BRIEN, E.T., YEOMAN, W.B., & HOBBY, J.A.E. (1971)
Hepatorenal damage from toluene in a "glue sniffer". Br. med.
J., 2: 29-30.
OGATA, M. & FUJII, T. (1979) Urinary excretion of hippuric
acid and m-methylhippuric acid after administration of toluene
and m-xylene mixture to rats. Int. Arch. occup. environ.
Health, 43(1): 45-51.
OGATA, M. & MIYAKE, Y. (1973) Identification of substances
in petroleum causing objectionable odour in fish. Water Res.,
7: 1493-1504.
OGATA, M. & MIYAKE, Y. (1978) Disappearance of aromatic
hydrocarbons and organic sulfer compounds from fish flesh
reared in crude oil suspension. Water Res., 12(12): 1041-1044.
OGATA, M., TOMOKUNI, K., & TAKATSUKA, Y. (1970) Urinary
excretion of hippuric acid and m- or p-methylhippuric acid in
the urine of persons exposed to vapours of toluene and m- or
p-xylene as a test of exposure. Br. J. ind. Med., 27(1):
43-50.
OGATA, M., TAKATSUKA, Y., & TOMOKUNI, K. (1971) Excretion of
hippuric acid and m- or p-methylhippuric acid in the urine of
persons exposed to vapours of toluene and m- or p-xylene in an
exposure chamber and in workshops, with specific reference to
repeated exposures. Br. J. ind. Med., 28(4): 382-385.
OGATA, M., SAEKI, T., KIRA, S., HASEGAWA, T., & WATANABE, S.
(1974) Distribution of toluene in mouse tissues. Jpn. J. ind.
Health, 16: 23-25.
OLIVER, J.S. (1982) The analytical diagnosis of solvent
abuse. Human Toxicol., 1: 293-297.
OLIVER, J.S. & WATSON, J.M. (1977) Abuse of solvents "for
kicks": a review of 50 cases. Lancet, 9: 84-86.
OTSUN, R., WILLIAMS, D.T., & BOTHWELL, P.D. (1980) Volatile
organic compounds in water at thirty Canadian potable water
treatment facilities. J. Assoc. Off. Anal. Chem., 65:
1370-1374.
OVRUM, P., HULTENGREN, M., & LINDQUIST, T. (1978) Exposure
to toluene in a photogravure printing plant. Concentration in
ambient air and uptake in the body. Scand. J. Work environ.
Health, 4(3): 237-245.
PAGNOTTO, L.D. & LIEBERMAN, L.M. (1967) Urinary hippuric
acid excretion as an index of toluene exposure. Am. Ind. Hyg.
Assoc. J., 28: 129-134.
PAKSY, K.A., MOLNAR, J., NARAY, M., & BARCZA, G. (1982)
Comparative study on the acute effects of benzene, toluene,
and m-xylene in the rat. Acta physiol. Acad. Sci. Hung. tomus,
59(4): 317-324.
PARMEGGIANI, L. & SASSI, C. (1954) [Occupational hazard from
toluene: environmental investigations and clinical research in
chronic poisoning.] Med. Lav., 45: 574-583 (in Italian with
English summary).
PAWAR, S.S., MUNGIKAR, A.M., & MAKHIJA, S.J. (1976)
Phenobarbital-induced effect on pulmonary and hepatic
microsomal ethylmorphine N-demethylase and lipid peroxidation
during intoxication of organic solvents in rats. Bull.
environ. Contam. Toxicol., 15(3): 357-365.
PELLIZZARI, E.D. (1979) Information on the characterization
of ambient organic vapors in areas of high chemical pollution,
Research Triangle Park, North Carolina, US Environmental
Protection Agency, Health Effects Research Laboratory
(Contract No. 68-02-27213).
PELLIZZARI, E.D., HARTWELL, T.D., HARRIS, B.S.H., WADDELL,
R.D., WHITAKER, D.A., & ERICKSON, M.D. (1982) Purgeable
organic compounds in mother's milk. Bull. environ. Contam.
Toxicol., 28: 322-328.
PERBELLINI, L., LEONE, R., FRACASSO, M.E., BRUGNONE, F., &
VENTURINI, M.S. (1982) Metabolic interaction between
n-hexane and toluene in vivo and in vitro. Int. Arch. occup.
environ. Health, 50: 351-358.
PERRY, R.A., ATKINSON, R., & PITTS, J.N., Jr (1977) Kinetics
and mechanism of the gas phase reaction of OH radicals with
aromatic hydrocarbons over the temperature range 296-473 K.
J. Phys. Chem., 81(4): 296-403.
PETERSON, R.G. & BRUCKNER, J.V. (1978) Measurement of
toluene levels in animal tissues. In: Sharp, C.W. & Carrol,
L.T., ed. Voluntary inhalations of industrial solvents,
Rockville, Maryland, National Institute on Drug Abuse,
pp. 333-342.
PFAFFLI, P., SAVOLAINEN, H., KALLIOMAKI, P.L., & KALLIOKOSKI,
P. (1979) Urinary o-cresol in toluene exposure. Scand. J.
Work environ. Health, 5(3): 286-289.
PILAR, S. & GRAYDON, W.F. (1973) Benzene and toluene
distribution in Toronto atmosphere. Environ. Sci. Technol.,
7(7): 628-631.
PIOTROWSKI, J.K. (1967) Quantitative estimate of the
absorption of toluene in people. Med. Prac., 18: 214-223.
POEL, W.E. (1963) Skin as a test site for the bioassay of
carcinogens and carcinogen precursors. Conference on the
Biology of Cutaneous Cancer. Natl Cancer Inst. Monogr., 10:
611-625.
POGGI, G., GIUSIANI, M., PALAGI, U., PAGGIARO, P.L., LOI,
A.M., DAZZI, F., SIELARI, G., & BASCHIERI, L. (1982)
High-performance liquid chromatography for the quantitative
determination of the urinary metabolites of toluene, xylene,
and styrene. Int. Arch. occup. environ. Health, 50: 25-31.
POTERA, G.T. (1975) The effects of benzene, toluene, and
ethyl benzene on several important members of the estuarine
ecosystem. Diss. Abstr. B., 36(5): 2010.
POWARS, D. (1965) Aplastic anaemia secondary to glue
sniffing. N. Engl. J. Med., 273: 700-702.
PREMEL-CABIC, A., CAILLEUX, A., & ALLAIN, P. (1974)
Identification et dosage par chromatographie en phase gazeuse
de quinze solvants organiques dans le sang. Clin. Chim. Acta.,
56: 5-11.
PRESS, E. & DONE, A.K. (1967a) Solvent sniffing. I.
Physiologic effects and community control measures for
intoxication from the intentional inhalation of organic
solvents. Pediatrics, 39(3): 451-461.
PRESS, E. & DONE, A.K. (1967b) Solvent sniffing. II.
Physiologic effects and community control measures for
intoxication from the intentional inhalation of organic
solvents. Pediatrics, 39(4): 611-622.
PRICE, K.S., WAGGY, G.T., & CONWAY, R.A. (1974) Brine shrimp
bioassay and seawater BOD of petrochemicals. J. Water Pollut.
Contr. Fed., 46(1): 63-77.
PROCKOP, L.D. (1977) Multifocal nervous system damage from
inhalation of volatile aromatic hydrocarbons. J. occup. Med.,
19: 139-140.
PRYOR, G.T., HOWD, R.A., MALIK, R., & REBERT, C.S. (1978)
Biomedical studies on the effects of abused inhalant mixtures,
Rockville, Maryland, National Institute on Drug Abuse (Annual
Progress Report No. 2, Contract No. 271-77-3402).
PYYKKO, K. (1980) Effects of methylbenzenes on microsomal
enzymes in rat liver, kidney, and lung. Biochim. Biophys.
Acta, 633: 1-9.
PYYKKO, K. (1983) Age- and sex-related differences in rat
liver microsomal enzymes and their inducibility by toluene.
Acta pharmacol. toxicol., 53(5): 401-409.
PYYKKO, K., TAHTI, H., & VAPAATALO, H. (1977) Toluene
concentrations in various tissues of rats after inhalation and
oral administration. Arch. Toxicol., 38: 169-176.
QUICK, A.J. (1931) The conjugation of benzoic acid in the
urine. J. Biol. Chem., XCII(1): 65-85.
RADZIKOWSKA-KINTZI, H. & JAKUBOWSKI, M. (1981) Internal
standardization in the head space analysis of organic solvents
in blood. Int. Arch. occup. environ. Health, 49: 115-123.
RASMUSSEN, R.A. & KHALIL, M.A.K. (1983) Atmospheric benzene
and toluene. Geophys. Res. Lett., 10(11): 1096-1099.
RAWLINGS, G.D. & SAMFIELD, M. (1979) Textile plant
wastewater toxicity. Environ. Sci. Technol., 13(2): 160-164.
REA, T.M., NASH, J.F., ZABIK, J.E., BORN, G.S., & KESSLER,
W.V. (1984) Effects of toluene inhalation on brain biogenic
amines in the rat. Toxicology, 31: 143-150.
REID, F.H. & HALPIN, W.R. (1968) Determination of
halogenated and aromatic hydrocarbons in air by charcoal tube
and gas chromatography. Am. Ind. Hyg. Assoc. J., 29(4): 390-
396.
REISIN, E., TEICHER, A., JAFFE, R., & ELIAHOU, H.E. (1975)
Myoglobinuria and renal failure in toluene poisoning.
Br. J. ind. Med., 32(2): 163-164.
REYNOLDS, E.S. (1972) Comparison of early injury to liver
endoplasmic reticulum by halomethanes, hexachloroethane,
benzene, toluene, bromobenzene, ethionine, thioacetamide, and
dimethylnitrosamine. Biochem. Pharmacol., 21(19): 2555-2561.
RIIHIMAKI, V. (1979) Conjugation and urinary excretion of
toluene and m-xylene metabolites in a man. Scand. J. Work
environ. Health, 5(2): 135-142.
RIIHIMAKI, V. & PFAFFLI, P. (1978) Percutaneous absorption
of solvent vapors in man. Scand. J. Work environ. Health,
4(1): 73-85.
ROUBAL, W.T., STRANAHAM, S.I., & MALIN, D.C. (1978) The
accumulation of low molecular weight aromatic hydrocarbons of
crude oil by Coho salmon (Oncorhynchus kisutch) and starry
flounder (Platichthys stellatus). Arch. environ. Toxicol., 7:
237-244.
ROUSKOVA, V. (1975) Photic stimulation in early diagnosis of
the effects of some harmful industrial substances on the
central nervous system. Int. Arch. Arbeitsmed., 34(4): 283-299.
RTECS (1984) Registry of toxic effects of chemical
substances, National Institute for Occupational Safety and
Health, US Department of Health and Human Services (RTECS
Microfiche Quarterly Complete File, October 1984).
RUSS, G., CLARKSON, A.R., WOODROFFE, A.J., SEYMOUR, A.E., &
CHENG, I.K.P. (1981) Renal failure from "glue sniffing".
Med. J. Aust., 2: 121-122.
RYAN, J.P. & FRITZ, J.S. (1978) Determination of trace
organic impurities in water using thermal desorption from XAD
resin. J. chromatogr. Sci., 16: 488-492.
SASA, M., IGARASHI, S., MIYAZAKI, T., MIYAZAKI, K., NAKANO,
S., & MATSUOKA, I. (1978) Equilibrium disorders with diffuse
brain atrophy in long-term toluene sniffing. Arch.
Otorhinolaryngol., 221(3): 163-169.
SATO, A. & NAKAJIMA, T. (1978) Differences following skin or
inhalation exposure in the absorption and excretion kinetics
of trichloroethylene and toluene. Br. J. ind. Med., 35: 43-49.
SATO, A. & NAKAJIMA, T. (1979a) Partition coefficients of
some aromatic hydrocarbons and ketones in water, blood, and
oil. Br. J. ind. Med., 36(3): 231-234.
SATO, A. & NAKAJIMA, T. (1979b) Dose-dependent metabolic
interaction between benzene and toluene in vivo and in vitro.
Toxicol. appl. Pharmacol., 48(2): 249-256.
SATO, A., FUJIWARA, Y., & NAKAJIMA, T. (1974a) Solubility of
benzene, toluene, and m-xylene in various body fluids and
tissues of rabbits. Jpn. J. ind. Health, 16(1): 30-31.
SATO, A., NAKAJIMA, T., FUJIWARA, Y., & HIROSAWA, K. (1974b)
Pharmacokinetics of benzene and toluene. Int. Arch.
Arbeitsmed., 33(3): 169-182.
SATO, A., NAKAJIMA, T., & KOYAMA, Y. (1981) Dose-related
effects of single dose of ethanol on the metabolism in rat
liver of some aromatic and chlorinated hydrocarbons. Toxicol.
appl. Pharmacol., 60: 8-15.
SATRAN, R. & DODSON, V.N. (1963) Toluene habituation. Report
of a case. N. Engl. J. Med., 268(13): 719-721.
SAUER, T.C., Jr, SACKETT, W.M., & JEFFREY, L.M. (1978)
Volatile liquid hydrocarbons in the surface water of the Gulf
of Mexico. Mar. Chem., 7: 1-16.
SAUNDERS, R.A., BLACHLY, C.H., KORACINA, R.A., LAMONTAGNE,
R.A., SWINNERTON, J.W., & SAAFELD, F.E. (1975)
Identification of volatile organic contaminants in Washington
DC municipal water. Water Res., 99: 1143-1145.
SAVOLAINEN, H. (1978) Distribution and nervous system
binding of intraperitoneally-injected toluene. Acta pharmacol.
toxicol., 43(1): 78-80.
SCHIKLER, K.N., SEITZ, K., RICE, J.F., & STRADER, T. (1982)
Solvent abuse associated cortical atrophy. J. Adolescent
Health Care, 3: 37-39.
SCHNEIDER, W., FROHNE, J.C., & BRUDERRECK, H. (1978)
Determination of hydrocarbons in the parts per 109 range using
glass capillary columns coated with aluminum oxide.
J. Chromatogr., 155: 311-327.
SCHMID, E. & BAUCHINGER, M. (1984) Recovery of the
chromosomal changes enduced by occupational toluene exposure.
In: The 14th Annual Meeting of EEMS, Moscow, 1984, pp. 440-441.
SEIFERT, B. & ABRAHAM, H.-J. (1982) Indoor air
concentrations of benzene and some other aromatic
hydrocarbons. Ecotoxicol. environ. Saf., 6: 190-192.
SEIFERT, B. & ABRAHAM, H.-J. (1983) Use of passive samplers
for the determination of gaseous organic substances in indoor
air at low concentration levels. Intern. J. environ. anal.
Chem., 13: 237-253.
SEPPALAINEN, A.M. (1982) Neurophysiological findings among
workers exposed to organic solvents. Acta neurol. Scand.,
66(Suppl. 92): 109-116.
SEPPALAINEN, A.M., HUSMAN, K., & MARTENSON, C. (1978)
Neurophysiological effects of long-term exposure to a mixture
of organic solvents. Scand. J. Work environ. Health, 4(4):
304-314.
SEXTON, K. & WESTBERG, H. (1980) Ambient hydrocarbon and
ozone measurements downwind of a large automotive painting
plant. Environ. Sci. Technol., 14(3): 329-332.
SHERWOOD, R.J. (1976) Ostwald solubility coefficients of
some industrially important substances. Br. J. ind. Med.,
33(2): 106-107.
SHIGETA, S., AIKAWA, H., MISAWA, T., & KONDO, A. (1978)
Effect of single exposure to toluene on Sidman avoidance
response in rats. J. toxicol. Sci., 3(4): 305-312.
SHIGETA, S., AIKAWA, H., & MISAWA, T. (1982) Effects of
maternal exposure to toluene during pregnancy on mouse embryos
and fetuses. Tokai J. exp. clin. Med., 7(2): 265-270.
SHIRABE, T., TSUDA, T., TERAO, A., & ARAKI, S. (1974) Toxic
polyneuropathy due to glue sniffing: report of two cases with
a light and electron-microscopic study of the peripheral
nerves and muscles. J. neurol. Sci., 21(1): 101-113.
SLOOF, W. (1979) Detection limits of a biological monitoring
system based on fish respiration. Bull. environ. Contam.
Toxicol., 23: 517-523.
SMITH, J.N., SMITHIES, R.H., & WILLIAMS, R.T. (1954) Studies
in detoxication. 55. The metabolism of alkylbenzenes. (a)
Glucuronic acid excretion following the administration of
alkylbenzenes. (b) Elimination of toluene in the expired air
of rabbits. Biochem. J., 56: 317-320.
SMITH, R.V. & ROSAZZA, J.P. (1974) Microbial models of
mammalian metabolism. Aromatic hydroxylation. Arch. Biochem.
Biophys., 161: 551-558.
SMOYER, J.C., SHAFFER, D.C., & DeWITT, I.L. (1971) A
programme to sample and analyse air pollution in the vicinity
of a chemical reclamation plant. Inst. Environ. Sci. Tech.
Meet. Proc., 17: 339-345.
SMYTH, H.F. & SMYTH, H.F., Jr (1928) Inhalation experiments
with certain lacquer solvents. J. ind. Hyg., 10(8): 261-271.
SMYTH, H.F., Jr, CARPENTER, C.P., WEIL, C.S., POZZANI, U.C.,
STRIEGEL, J.A., & NYCUM, J.S. (1969a) Range-finding toxicity
data list. VII. Am. Ind. Hyg. Assoc. J., 30(5): 470-476.
SNOW, L., MACNAIR, P., & CASTO, B.C. (1981) Mutagenesis
testing of toluene in Salmonella strains TA 100 and TA 98,
Research Triangle Park, North Carolina, US Environmental
Protection Agency (Report prepared by Northrup Services, Inc).
SOKOL, J. & ROBINSON, J.L. (1963) Glue sniffing. West. Med.,
4: 192-193, 196, 214.
SPECK, B. & MOESCHLIN, S. (1968) [Effect of toluene, xylene,
chloramphenicol, and thiouracil on bone marrow. Experimental
autoradiographic study with thymidine-3H.] Schweiz. Med.
Wochenschr., 98(42): 1684-1686 (in German).
SRBOVA, J. & TEISINGER, J. (1952) [Absorption and
elimination of toluene in man.] Prac. Lek., 4: 41 (in Czech).
SRBOVA, J. & TEISINGER, J. (1953) [Metabolism of toluene.]
Prac. Lek., 5: 259-263 (in Czech).
STREICHER, H.Z., GABOW, P.A., MOSS, A.H., KONO, D., & KAEHNY,
W.D. (1981) Syndromes of toluene sniffing in adults.
Ann. intern. Med., 94: 758-762.
SUBRAMANIAN, V., SUGUMARAN, M., & VAIDYANATHAN, C.S. (1978)
Double hydroxylation reactions in microorganisms. J. Indian
Inst. Sci., 60(8): 173-178.
SUTTON, C. & CALDER, J.A. (1975) Solubility of alkylbenzenes
in distilled water and seawater at 25 °C. J. Chem. Eng. Data,
20: 320-322.
SUZUKI, H. (1973) [Autonomic nervous responses to
experimental toluene exposure in humans.] Jpn. J. ind. Health,
15: 379-384 (in Japanese).
SUZUKI, T., KASHIMURA, S., & UMETSU, K. (1983) Thinner abuse
and aspermia. Med. Sci. Law, 23(3): 199-202.
SVIRBELY, J.L., DUNN, R.C., & VON OETTINGEN, W.F. (1943) The
acute toxicity of vapours of certain solvents containing
appreciable amounts of benzene and toluene. J. ind. Hyg.
Toxicol., 25: 366-373.
SYROVADKO, O.N. (1977) [Working conditions and health status
of women handling organosiliceous varnishes containing
toluene.] Gig. Tr. Prof. Zabol., 12: 15-19 (in Russian with
English summary).
SZADKOWSKI, D., PEIFFER, D., & ANGERER, J. (1976)
[Evaluation of occupational exposure to toluene with special
reference to hepatotoxic revelancy.] Med. Monatsschr., 30(1):
25-28 (in German).
SZILARD, S., DENES, S., & MARTA, B. (1978) [On the
toxicology of the toluene.] Morph. es lg. Orv. Szemle., 18(2):
117-124 (in Hungarian).
TABAK, H.H., QUAVE, S.A., MASHNI, C.I., & BARTH, E.F. (1981)
Biodegradability studies with organic priority pollutants
compounds. J. Water Pollut. Contr. Fed., 53: 1503-1518.
TAHER, S.M., ANDERSON, R.J., MCCARTNEY, R., POPOVTZER, M.M., &
SCHRIER, R.W. (1974) Renal tubular acidosis associated with
toluene sniffing. N. Engl. J. Med., 290(14): 765-768.
TAHTI, H., RUUSKA, J., & VAPAATALO, H. (1977) Toluene
toxicity studies on rats after 1 week inhalation exposure.
Acta pharmacol. toxicol., 41(suppl. 4): 78.
TAHTI, H., KARKKAINEN, S., PYYKKO, K., RINTALA, E., KATAJA,
M., & VAPAATALO, H. (1981) Chronic occupational exposure to
toluene. Int. Arch. occup. environ. Health, 48(1): 61-69.
TAKEUCHI, Y. (1969) Experimental studies on the toluene
poisoning, chiefly on the findings of peripheral blood and
adrenal gland. Ind. Health, 7: 31-45.
TAKEUCHI, Y. & HISANAGA, N. (1977) The neurotoxicity of
toluene. EEG changes in rats exposed to various
concentrations. Br. J. ind. Med., 34(4): 314-324.
TAKEUCHI, Y. & SUZUKI, H. (1975) Change of convulsion
threshold in the rat exposed to toluene. Ind. Health, 13:
109-114.
TAKEUCHI, Y., TANAKA, T., MATSUMOTO, T., & MATSUSHITA, T.
(1972) Response of diencephalon-hypophysis adrenal cortex
system in exposure to toluene vapour. Jpn. J. ind. Health,
14(6): 543-553.
TAKEUCHI, Y., HISANAGA, N., & ONO, Y (1979) Changes of sleep
cycles and EEG in rats chronically exposed to toluene vapour.
Arch. Hig. Rada Toksikol., 30(Suppl.): 467-475.
TAKEUCHI, Y., ONO, Y., & HISANAGA, N. (1981a) An
experimental study on the combined effects of n-hexane and
toluene on the peripheral nerve of the rat. Br. J. ind. Med.,
38: 14-19.
TAKEUCHI, Y., HISANAGA, N., ONO, Y., OGAWA, Y., HAMAGUCHI, Y.,
& OKAMOTO, S. (1981b) Cerebellar dysfunction caused by
sniffing of toluene-containing thinner. Ind. Health, 19:
163-169.
TARSH, M.J. (1979) Schizophreniform psychosis caused by
sniffing toluene. J. Soc. Occup. Med., 29(4): 131-133.
TATKEN, R.L. & LEWIS, R.J., Sr (1983) Registry of toxic
effects of chemical substances, 1981-1982 ed., Washington DC,
US Department of Health and Human Services, Public Health
Service, Centers for Disease Control, National Institute for
Occupational Safety and Health, Vol. 1.
TATRAI, E., HUDAK, A., & UNGVARY, GY. (1979) Simultaneous
effect on the rat-liver of benzene, toluene, xylene, and CCL4.
Acta physiol. Acad. Sci. Hung., 53(2): 261.
TATRAI, E., RODICS, K., & UNGVARY, GY. (1980) Embryotoxic
effects of simultaneously-applied exposure of benzene and
toluene. Fol. Morpholog., 28(3): 286-289.
TAUSSON, W.O. (1929) [Oxidation of benzene hydrocarbons by
bacteria.] Planta., 7: 735-758 (in German).
TAYLOR, G.J. & HARRIS, W.S. (1970) Glue sniffing causes
heart block in mice. Science, 170: 866-868.
TEISINGER, J. & SRBOVA, J. (1955) L'élimination de l'acide
benzoïque dans l'urine et son rapport avec la concentration
maximum tolérable de toluène dans l'air. Arch. Mal. prof.,
16(3): 216-220.
THAM, R., LARSBY, B., ERIKSSON, B., BUNNFORS, I., ODKVIST, L.,
& LIEDGREN, C. (1982) Electronystagmographic findings in
rats exposed to styrene or toluene. Acta otolaryngol., 93:
107-112.
THOMAS, R.E. & RICE, S.D. (1979) The effect of exposure
temperatures on oxygen consumption and opercular breathing
rates of pink salmon fry exposed to toluene, naphthalene, and
water-soluble fractions of Cook Inlet crude oil and No. 2 fuel
oil. Mar. Pollut. funct. Res., 79: 39-52.
TOFTGARD, R., NILSEN, O.G., & GUSTAFSSON, J.A. (1982)
Dose-dependent induction of rat liver microsomal cytochrome
P-450 and microsomal enzymatic activities after inhalation of
toluene and dichloromethane. Acta pharmacol. toxicol., 51:
108-114.
TOUTANT, C. & LIPPMANN, S. (1979) Fetal solvents syndrome.
Lancet, June 23: 1356.
TOWFIGHI, J., GONATAS, N.K., PLEASURE, D., COOPER, H.S., &
McCREE, L. (1976) Glue sniffer's neuropathy. Neurology, 26:
238-243.
TREVISAN, A. & CHIESURA, P. (1978) Clinical research on the
hepatotoxicity of toluene. Ital. J. Gastroenterol., 10(3): 210.
TSANI-BAZACA, E., MCINTYRE, A.E., LESTER, J.N., & PERRY, R.
(1982) Ambient concentrations and correlations of
hydrocarbons and halocarbons in the vacinity of an airport.
Chemosphere, 11: 11-23.
TUNEK, A., HOGSTEDT, B., & OLOFSSON,T. (1982) Mechanism of
benzene toxicity. Effects of benzene and benzene metabolites
on bone marrow cellularity, number of granulopoietic stem
cells, and frequency of micronuclei in mice. Chem.-biol.
Interact., 39: 129-138.
TUTE, M.S. (1971) Principles and practice of Hansch
analysis a guide to structure-activity correlations for the
medical chemist. Adv. Drug Res., 5:: 1-77.
UMBERGER, C.J. & FIORESE, F.F. (1963) Colorimetric method
for hippuric acid. Clin. Chem., 9(1): 91-96.
UNGVARY, GY. (1984) The possible contribution of industrial
chemicals (organic solvents) to the incidence of congenital
defects caused by teratogenic drugs and consumer goods. An
experimental study. In: Brent, T. & Klingberg, N., ed.
Prevention of physical and mental congenital defects. Part A.
The scope of the problem, New York, A.R. Liss Inc.
UNGVARY, GY. & TATRAI, E. (1984) On the embryotoxic effects
of benzene and its alkyl derivatives in mice, rats, and
rabbits. In: Proceedings of the 25th Congress of the European
Society of Toxicology, Budapest, 1984 (No. 134).
UNGVARY, GY., HUDAK, A., BORS, Z., & FOLLY, G. (1976) The
effect of toluene on the liver assayed by quantitative and
morphological methods. Exp. mol. Pathol., 25(1): 49-59.
UNGVARY, GY., TATRAI, E., BARCZA, GY., & KRASZNAI, GY.
(1979) [Acute poisoning effects of toluene, o-, m-, p-xylene,
and their mixtures.] Munkavedelem, 25(7-9): 37-38 (in
Hungarian).
UNGVARY, GY., MANYAI, S., TATRAI, E., SZEBERENYI, SZ., CSEH,
R.J., MOLNAR, J., & FOLLY, G. (1980) Effect of toluene
inhalation on the liver of rats: dependence on sex dose and
exposure time. J. Hyg. Epidemiol. Microbiol. Immunol. Praha.,
24: 242-252.
UNGVARY, GY., SZEBERENYI, SZ., & TATRAI, E. (1981) The
effect of benzene and its methyl derivatives on the MFO
system. In: Gut, I., Cikrt, M., & Plaa, G.L., ed. Industrial
and environmental xenobiotics, Berlin, New York, Springer-
Verlag, pp. 285-292.
UNGVARY, GY., TATRAI, E., SZEBERENYI, SZ., RODICS, K.,
LORINCZ, M., & BARCZA, GY. (1982) Effect of toluene exposure
on the liver under different experimental conditions.
Exp. mol. Pathol., 36: 347-360.
UNGVARY, GY., TATRAI, E., LORINCZ, M., & BARCZA, GY. (1983)
Combined embryotoxic action of toluene, a widely used
industrial chemical, and acetylsalicylic acid (aspirin).
Teratology, 27: 261-269.
US NRC (1980) The alkyl benzenes, Washington DC, National
Academy Press (Committee on Alkyl Benzene Derivatives, Board
on Toxicology and Environmental Health Hazards, Assembly of
Life Sciences, National Research Council).
US EPA (1975a) New Orleans area water supply study. Analysis
of carbon and resin extracts, Athens, Georgia, US
Environmental Protection Agency, Analytical Branch, Southeast
Environmental Research Laboratory (Prepared for the Lower
Mississippi River Branch, Surveillance and Analysis Division,
Region VI).
US EPA (1975b) Preliminary assessment of suspended
carcinogens in drinking-water, Washington DC, US Environmental
Protection Agency (Report to Congress).
US EPA (1977) National organic monitoring survey: general
review of results and methodology, Phases I-III, Washington
DC, US Environmental Protection Agency.
US EPA (1980) Exposure assessments of priority pollutants:
toluene. In: Little, A.D., ed. Storet water quality
information system, Washington DC, US Environmental Protection
Agency (October 1980).
US NIOSH (1973) Criteria for a recommended standard.
Occupation exposure to toluene, US National Institute for
Occupational Safety and Health, 108 pp (HSM 73-11023, US DHEW,
NTIS No. PB-222-219/8).
VAN DOORN, R., BOS, R.P., BROUNS, R.M.E., LEYDEKKERS, C.M., &
HENDERSON, P.TH. (1980) Effect of toluene and xylenes on
liver glutathione and their urinary excretion as mercapturic
acids in the rat. Arch. Toxicol., 43(4): 293-304.
VEITH, G.D., CALL, D.J., & BROOKE, L.T. (1983)
Structure-toxicity relationships for the fathead minnow,
Pimephales promelas: narcotic industrial chemicals. Can. J.
Fish aquatic Sci., 40(6): 743-748.
VEULEMANS, H. & MASSCHELEIN, R. (1978a) Experimental human
exposure to toluene. I. Factors influencing the individual
respiratory uptake and elimination. Int. Arch. occup. environ.
Health, 42(2): 91-103.
VEULEMANS, H. & MASSCHELEIN, R. (1978b) Experimental human
exposure to toluene. II. Toluene in venous blood during and
after exposure. Int. Arch. occup. environ. Health, 42(2):
105-117.
VEULEMANS, H. & MASSCHELEIN, R. (1979) Experimental human
exposure to toluene. III. Urinary hippuric acid excretion as a
measure of individual solvent uptake. Int. Arch. occup.
environ. Health, 43(1): 53-62.
VEULEMANS, H., VAN VLEM, E., JANSSENS, H., & MASSCHELEIN, R.
(1979) Exposure to toluene and urinary hippuric acid
excretion in a group of heliorotagravure printing workers.
Int. Arch. occup. environ. Health, 44: 99-107.
VIJAYALAXMI & EVANS, HJ. (1982) In vivo and in vitro effects
on cigarette smoke on chromosomal damage and sister-chromatid
exchange in human peripheral blood lymphocytes. Mutat. Res.,
92: 321-332.
VITENBERG, A.G., STOLYAROV, B.V., & SMIRNOVA, S.A. (1977)
[Gas chromatographic determination of traces of aromatic
hydrocarbons and alcohols in water by the equilibrium vapor
analysis method.] Vestn. Leningr. Univ., Fiz. Khim., 3:
132-139 (in Russian).
VOIGTS, A. & KAUFMAN, C.E., Jr (1983) Acidosis and other
metabolic abnormalities associated with paint sniffing. South.
med. J., 76(4): 443-447.
VON OETTINGEN, W.F., NEAL, P.A., & DONAHUE, D.D. (1942a) The
toxicity and potential dangers of toluene: preliminary report.
J. Am. Med. Assoc., 118(8): 579-584.
VON OETTINGEN, W.F., NEAL, P.A., DONAHUE, D.D., SVIRBELY,
J.L., BAERNSTEIN, H.D., MONACO, A.R., VALAER, P.J., &
MITCHELL, J.L. (1942b) The toxicity and potential dangers of
toluene with special reference to its maximal permissible
concentration, US Public Health Service, 50 pp (Public Health
Bulletin No. 279).
WAHLBERG, J.E. (1976) Percutaneous toxicity of solvents. A
comparative investigation in the guinea-pig with benzene,
toluene, and 1,1,2-trichloroethane. Ann. occup. Hyg., 19(2):
115-119.
WALDRON, H.A., CHERRY, N., & VENABLES, H. (1982) Solvent
exposure and liver function. Lancet, December 4: 1276.
WALDRON, H.A., CHERRY, N., & JOHNSTON, J.D. (1983) The
effects of ethanol in blood toluene concentrations. Int. Arch.
occup. environ. Health, 51: 365-369.
WALKER, J.D. & COLWELL, R.R. (1976) Measuring the potential
activity of hydrocarbon-degrading bacteria. Appl. environ.
Microbiol., 31(2): 189-197.
WALKER, P. (1976) Air pollution assessment of toluene,
Research Triangle Park, North Carolina, US Environmental
Protection Agency (Publication No. MTR-7215) (Prepared by the
Mitre Corporation, McLean, Virginia, Contract No. 68-02-1495)
(Available from the National Technical Information Service,
Springfield, Virginia, NTIS PB 256-735).
WALTER, P.V., MASLYN, R.T., SHAFFER, G.P., & DANIELS, C.A.
(1977) Glue sniffing: the continuing menace. Drug Forum,
9(3): 193-197.
WATHNE, B.M. (1983) Measurement of benzene, toluene, and
xylenes in urban air. Atmosph. Environ., 17(9): 1713-1722.
WARD, G.S., PARRISH, P.R., & RIGBY, R.A. (1981) Early life
stage toxicity tests with a saltwater fish: effects of eight
chemicals on survival, growth, and development of sheephead
minnows (Cyprinodon variegatus). J. Toxicol. environ. Health,
8: 225-240.
WATSON, J.M. (1979) Glue sniffing: two case reports.
Practitioner, 222(1332): 845-847.
WEAST, R.C. (1977) CRC handbook of chemistry and physics,
58th ed., Cleveland, Ohio, Chemical Rubber Co.
WEI, K.S. & ADELMAN, A.H. (1969) The photooxidation of
toluene. The role of an excited charge-transfer complex. Tetra
Lett., 38: 3297.
WEISENBERGER, B.L. (1977) Toluene habituation. J. occup.
Med., 19(8): 569-570.
WHITE, L.D., TAYLOR, D.G., MAUER, P.A., & KUPEL, R.E. (1970)
A convenient optimized method for the analysis of selected
solvent vapors in the industrial atmosphere. Am. Ind. Hyg.
Assoc. J., 31: 225-232.
WHITMAN, N.E. & JOHNSTON, A.E. (1964) Sampling and analysis
of aromatic hydrocarbon vapors in air a gas-liquid
chromatographic method. Am. Ind. Hyg. Assoc. J., 25:: 464-469.
WHO (1981) Recommended health-based limits in occupational
exposure to selected organic solvents, Geneva, World Health
Organization (Report of a Study Group) (Technical Report
Series 664).
WILLIAMS, N.H. (1965) Gas chromatographic techniques for the
identification of low concentrations of atmospheric
pollutants. Anal. Chem., 37: 1723-1732.
WILSON, R.H. (1943) Toluene poisoning. J. Am. Med. Assoc.,
123(17): 1106-1108.
WILSON, J.T., ENFIELD, C.G., DUNLAP, W.J., CROSBY, R.L.,
FOSTER, D.A., & BASKIN, L.B. (1981) Transport and fate of
selected organic pollutants in a sandy soil. J. environ.
Qual., 40: 501-506.
WINNEKE, G. (1982) Acute behavioral effects of exposure to
some organic solvents: psychophysiological aspects. Occup.
Neurol. Acta neurol. Scand., 66(suppl. 92): 117-129.
WINTERS, W.D., FERRAR-ALLADO, T., GUZMAN-FLORES, C., &
ALCARAZ, M. (1972) The cataleptic state induced by ketamine:
review of the neuropharmacology of anesthesia.
Neuropharmacology, 11: 303-315.
WITHEY, R.J. & HALL, J.W. (1975) The joint toxic action of
perchloroethylene with benzene or toluene in rats. Toxicology,
4(1): 5-15.
WOIWODE, W. & DRYSCH, K. (1981) Experimental exposure to
toluene. Further consideration of cresol formation in man.
Br. J. ind. Med., 38: 194-197.
WOIWODE, W., WODARZ, R., DRYSCH, K., & WEICHARDT, H. (1979)
Metabolism of toluene in man: gas-chromatographic
determination of o-, m-, and p-cresol in urine. Arch.
Toxicol., 43: 93-98.
WOLF, M.A., ROWE, V.K., McCOLLISTER, D.D., HOLLINGSWORTH,
R.L., & OYEN, F. (1956) Toxicological studies of certain
alkylated benzenes and benzene. Arch. ind. Health, 14: 387-398.
WOOD, R.W., REES, D.C., & LATIES, V.G. (1983) Behavioural
effects of toluene are modulated by stimulus control. Toxicol.
appl. Pharmacol., 68(3): 462-472.
WYSE, D.G. (1973) Deliberate inhalation of volatile
hydrocarbons: a review. Can. Med. Assoc. J., 108: 71-74.
YAMAOKA, Y. & TANIMOTO, T. (1977) [Behaviour of organic
matter in polluted coastal areas. I. Organic matter in Kraft
Pulp Mill effluent in Hiro Bay.] Nippon-Kauaku Kaishi, 10:
1554-1559 (in Japanese).
YAMAWAKI, S., SEGAWA, T., & SARAI, K. (1982) Effects of
acute and chronic toluene inhalation on behaviour and
(3H)-serotonin binding in rats. Life Sci., 30: 1997-2002.