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Review Draft
DRAFT
Do Not Quote or Cite
HEALTH ASSESSMENT DOCUMENT
FOR
TOLUENE
Notice:
This document is a preliminary draft. It has not been
formally released by EPA and should not at this stage be
construed to represent Agency policy. It is being circu-
lated for comment on its technical accuracy and policy
implications.
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Environmental Criteria and Assessment Office
Research Triangle Park, North Carolina 27711
Project Coordinator: Mark M. Greenberg
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TABLE OF CONTENTS
1. EXECUTIVE SUMMARY 1-1
1.1. ENVIRONMENTAL SOURCES, FATE, AND LEVELS 1-1
1.2. EFFECTS ON HUMANS 1-4
1.3. ANIMAL STUDIES 1-5
1.4. ABSORPTION, DISTRIBUTION, METABOLISM, ELIMINATION,
AND RELATED PHARMACOKINETICS 1-7
1.5. CARCINOGENICITY, MUTAGENICITY, AND TERATOGENICITY 1-8
1.6. EFFECTS ON ECOSYSTEMS 1-9
1.7. RISK ASSESSMENT 1-10
2. INTRODUCTION 2-1
3. PHYSICAL AND CHEMICAL PROPERTIES 3-1
3.1. SYNONYMS AND TRADE NAMES 3-1
3.2. IDENTIFICATION NUMBERS 3-1
3.3- STRUCTURE, MOLECULAR FORMULA, AND MOLECULAR WEIGHT 3-1
3.4. PHYSICAL PROPERTIES 3-1
3.1.1. Description 3-1
3.4.2. Other Physical Properties 3-2
3.4.3. Significance of Physical Properties with
Respect to Environmental Behavior 3-2
3.5. CHEMICAL PROPERTIES 3-3
4. PRODUCTION, USE, AND RELEASES TO THE ENVIRONMENT 4-1
4.1. MANUFACUTRING PROCESS TECHNOLOGY 4-1
4.1.1. Petroleum Refining Processes 4-1
4.1.2. By-Product of Styrene Production 4-3
4.1.3. By-Product of Coke-Oven Operation 4-3
4.2. PRODUCERS 4-4
4.3. USERS 4-11
4.4. ENVIRONMENTAL RELEASE 4-14
4.4.1. Emission from Production Sources 4-14
4.4.2. Emission from Toluene Usage 4-20
4.4.3. Emission from Inadvertent Sources 4-25
4.4.4. Sum of Emissions from All Sources 4-28
4.5. USE OF TOLUENE IN CONSUMER PRODUCTS 4-28
5. INDUSTRY ABATEMENT PRACTICES 5-1
5.1. ABATEMENT PRACTICES FOR INADVERTENT SOURCES 5-1
5.2. ABATEMENT PRACTIVES FOR SOLVENT USAGE 5-2
5.3. ABATEMENT FOR COKE OVEN EMISSIONS 5-3
5.4. ABATEMENT FOR EMISSIONS FROM MANUFACTURING SITES 5-3
5.5. ABATEMENT PRACTICES FOR RAW AND FINISHED WATERS 5-3
5.6. ECONOMIC BENEFITS OF CONTROLLING TOLUENE EMISSIONS 5-4
6. ENVIRONMENTAL FATE, TRANSPORT, AND PERSISTENCE 6-1
6.1. AIR 6-1
6.1.1. Fate in Air 6-1
6.1.2. Transport 6-5
IV
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PREFACE
The Office of Health and Environmental Assessment, in consultation with
an Agency workgroup, has prepared this health assessment to serve as a "source
document" for Agency-wide use. This assessment will help insure consistency
in the Agency's consideration of the relevant scientific health data asso-
ciated with toluene.
In the development of the assessment document, the scientific literature
has been inventoried, key studies have been evaluated, and summary/conclusions
have been prepared so that the chemical's toxicity and related characteristics
are qualitatively identified. Observed-effect levels and dose-response rela-
tionships are discussed, where appropriate, so that the nature of the adverse
health responses are placed in perspective with observed environmental levels.
n i
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TABLE OF CONTENTS (cont.)
10.6. COMPARISON BETWEEN EXPOSURE DATA BASED ON THEORETICAL AND
EXPERIMENTAL VALUES 10-14
11. EFFECTS ON HUMANS 11-1
11.1. EFFECTS ON THE NERVOUS SYSTEM 11-2
11.1.1. Central Nervous System 11-2
11.1.2. Peripheral Nervous System 11-22
11.2. EFFECTS ON THE BLOOD AND HEMATOPIETIC TISSUE 11-26
11.2.1. Bone Marrow 11-26
11.2.2. Blood Coagulation 11-35
11.2.3. Phagocytic Activity of Leukocytes 11-35
11.2.4. Immunocompetence 11-36
11.3. EFFECTS ON THE LIVER 11-37
11.4. EFFECTS ON THE KIDNEYS 11-40
11.5. EFFECTS ON THE HEART 11-45
11.6. EFFECTS ON MENSTRUATION 11-46
11.7 EFFECTS ON THE RESPIRATORY TRACT AND THE EYES 11-47
11.7.1. Effects of Exposure 11-47
11.7.2. Sensory Thresholds 11-49
11.8 EFFECTS ON THE SKIN 11-51
11.9 SUMMARY 11-51
12. ANIMAL TOXICOLOGY -12-1
12.1. SPECIES SENSITIVITY 12-1
12.1.1. Acute Exposure to Toluene 12-1
12.1.2. Subchronic and Chronic Exposure to Toluene 12-19
12.2. EFFECTS ON LIVER, KIDNEY, AND LUNGS 12-24
12.2.1. Liver 12-24
12.2.2. Kidney 12-29
12.2.3. Lungs 12-30
12.3. BEHAVIORAL TOXICITY AND CENTRAL NERVOUS SYSTEM EFFECTS 12-31
12.3.1. Effect of Solvent-Sniffing Abuse 12-32
12.3.2. Effects on Simple and Complex Behavioral Performance 12-36
12.3.3. Effect on Electrical Activity of the Brain and Sleep 12-40
12.3.4. Effect on Meuromodulators 12-43
12.3.5. Minimal Effect Levels 12-43
12.4. EFFECTS ON OTHER ORGANS 12-44
12.4.1. Blood-Forming Organs 12-44
12.4.2. Cardiovascular Effects 12-52
12.4.3. Gonadal Effects 12-53
12.5. SUMMARY 12-53
13. PHARMACOKINETIC CONSIDERATIONS IN HUMANS AND IN ANIMALS 13-1
13-1. ROUTES OF EXPOSURE AND ABSORPTION 13-1
13.2. DISTRIBUTION 13-11
13.3. METABOLISM 13-16
13.4. EXCRETION 13-23
13.5. SUMMARY 13-33
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TABLE OF CONTENTS (cont.)
6.2. AQUATIC MEDIA 6-6
6.2.1. Fate 6-6
6.2.2. Transport 6-7
6.3., SOIL 6-9
6.3.1. Fate 6-9
6.3.2. Transport 6-10
6.4. ENVIRONMENTAL PERSISTENCE 6-11
6.4.1. Biodegradation and Biotransformation 6-11
7. ENVIRONMENTAL AND OCCUPATIONAL CONCENTRATIONS 7-1
7.1. ENVIRONMENTAL LEVELS 7-1
7.1.1. Air 7-1
7.1.2. Aqueous Media 7-4
7.1.3. Sediment 7-12
7.1.4. Edible Aquatic Organisms 7-13
7.1.5. Solid Wastes and Leachates 7-13
7.2. OCCUPATIONAL CONCENTRATIONS 7-13
7.3. CIGARETTE SMOKE 7-18
8. ANALYTICAL METHODOLOGY 8-1
8.1. AIR 8-1
8.1.1. Ambient 8-1
• 8.1.2. Occupational Air 8-5
8.1.3. Forensic Air 8-9
8.1.4. Gaseous Products from Pyrolysis of Organic Wastes 8-10
8.2. WATER 8-10
8.2.1. Sampling 8-10
8.2.2. Analysis 8-11
8.3. SOILS AND SEDIMENTS 8-1U
8.3.1. Sampling 8-14
8.3.2. Analysis 8-15
8.4. CRUDE OIL AND ORGANIC SOLVENTS 8-16
8.5. BIOLOGICAL SAMPLES 8-16
8.5.1. Blood 8-16
8.5.2. Urine 8-16
8.6. FOODS 8-17
8.7 CIGARETTE SMOKE 8-17
9. EXPOSED POPULATIONS 9-1
10. EXPOSURE ASSESSMENT 10-1
10.1. EXPOSURE VIA INHALATION 10-2
10.1.1. Theoretical Modeling 10-3
10.1.2. Inhalation Exposure Based on Monitoring Data 10-8
10.2. INGESTION EXPOSURE BASED ON MONITORING DATA 10-11
10.2.1. Exposure from Drinking Water 10-11
10.2.2. Exposure from Edible Aquatic Organisms 10-11
10.3. OCCUPATIONAL EXPOSURE 10-12
10.4. CIGARETTE SMOKERS 10-13
10.5. LIMITATIONS OF EXPOSURE ASSESSMENT BASED ON MONITORING DATA 10-13
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LIST OF TABLES
4-1 U.S. Production of Isolated Toluene in 1978 4-2
4-2 Isolated and Non-Isolated Toluene Available in the
United States in 1978 4-5
4-3 Producers of Isolated Toluene from Catalytic Reforming
in 1978 4-6
4-4 Producers of Isolated Toluene from Pyrolysis Gasoline 4-8
4-5 Producers of Isolated Toluene from Styrene By-Product 4-9
4-6 Producers of Isolated Toluene from .Coke-Oven Crude
Light Oi 1 s 4-10
4-7 Consumption of Isolated and Non-Isolated Toluene in
Different Usages 4-12
4-8 Consumers of Toluene for the Manufacture of Benzene by
HDA Process 4-13
4-9 Producers of Toluene Diisocyanate (TDI) in 1978 4-15
4-10 Other Toluene Chemical Intermediate Users in 1978 4-16
4-11 Toluene Air Emission Factors from Production Sources 4-18
4-12 Estimated Atmospheric Toluene Emissions from Four
Major Production Sources 4-19
4-13 Toluene Emission Factors in Wastewater from Coke-Oven
Operation 4-21
4-14 Toluene Released in Different Media from Coke-Oven
Wastewater 4-22
4-15 Toluene Emission Factors for Its Uses 4-23
4-16 Estimated Toluene Emission from Different Uses 4-24
4-17 Toluene Released in Aqueous Media From Use as a
Solvent in Various Industries 4-26
4-18 Toluene Emission from Different Inadvertent Sources 4-27
4-19 Total Yearly Release of Toluene into Different Media 4-29
4-20 Consumer Product Formulations Containing Toluene 4-30
6-1 Rate Constants for Reactions of Toluene with Reactive
Species in the Atmosphere 6-3
7-1 Atmospheric Concentrations of Toluene 7-2
7-2 Distribution of U.S. Surface Waters Within a Certain
Toluene Concentration Range 7-6
vm
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TABLE OF CONTENTS (cont.)
14. CARCINOGENICITY, MUTAGENICITY, AND TERATOGENICITY 11-1
14.1. CARCINOGENICITY 14-1
14.2. MUTAGENICITY 14-2
• 14.2.1. Mutagenesis in Microorganisms 14-2
14.2.2. Growth Inhibition Tests in Bacteria 14-4
14.2.3. Mutagenesis in Cultured Mammalian Cells 14-6
14.3. TERATOGENICITY 14-17
14.3.1. Animal Studies 14-17
14.3.2. Human Reports 14-25
14.4. SUMMARY 14-26
15. SYNERGISMS AND ANTAGONISMS AT THE PHYSIOLOGICAL LEVEL 15-1
15.1. BENZENE AND TOLUENE 15-1
15.2. XYLENES AND TOLUENE 15-3
15.3. TOLUENE AND OTHER SOLVENTS 15-4
16. ECOSYSTEM CONSIDERATIONS 16-1
16.1. EFFECTS ON VEGETATION 16-1
16.1.1. Introduction 16-1
16.1.2. Effects of Toluene on Plants 16-1
16.2. BIOCONCENTRATION, BIOACCCUMULATION, AND BIOMAGNIFICATION
POTENTIAL 16-10
1613. EFFECTS ON MICROORGANISMS 6-16
17. EFFECTS ON AQUATIC SPECIES 17-1
17.1. GUIDELINES FOR EVALUATION 17-1
17.2. EFFECTS OF ACCIDENTAL SPILLS 17-3
17.3. LABORATORY STUDIES OF TOXICITY 17-3
17.3.1. Lethal Effects 17-3
17.3.2. Sublethal Effects 17-21
18. HUMAN RISK ASSESSMENT 18-1
18.1. EXISTING GUIDELINES AND STANDARDS 18-1
18.1.1. Air 18-1
18.1.2. Water 18-2
18.1.3. Food 18-3
18.2. INHALATION EXPOSURES 18-4
18.2.1. Effects of Single Exposures 18-4
18.2.2. Effects of Intermittent Exposures Over
Prolonged Periods 18-7
18.2.3. Acceptable Daily Intake (ADI) Based on
Inhalation Exposure 18-12
18.3. ORAL EXPOSURES 18-14
18.4. DERMAL EXPOSURES 18-15
18.5. RESPONSES OF SPECIAL CONCERN 18-16
18.5.1. Carcinogenicity 18-16
18.5.2. Mutagenicity 18-16
18.5.3. Teratogenicity 18-18
18.6. CURRENT POTENTIAL HAZARDS TO HUMANS 18-20
REFERENCES R-1
vii
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LIST OF TABLES
(continued)
Page
11-13 Frequency of Lens Changes and Distribution by Exposure Time
in 69 Age-Matched Pairs of Car Painters and'Railway
Engi neers 11-50
12-1 Acute Effects of Toluene 12-2
12-2 Subchronic Effects of Toluene 12-7
12-3 24-Month Chronic Exposure of Fischer 344 Rats Exposed 6 Hours/
Day, 5 Days/Week to Toluene by Inhalation 12-22
12-4 24-Month Chronic Exposure of Fischer 344 Rats Exposed 6 Hours/
Day, 5 Days/Week to Toluene by Inhalation 12-23
12-5 Behavioral Effects of Tol uene 12-37
12-6 Central Nervous System Effects of Tol uene 12-41
12-7 Myelotoxicity Effects of Toluene 12-45
12-8 Weekly Blood Picture of Normal Rats and Rats Exposed to 600
and 2500 ppm of Toluene 7 Hours/Day, 5 Days/Week, for
5 Weeks 12-48
13-1 Uptake of Toluene in Thin and Obese Men During Exposure to a
Toluene Concentration of 375 mg/m3 (100 ppm) 13-6
13-2 Partition Coefficients for Toluene at 37°C 13-12
13-3 Toluene Concentrations in Workplace Air and Peripheral Venous
Bl ood of Exposed Workers 13-32
14-1 Epidermal Tumor Yield in 20-Week Two-Stage Experiments 14-3
14-2 Microbial Mutagenicity Assays 14-5
14-3 Rat Bone Marrow Cell Aberrations Following Intra-peritoneal
Injections of Toluene 14-10
14-4 Frequency of Unstable and Stable Chromosome Changes and
Chromosome Counts in Subjects Exposed to Benzene or Toluene
or Both 14-12
14-5 Effect of Occupational Toluene Exposure and Smoking on
Chromosomal Aberrations and Sister Chromated Exchanges 14-14
14-6 Chromosome Aberrations in Rotoprinting Factory Workers 14-15
14-7 Teratogenicity Evaluation of Toluene in CFY Rats and
CFLP Mice 14-19
14-8 Teratogenic Effects of Exposure to Toluene, Benzene, and a
Combination of Toluene and Benzene in CFY Rats 14-22
14-9 Teratogenicity and Reproductive Performance Evaluation in
Rats Exposed to Tol uene 14-24
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LIST OF TABLES
(continued)
7-3 Percent Distribution of U.S. Wastewaters Within a Certain
Toluene Concentration Range 7-7
7-4 Detection Frequency of Toluene in Industrial Wastewaters 7-9
7-5 Toluene Concentrations in Different Work Areas of a
Rotogravure Plant in Milan, Italy 7-15
7-6 Toluene Exposure Levels for Different Occupational Groups 7-16
7-7 Toluene Concentrations in Work Areas of Leather Finishing
and Rubber Coating Plants 7-17
7-8 Toluene Concentrations in Selected Work Areas of Tire
Manufacturing Plants 7-19
9-1 Population Distribution and Inhalation Exposure Levels of
Toluene from Different Sources 9-2
10-2 Population Distribution and Inhalation Exposure Levels of
Toluene from Different Sources 10-7
10-3 Toluene Exposure Under Different Exposure Scenarios 10-10
10-4 Exposed Population and Exposed Amount of Toluene from
Dispersion Modelling 10-15
11-1 Effects of Controlled 8-hour Exposures to Pure Toluene on
Three Human Subjects 11-3
11-2 Effect of Toluene Exposure on the Performance of Perceptual
Speed and Reaction Time Tests 11-7
11-3 Mean Concentrations of Organic Solvents in the Breathing
Zone of 40 Car Painters 11-15
11-4 Performance Tests: Means, Standard Deviations and Significances
Between the Group Means (Age-Matched Groups) 11-16
11-5 Rorschach Personality Test Variables: Means, Standard
Deviations, and Significances Between the Group Means
(Age-Matched Groups) 11-17
11-6 Encephalopathic Effects of Chronic Toluene Abuse 11-20
11-7 Results of Neurological and Muscular Function Tests of
Toluene-Exposed Female Shoemakers 11-23
11-8 Results of Blood Examinations Performed on Toluene-Exposed
Airplane Painters 11-27
11-9 Analysis of Paint Used by Painters. 11-29
11-10 Hematologic Examination of 889 Rotogravure Workers 11-33
11-11 Renal Function Investigations of Glue Sniffers 11-42
11-12 Toluene- Induced Metabolic Acidosis 11-44
IX
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LIST OF FIGURES
6-1 Proposed Reaction Pathways of Toluene Under Atmospheric
6-2
12-1
13-1
Condi ti ons
Microbial Metabolism of Toluene
Toluene Levels in Tissue and Behavioral Performance...
Metabolism of Toluene in Humans and Animals
16^4
s-is
, 12-34
13-17
16-1 Phytoplankton Growth in Various Concentrations of Toluene 16-4
16-2 Growth of Chlorella Vulgaris in Media Containing Toluene 16-6
xn
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LIST OF TABLES
(continued)
Page
16-1 Concentrations of Toluene in Stoppered Flasks 16-3
16-2 Toxic Effects of Toluene to Algae 16-7
16-3 Toxic Effects of Toluene Vapor on Carrots, Tomatoes, and
Barley 16-9
17-1 Acute Toxicity of Toluene to Fish and Aquatic Invertebrates 17-5
xi
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The following members of the inter-Agency Toluene Advisory Panel reviewed
early drafts of this document and submitted valuable comments:
Dr. Nancy Adams
Health Standards Division
Occupational Safety and Health Administration
Washington, DC
Dr. Michael Bolger
Division of Toxicology
Food and Drug Administration
Washington, DC
Amy Borenstein
OPE
U.S. EPA
Washington, DC
Josephine Brecher
CSD
U.S. EPA
Washington, DC
George E. Cushmac
Department of Transportation
Washington, DC
Arnold Edelman
OTI
U.S. EPA
Washington, DC
Dr. Penelope A. Fenner-Crisp
Officer of Drinking Water
U.S. EPA
Washington, DC
Dr. John R. Fowle
REAG/OHEA
U.S. EPA
Washington, DC
David Friedman
Officer of Solid Waste
U.S. EPA
Washington, DC
Frank Gostomski
OWRS
U.S. EPA
Washington, DC
xiv
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AUTHORS AND REVIEWERS
This document was prepared by the following members of the Center for
Chemical Hazard Assessment, Syracuse Research Corporation, Syracuse, New York:
Dipak Basu
Stephen Bosch
Joan Colman
Patrick Durkin
Knowlton Foote
Arthur Rosenberg
Ethel Ryan
Richard Sugatt
xm
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Dr. Dharm Singh
CAG/OHEA
U.S. EPA
Washington, D.C.
Michael Slimak
OWRS
U.S. EPA
Washington, DC
Dr. Douglas L. Smith
National Institute of Occupational Safety and Health
Rockville, MD
Doreen Sterling
Office of Toxics Integration
U.S. EPA
Washington, DC
Wade Talbot
Office of Health Research
U.S. EPA
Washington, DC
xvi
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Mark Greenberg
ECAO/OHEA
U.S. EPA
Research Triangle Park, NC
AT Jennings
OPM/OPE
U.S. EPA
Washington, DC
Alan Jones
OPE
U.S. EPA
Washington, DC
Frank Kirwan
OAQPS
U.S. EPA
Durham, NC
Stephen Kroner
MDSD
U.S. EPA
Washington, DC
Dr. Donna Kuroda
REAG/OHEA
U.S. EPA
Washington, DC
Wanda LeBleu-Biswas
Office of Solid Waste
U.S. EPA
Washington, DC
Graig R. McCormack
Office of Toxic Substances
U.S. EPA
Washington, DC
Dr. Thomas McLaughlin
EAG/OHEA
U.S. EPA
Washington, DC
Dr. Lakshmi Mishra
Consumer Products Safety Commission
Bethesda, MD
Dr. Debdas Mukerjee
ECAO/OHEA
U.S. EPA
Cincinnati, OH
xv
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in drinking water* and the flesh of edible fish. Dermal exposure to toluene is
only important in the workplace. The estimated quantities of toluene taken in by
the general public from each source are between a trace and 94 mg/week by inhala-
tion (depending on whether an individual resides in an urban or rural area or
near an industry that uses toluene) and 0.0 to 0.75 mg/week from food and water.
Occupational exposure (up to 18,000 mg/week) or cigarette smoking (14 mg/week
from 140 cigarettes) will increase an individual's exposure to toluene:
Although there are technical problems with estimating inhalation exposure to
toluene, there is reasonable agreement between the values obtained by dispersion
modeling and those obtained from calculations using monitoring data.
The total amount of toluene produced in the United States in 1978 was
«»
3595 million kg. The majority (96.5/1) is produced by catalytic reformation from
selected petroleum fractions, and the remainder is produced from pyrolytic
cracking, and as a recovered by-product of styrene production and coke oven
emission. This value of 3595 million kg is for isolated toluene and, accounts for
only 11} of the total toluene produced, the remaining 89} of the toluene produced
•
is not isolated as pure toluene but is a benzene-toluene-xylene mixture used in
gasoline. Other uses of toluene are feed stock for the production of benzene and
other chemicals, as a gasoline additive, and as a solvent.
Activities associated with automobiles (marketing and evaporation of gaso-
line and automobile exhaust) are the largest single atmospheric source of toluene
release (677 million kg/year), with industries using toluene as a solvent (the
paint and coating, adhesive, ink, and pharmaceutical industries) being the
second largest source of toluene in the atmosphere (375 million kg/year). These
two sources account for 75} of the toluene emitted to the atmosphere. The amount
of toluene released to other media in the environment is small and is equal to
approximately 0.15} of the total amount released to the atmosphere.
1-2
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1. EXECUTIVE SUMMARY
1.1. ENVIRONMENTAL SOURCES, FATE, AND LEVELS
Toluene, a homolog of benzene that contains a single methyl group, is a
clear, colorless liquid at room temperature. The molecular formula of toluene is
C_Hg and the molecular weight is 92.13. The structural formula is given below.
CH,
Other physical properties of toluene include a melting point of -95°C, a
boiling point of 110.6°C, a flash point of U.W°C, a vapor pressure of 28.7 torr
at 25°C, and a density of 0.8669 g/mfc at 20°C. Toluene is slightly soluble in
both fresh and salt water (535 mg/i and 379 mg/i, respectively) at a temperature
of 25°C. The physical properties of toluene would indicate that toluene in the
environment is likely to be present in the air, and that toluene originally
present in water may be transferred to the atmosphere. Toluene can undergo
photochemical reactions, particularly under atmospheric smog conditions. In
aqueous media under the conditions of water chlorination, toluene may be
chlorinated followed by subsequent hydrolysis to benzaldehyde. This reaction
may account for the benzaldehyde detected in some finished drinking waters.
The general population may be exposed to toluene through inhalation of air,
ingestion of food or water, or through dermal exposure. The four largest sources
of emission of toluene to the atmosphere are, in descending order of importance,
automobile use, industrial use of toluene as a solvent, coke ovens, and toluene-
producing industries. Other than exposure via the air, toluene has been detected
1-1
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energy suggests that toluene will be degraded rapidly by microbial species pro-
liferating at the expense of the compound and will not accumulate significantly
in the environment.
1.2. EFFECTS ON HUMANS
Toxicity studies of humans have primarily involved evaluation of indivi-
duals exposed to toluene via inhalation in experimental or occupational settings
or during episodes of intentional abuse. The health effect of primary concern is
dysfunction of the central nervous system (CMS). Acute experimental and occupa-
tional exposures to toluene in the range of 200 to 1500 ppm have elicited dose-
related CNS alterations such as fatigue, confusion, and incoordination, as well
as impairments in reaction time and perceptual speed. Following initial CNS
excitatory effects (e.g., exhilaration, lightheadedness), progressive develop-
ment of narcosis has characterized acute exposures to excessive concentrations
of toluene (i.e., levels approaching the air saturation concentration of
approximately 30,000 ppm). Repeated occupational exposures to toluene over a
period of years at levels of 200 to MOO ppm have resulted in some evidence of
neurologic effects, and chronic exposure to mixtures of solvent vapors contain-
ing predominantly toluene at levels of 30 to 100 ppm have resulted in impaired
performance on tests for intellectual and psychomotor ability and muscular func-
tion. Prolonged abuse of toluene or solvent mixtures containing toluene have, on
occasion, led to residual or permanent CNS effects.
Early reports of occupational exposures ascribed oyelotoxic effects to
toluene, but the majority of recent evidence indicates that toluene is not toxic
toward the blood or bone marrow. The myelotoxic effects previously attributed to
toluene currently are considered to have been the result of concurrent exposure
to benzene, which was typically present as a contaminant. Acute exposures to
-------
The preferred method for the monitoring of toluene in ambient air consists
of sorbent collection, thermal elution, and GC-FID determination. For a 25 i
sample, the detection limit is <0.1 ppb. Purge and trap with GC-photoionization
detection is the most widely used method for the anal/sis of toluene in aqueous
samples. With a 5 mi sample, the method has a detection limit of 0.1 ppb.
Toluene is the most prevalent aromatic hydrocarbon in the atmosphere, with
average measured levels ranging from 0.14 to 59 ppb. Toluene has also been
detected in surface waters and in treated wastewater effluents at levels
generally below 10 ppb. A concentration of toluene as high as 19 ppb has been
detected in a drinking water supply. In a study of toluene levels in the tissue
of edible aquatic organisms, 95$ of the samples contained less than 1 ppm of
toluene. The atmosphere is the major environmental receiver for toluene. It has
been estimated that approximately 124 million people in the U.S. are exposed to
atmospheric toluene at a concentration level greater than 1 ug/nr.
Toluene released to the aquatic or soil environment is at least partly
removed by biodegradation. There is little information on the rate and extent of
biodegradation in soil; however, in one study, a half-life of between 20 and
60 min was observed in soil containing toluene-degrading bacteria, and in a
second study 20 to 60$ of toluene was removed following percolation through
110 cm of sand. As a result of the limited number of studies available, the
extent of toluene degradation in soil cannot be determined, although studies with
pure cultures indicate that a variety of bacteria and fungi can use toluene, and
some pure cultures have been isolated that can use toluene as a sole source of
carbon. Toluene is also readily biodegraded in aqueous media, both in surface
water and during wastewater treatment; however, disappearance of toluene from
aqueous media is mainly through evaporation and transport to the atmosphere. The
conversion of toluene to compounds that can be used as sources of carbon and
1-3
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linked with depression of activity. Levels below 1000 ppm vapor have little or
no effect on gross observations of behavior, although lower levels have been
observed to have an effect using more sensitive methods of assay (i.e., detection
of changes in cognition and brain neuromodulator levels).
Although early studies suggested toluene induced myelotoxicity, most
studies using toluene that contained negligible amounts of benzene have not
produced injury on blood-forming organs; however, 3 Russian studies and 1
Japanese study have reported leukocytesis, impaired leukopoiesis, or chromosomal
damage in the bone marrow.
Inhalation of concentrations up to 1085 ppm toluene for 6 weeks or 300 ppm
for 24 months, and ingestion of 590 mg toluene/kg body weight for 6 months pro-
duced no liver damage; however, several studies noted an increase of liver weight
or a slight histological change suggestive of possible liver damage at higher
levels of exposure (=2000 ppm in rats) or in animals treated with 0.05 mZ/100 g
body weight by the intraperitoneal route.
i
Renal injury was noted in rats, dogs, and guinea pigs after subacute inhala-
tion of toluene vapors at doses in excess of 600 ppm in three studies, while no
renal damage was found in other subacute and subchronic studies in which rats,
dogs, guinea pigs, and monkeys inhaled vapors up to a concentration of 1085 ppm
or ingested 590 mg toluene/kg body weight.
Although no effect was observed in the lungs of rats, guinea pigs, dogs, or
monkeys after exposure to 1085 ppm toluene vapor intermittently for 6 weeks, in
rats after inhalation of up to 300 ppm toluene for 2U months, or in rats after
ingestion of 590 mg toluene/kg body weight for 6 months, other studies noted
irritation effects in the respiratory tract in dogs, guinea pigs, and rats.
Sensitization of the.heart in mice, rats, and dogs was reported after inhalation
of toluene.
1-6
-------
toluene have not resulted in any definite effects on heart rate or blood pres-
sure.
C
Liver enlargement was reported in an early study of painters exposed to 100-
1100 ppm toluene for 2 weeks to more than 5 years, but this effect was not
associated with clinical evidence of liver disease or corroborated in subsequent
studies. Chronic occupational exposure to toluene or intensive exposure via glue
or thinner sniffing generally has not been associated with abnormal liver func-
tion. Evidence of renal dysfunction has been observed in workers who were
accidentally overexposed to toluene and in toluene abusers, but studies of
workers exposed to 100 to 1100 ppm toluene for 2 weeks to 5 years and 60 to
100 ppm toluene for over 3 years did not report abnormal urinalysis findings.
Several reports have appeared recently that associate deliberate inhalation of
toluene with metabolic acidosis.
Dysmenorrhea has been reported in women exposed 'for over three years to 60
to 100 ppm toluene and concommitantly to 20 to 50 ppm gasoline in a "few" working
places. Disturbances of menstruation have also been reported in female workers
exposed concurrently to toluene, benzene, and xylene, and to toluene and other
unspecified solvents.
Single short-term exposures to. moderate levels of toluene have, on occa-
sion, been reported to cause transitory eye and respiratory tract irritation, but
irritative effects have generally not been observed in workers exposed repeti-
tively to toluene. Dermal contact with toluene may cause skin damage due to its
degreasing action.
1.3. ANIMAL STUDIES
The most pronounced effect of toluene in animal studies is on the central
nervous system. Acute exposure to inhalation of high levels of toluene has been
1-5
-------
dose or whether the chemical was administered orally or by inhalation. Much of
the remaining toluene is exhaled unchanged. The excretion of toluene and its
metabolites is rapid; the major portion occurs within 12 hours of oral adminis-
tration or the end of inhalation exposure.
1.5. CARCINOGEHKCITY, MOTAGENICITY, AND TERATOGENICITY
Inhalation exposure to toluene at concentrations of up to 300 ppm for
24 months did not produce an increased incidence of neoplastic, proliferative,
Inflammatory, or degenerative lesions in various organs of rats relative to
unexpoaed controls. Other studies indicate that toluene is not carcinogenic when
applied topically to the shaved skin of laboratory animals and that it does not
promote the development of skin tumors following initiation with DMBA.
Toluene has been shown to be non-mutagenic in a battery of microbial,
mammalian cell, and whole organism test systems. The Russian literature reported
chromosome aberrations in the bone marrow cells of rats exposed subcutaneously
and via inhalation to toluene, but these findings have not been corroborated in
other studies of rats following intraperitoneal injection of toluene, in human
lymphocytes exposed to toluene in culture, or in lymphocytes from workers chroni-
cally exposed to toluene.
Toluene has been reported to induce cleft palates and embryotoxic effects in
mice following oral exposure, but it was not teratogenic in mice or rats follow-
ing inhalation exposure. Embryotoxic effects (increased incidence of skeletal
anomalies and signs of retarded skeletal development, low fetal weights) and
increased maternal toxicity were noted, however, in some of the rats and mice
exposed via inhalation.
1-8
-------
The acute oral toxicity (LD5Q) of toluene in rats is in the range of 6.0 to
7.5 g/kg, which indicates only slight toxicity in this species. An acute dermal
toxicity (LD_Q) was reported to be 14.1 mi/kg in the rabbit. Slight to moderate
irritation was noted in rabbit and guinea pig skin and the rabbit cornea after
application to the skin or eye. An LC Q by inhalation in the range of 5500 to
7000 ppm was reported in mice and of 4050 ppm in rats.
1.U. ABSORPTION, DISTRIBUTION, METABOLISM, ELIMINATION, AND RELATED
PHARMACOKINETICS
Toluene is readily absorbed from the respiratory tract. Studies with humans
indicate that the total amount of toluene absorbed is proportional to the concen-
tration of toluene in inspired air, the length of exposure, and pulmonary venti-
lation, which in turn depends upon the level of physical activity. Approximately
50% of the amount inspired is retained in the body. Absorption of toluene from
the gastrointestinal tract is probably fairly complete, based on excretion data
from experimental animals. Toluene is absorbed less readily through the skin
than through the respiratory or gastrointestinal tracts.
Animals given toluene orally or by inhalation had high concentrations of
toluene in their adipose tissue and bone marrow, and moderately high concentra-
tions of toluene and its metabolites in liver and kidney. These results are
reasonable based on tissue-blood partition coefficients and known routes of
metabolism and excretion.
The initial step in the metabolism of toluene is side-chain hydroxylation by
the hepatic mixed-function oxidase system, followed by oxidation to benzoic
acid. Benzoic acid is then conjugated with glycine to form hippuric acid and
excreted in the urine. In both humans and animals, 60 to 75% of the absorbed
toluene can be accounted for as hippuric acid in the urine, regardless of the
1-7
-------
1.7. HEALTH EFFECTS SUMKARY
Considerable information is available on the effects of toluene on humans
and experimental; animals after inhalation exposures. The data on oral exposure
are much less satisfactory, although one acceptable subchronic oral study using
rats is available. No information on dermal exposures suitable for use in human
risk assessment was encountered.
Based on a few studies involving controlled exposures of humans to toluene
vapors as well as some reports of occupational incidents and voluntary abuse
("glue sniffing"), the dose-response relationships for the acute effects in
humans of single short-term exposures to toluene can be estimated as:
>37 ppm : Probably perceptible to most humans.
50 to 100 ppm : Subjective complaints (fatigue or
headache) but probably no observable
impairment of reaction time or coordi-
nation.
200 ppm : Mild throat and eye irritation.
100 to 300 ppm : Detectable signs of incoordination may
be expected during exposure periods up
to eight hours.
400 ppm : Lacrimation and irritation to the eyes
and throat.
300 to 800 ppm : Gross signs of incoordination may be
expected during exposure periods up to
eight hours.
1,500 ppm : Probably not lethal for exposure
periods of up to eight hours.
>4,000 ppm : Would probably cause rapid impairment
of reaction time and coordination.
Exposures of one hour or longer might
lead to narcosis and possibly death.
10,000 to 30,000 ppm : Onset of narcosis within a few minutes.
Longer exposures may be lethal.
1-10
-------
1.6. EFFECTS ON ECOSYSTEMS
The effects of toluene have been investigated using aquatic and terrestrial
microorganisms, aquatic invertebrates, fish, and higher plants. Toluene can
both stimulate and inhibit growth of bacteria and algae, depending on the species
and the concentration of toluene. The growth of most species of bacteria, algae,
and other microorganisms is not inhibited until the toluene concentration
exceeds 10 to 100 mg/i. Toluene is acutely toxic to aquatic invertebrates and
fish at concentrations ranging between 3 and 1180 mg/&. The lowest concentration
shown to cause sublethal effects in aquatic animals was 2.5 mg/i. Chronic
toxicity data was available for only one species of fish which was affected at
7.7 ppm but not at 3.2 ppm. Chronic effects occurred at a concentration that was
36 to 152 times lower than the acute LC5Q for this species, indicating that
chronic effects may occur at lower levels in more sensitive species. Toluene
concentrations between 0.1 and 1.0 ppm have been reported occasionally in sur-
face waters and sediments. These concentrations are sufficiently close to the
toxic concentrations for sensitive species to indicate that acute or chronic
toxic effects may occur in some polluted habitats, especially after accidental
spills of toluene. Toluene has only a low bioconcentration potential and is
metabolized and rapidly depurated front fish., which indicates that toluene is
unlikely to biomagnify through aquatic food webs. Toluene, however, has been
shown to impart an unpleasant taste to fish that inhabit contaminated water. The
ecosystem impacts of toluene spills or chronic low-level pollution are unknown.
Adverse effects may occur but probably are limited by rapid rates of loss of
toluene through evaporation and biodegradation.
1-9
-------
Because of the deficiencies in the studies on which these estimates are based as
well as variations in sensitivity to toluene that may be expected in the human
population, these estimates should be regarded as approximations only.
The subchronic and chronic inhalation data lend themselves less to the
definition of dose-response relationships. Most of the reports on human expo-
sures failed to define precisely levels or durations of exposure, involved rela-
tively small numbers of exposed individuals, and did not adequately control
exposure to other toxic agents. The animal data are of little use in supporting
the human data because humans appear to be more sensitive to toluene than the
experimental animals on which data are available.
Qualitatively, dermal exposure to toluene can cause skin damage, as is the
case with many solvents, but systemic signs of intoxication are likely to occur
only in cases of gross overexposure.
1-11
-------
2. INTRODUCTION
At the April 18, 1980 meeting of the Toxic Substances Priorities Committee,
a decision was made to develop a multimedia integrated risk assessment document
for toluene. One of the primary objectives of this undertaking was to minimize
or eliminate inter-agency and inter-office duplication of risk assessment docu-
mentation projects. This document on toluene will serve as a pilot to test the
feasibility and value of the multimedia integrated approach to environmental
risk assessment. Toluene was chosen for this pilot study primarily because of
its inclusion on a variety of program office priority lists, since it is a
chemical produced in large quantity and exposure to the compound is widespread.
Development of the toluene documentation project was directed by EPA's Environ-
mental Criteria and Assessment Office, ORD, Research Triangle Park - Project
Officer, Mr. Mark Greenberg.
In addition to the present document for toluene, two other recent reports
contain valuable health and environmental effects data on toluene. The first is
The Alkyl Benzenes, published in 1980 by the Board on Toxicology and Environ-
mental Health Hazards, Assembly of Life Sciences, National Research Council. The
second recent review, developed by the U.S. EPA in 1980, is the Ambient Water
Quality Critiera for Toluene. EPA Report UUO/5-80-075.
2-1
-------
3.4.2. Other Physical Properties.
Melting Point (Weast, 1977):
Boiling Point (Weast, 1977):
Density (g/ind, 20°C) (Weast, 1977):
Specific Gravity (15.6/15.6°C) (Cier, 1969)
Vapor Pressure (25°C) (Weast, 1977):
Vapor Density (air = 1) (Weast, 1977):
Percent in Saturated Air
(760 mm, 26°C) (Walker, 1976):
Density of Saturated Air-Vapor
Mixture (760 mm (air =1),
26°C) (Walker, 1976):
Solubility (Sutton and Calder, 1975):
Fresh water (25°C)
Sea water (25°C)
Flammable Limits (percent
by volume in air) (Walker, 1976):
Flash Point (closed cup) (Walker, 1976):
Autoignition Temperature (Walker, 1976):
Log Octanol-Water Partition
Coefficient (Tute, 1971):
Odor Threshold in Air (Walker, 1976):
Coke derived
Petroleum derived
Surface Tension (20°C) (Walker, 1976):
Liquid Viscosity (20°C) (Walker, 1976):
Refractive Index (68°F) (Cier, 1969):
Conversion Factor (in air, 25°C):
-95 °C
110.6°C
0.8669
0.8623
28.7 torr
3.20
3.94
1.09
534.8 mg/1
379.3 mg/Jl
1.17 to 7.10
40°F
552°C
2.69
U.68 ppm
2.14 ppm
28.53 dynes/cm
0.6 cp
1.49693
1 ppm =,3.77 mg/nr
1 mg/nr £ 0.265 ppm
3.t.3 Significance of Physical Properties with Respect to Environmental
Behavior. The volatility of toluene, as indicated by its relatively high vapor
pressure, is indicative that a substantial fraction of environmental toluene is
o
likely to be present in the vapor phase mixed with air. The relatively high
volatility of toluene, combined with its low solubility in water, may lead to
3-2
-------
3. PHYSICAL AND CHEMICAL PROPERTIES
Toluene is a homolog of benzene in which one hydrogen atom has been replaced
by a methyl group. Some of the relevant physical and chemical properties of
a
toluene are described below.
3.1. SYNONYMS AND TRADE NAMES
Methacide
Methylbenzene
Methylbenzol
Phenylmethane
Toluol
3.2. IDENTIFICATION NUMBERS
Chemical Abstracts Service (CAS) No.: 108-88-3
Registry of Toxic Effects of Chemical Substances (RTECS) No.: XS5250000
3.3- STRUCTURE, MOLECULAR FORMULA, AND MOLECULAR WEIGHT
Molecular Formula: C_Hg
Molecular Weight: 92.13
3.U. PHYSICAL PROPERTIES
3.4.1. Description. Toluene is a clear, colorless liquid at ambient temperature
that has a benzene-like odor. It is both volatile and flammable (The Merck
Index. 1976).
3-1
-------
At one time, the most significant use of toluene was in the production of
benzene by the"above reaction (Cier, 1969).
Toluene undergoes a reversible disproportionation and transalkylation reac-
tion in the presence of a catalyst (Cier, 1969)•
CH,
catalyst
Hydrogenation of toluene takes place readily to produce methylcyclohexane
(Cier, 1969).
n
catalyst
The reverse process of dehydrogenation of methylcyclohexane is the princi-
pal mode of toluene manufacture. Methylcyclohexane is found in petroleum frac-
tions, along with other naphthenes (Cier, 1969).
o
Oxidation of toluene under catalytic conditions yields benzoic acid as a
principal product (Cier, 1969).
CH
catalyst
c
))—COOK
Chlorination of toluene under actinic light conditions yields methyl sub-
stitution products (Cier, 1969).
Cl
C12
.Cl -r--:
2 hv
Cl,
Cl-
TV"
CC1.
-------
intermedia transfer of toluene from water to the air phase. The details of the
environmental fate of toluene as determined by its physical and chemical proper-
ties are discussed in Chapter 6.
The log octanol-water partition coefficient for toluene may have signifi-
cance in determining its affinity toward organics in soil and aquatic organisms.
The details of the bioconcentration factor for toluene based on the octanol-water
partition coefficient value are discussed in Chapter 9. The knowledge of physi-
cal properties such as flammable limits and flash point are important for the
safe handling and transport of toluene; data on density and solubility may be
necessary for health effect studies.
3.5. CHEMICAL PROPERTIES
Toluene undergoes substitution reactions, either on the aliphatic side
group (-CH_) or on the benzene ring. These substitutions occur exclusively at
the ortho (2) and para (4) positions marked in the following figure:
CH,
4
Nitration, sulfonation, halogenation, methylation, and chloromethylation
are some examples of substitution reactions. These reactions occur at a rate
between 2.1 and 467 times faster with toluene than with benzene (Cier, 1969).
The methyl group in toluene is susceptible to dealkylation to produce
benzene (Bradsher, 1977).
Thermal
O
3-3
-------
Materials (Cier, :T969). The actual concentration of toluene is not stipulated in
these specifications; however, the nitration grade (1°) and pure commercial
grade (2°) toluene are of 99.5 to 100> and 98.5 to 99.H% purity, respectively
(USZTC, 1980). ."All other grades include toluene and are used as solvent grade
and for blending aviation and motor gasoline. The non-fuel toluene (solvent
grade) is of 90 to 98.4* purity (OSITC, 1980).
Commercial toluene may contain benzene as an impurity. Therefore, all
health effect studies involving toluene should specify the quality of toluene
used for experimentation. If benzene is present in the toluene, it must be
demonstrated that the observed health effects are not wholly or partly due to
benzene. Because of this contamination, it may also be necessary to determine
the amount of benzene released to the environment due to industrial usage of
toluene.
In general, toluene is quite stable in air, and most of the chemical reac-
tions discussed above require specialized conditions. While some of the reac-
tions may have environmental significance, the majority of the chemical reac-
tions discussed above are conducted under conditions of commercial and research
applications.
3-6
-------
The hydrolysis of benzalchloride produces benzaldehyde (Gait, 1967).
The above reactions may have some significance with respect to chlorination
of drinking water. The oxidation of toluene that occurs in drinking water may be
one of the sources of benzaldehyde and benzoic acid detected in drinking water
(U.S. EPA, 1980).
In the presence of catalysts and in the absence of light, chlorination
produces &- and £-chlorotoluene (Cler, 1969).
In the vapor phase, toluene is relatively unreactive toward RO. radicals and
0_ found in the troposphere. It is, however, relatively more reactive toward OH
radicals; the products of the reaction are normally benzaldehyde and cresols
(Brown et al., 1975). This reaction may have significance with respect to the
fate of toluene in the atmosphere and is discussed in detail in Section 6.1.
Toluene forms azeotropes with a number of solvents, including paraffinics,
naphthenics, and alcoholic hydrocarbons. Azeotropes are important in the puri-
fication of toluene, in solvent technology, and in the recovery of toluene from
reaction mixtures (Cier, 1969).
Toluene is marketed as nitration grade (1°, boiling range of 1°C), pure
commercial grade (2°C), and all other grades. Generally accepted quality stan-
dards for the first two grades are given by the American Society for Testing and
3-5
-------
TABLE 4-1
U.S. Production of Isolated Toluene in 1978a
Production
Process
Catalytic reforming
Pyrolytic cracking
Styrene by-product
Coke oven by-product
TOTAL
Amount
Produced
(10b kg)
3110
324
135
26b
3595
Percent
of Total
86.5
9
3.8
0.7
100
aSource: ADL, 1981
This value does not include toluene obtained from tar distillers.
-------
4. PRODUCTION, USE, AND RELEASES TO THE ENVIRONMENT
4.1. MANUFACTURING PROCESS TECHNOLOGY
Toluene is produced primarily from three sources: (1) petroleum refining
processes, (2) indirectly as a by-product of styrene production, and
(3) indirectly as a by-product of coke-oven operations.
U.1.1. Petroleum Refining Processes. Low levels of toluene are present in crude
petroleum. Toluene is produced from petroleum by two processes: (1) catalytic
reforming and (2) pyrolytic cracking.
1.1.1.1. CATALYTIC REFORMING — The largest quantity of toluene produced in
the United States is generated in the catalytic reforming process. The total
estimated toluene produced in this process in 1978 was 3110 million kg. This
represents about 87} of the total amount of toluene produced in the United States
in 1978 (Table U-1).
Catalytic reforming involves the catalytic dehydrogenation of selected
petroleum fractions which are rich in naphthenic hydrocarbons to yield a mixture
of aromatics and paraffins. The proportions of aromatics and paraffins in the
refonnate depend upon the feedstock used and the severity of the reforming opera-
tion (Cier, 1969). At present, reforming operations are geared primarily to
produce a benzene-toluene-xylene (BTX) reformate from which the individual aro-
matics are recovered" (Cier, 1969). Toluene is isolated from the refonnate by
distillation, followed by washing with sulfuric acid and redistillation. Only a
small fraction of catalytic reformate, however, is utilized for isolating
U-1
-------
products; both of these by-products contain toluene. The production of toluene
from distillation of coal-tar is minimal (Mara et al., 1979); however, some
toluene is isolated from crude light oil. As shown in Table 4-1, approximately
26 million kg of toluene were isolated from coal-derived toluene in the year
1978. This amounted to about 0.7$ of the total isolated toluene produced during
the same year.
4.2. PRODUCERS
Of the total toluene produced in the United States for internal consumption,
only about 11£ is isolated as toluene (Table 4-2). The remainder stays in
gasoiine as a benzene-toluene-xylene (BTX) mixture. The total amount of toluene
available in the United States in 1978, both isolated and non-isolated, is shown
in Table 4-2.
The identification of isolated toluene producers, their estimated toluene
producing capacity, and the estimated amount of toluene produced in 1978 from
catalytic reforming, pyrolytic cracking, and styrene by-product are shown in
Tables 4-3, 4-4, and 4-5. The identification of the producers, of isolated
toluene from coke-oven by-product is given in Table 4-6; the capacity for iso-
lated toluene production and the actual amount of toluene produced are not given
because the data are unavailable. It should be pointed out that many producers
captively consume the toluene that they produce.
During 1979, the production of toluene from coke-oven operators had a
reported increase of 17.631 over 1978 (USITC, 1980). The production of toluene
from petroleum refiners has been reported to have decreased by 4.3J during the
same period (USITC, 1980). This resulted in a net decrease of 4.2} in the
overall isolated toluene production in 1979 as compared to 1978 (Table 4-1)
(USITC, 1980).
4-4
-------
toluene. The unseparated toluene in catalytic reformate is used for gasoline
blending.
4.1.1.2. PYROLYTIC CRACKING — The second largest quantity of toluene comes
from pyrolytic cracking. Of the total isolated toluene produced in the United
States in 1978, approximately 9$ (324 million kg) was obtained from this source
(Table 4-1).
When heavier hydrocarbons, such as hydrocarbon condensates, naphtha, and
gas oil, are pyrolytically cracked for the manufacture of .olefins, pyrolysis
gasoline is produced as a by-product. The amount of pyrolysis gasoline produced
from pyrolytic cracking depends on the feedstock and the manufacturing condi-
tions (Mara et al., 1979). The by-product, pyrolysis gasoline, contains a high
percentage of aromatics. Toluene can be isolated from pyrolysis gasoline by
distillation, removal of any olefins and diolefins, and redistillation. Not all
pyrolysis gasoline produced in the United States is utilized for the production
of isolated toluene.
4.1.2. By-Product of Styrene Production. When styrene is produced by the
dehydrogenation of ethylbenzene, some toluene is also synthesized as a by-
product. The toluene isolated from the by-product is not suitable for chemical
or solvent use. Therefore, toluene obtained from this source is used either for
gasoline blending or as feed for the manufacture of benzene by the hydrodealkyla-
tion process (Mara et al., 1979). In 1978, approximately 135 million kg of
isolated toluene, which was about 4$ of the total, was obtained as the by-product
of styrene production (Table 4-1).
4.1.3. By-Product of Coke-Oven Operation. The production of coke by the high-
temperature carbonization of coal yields coal-tar and crude light oil as by-
4-3
-------
TABLE 4-3
Producers of Isolated Toluene from Catalytic Reforming in 1978a
Company and Location
Amerada Hess - St. Croix, VI
American Petrofina - Big Spring, TX
Beaumont, TX
Ashland Oil - Catlettsburg, KY
N. Tonawanda, NY
Arco - Houston, TX
Wilmington, CA
Charter Oil - Houston, TX
Coastal States - Corpus Christi, TX
Commonwealth - Penuelas, PR
Crown - Pasadena, TX
Exxon - Bay town, TX
Getty - Delaware City, DE
El Dorado, KS
Gulf - Alliance, LA
Philadelphia, PA
Port Arthur, TX
Kerr McGee - Corpus Christi, TX
Marathon - Texas City, TX
Mobil - Beaumont, TX
Monsanto - Chocolate Bayou, TX
Pennzoil - Shreveport, LA
Phillips - Sweeney, TX
Guayama, PR
Quintana-Howell - Corpus Christi, TX
Shell - Deer Park, TX
Toluene
Capacity
(10b kg)
460
164
125
99
39
125
49
39
56
395
46
411
20
194
92
49
148
72
280
33
—
33
335
56
197
Isolated Toluene Produced
(10b kg)
310
110
84
67
26
84
33
26
38
266
31
277
NA
13
130
62
33
100
49
189
22
NA
22
226
38
133
4-6
-------
TABLE M-2
Isolated and Non-Isolated Toluene Available
in the United States in 19?8a
Source
Catalytic reforming
Pyrolytic cracking
Styrene by-product
Coke oven by-product
Imports
Exports
SUBTOTAL
TOTAL
Isolated
3,110
32U
135
26
192
-364
3,M23
Quantity
(10b kg)
Non-Isolated as BTX
27,000
197
NA
96
NR
27,293
30,716
Source: ADL, 1981
NA = not applicable, NR * not reported
4-5
-------
TABLE 4-4
Producers of Isolated Toluene from Pyrolysis Gasoline
Company and Location
Toluene
Capacity
(10° kg)
Isolated Toluene Produced
(10° kg)
Arco - Chanelview, TX
Commonwealth - Penuelas, PR
Dow - Freeport, TX
Gulf - Cedar Bayou, TX
Mobil - Beaumont, TX
Monsanto - Chocolate Bayou, TX
Union Carbide - Taft, LA
TOTAL
105
49
13
66
16
132
66
447
76
36
9.4
48
15
96
48
328.4
Source: ADL, 1981
4-8
-------
Table 1-3. (cont.)
Company and Location
Sunoco - Corpus Christ! , TX
Marcus Hook, PA
Toledo, OH
Tulsan, OK
Tenneco - Chalmette, LA
Texaco - Port Arthur, TX
Westville. NJ
Union Oil - Lemont, XL
Union Pacific - Corpus Christi, TX
TOTAL
Toluene
Capacity
(10b kg)
138
151
21?
66
115
92
132
56
99
4613
Isolated Toluene Produced
(105 kg)
93
102
166
44
78
62
89
38
67
3108
aSource: ADL, 1981
1980 capacity for this producer was 85 million kg.
1980 capacity for this producer was 72 million kg.
NA = not applicable.
4-7
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TABLE U-6
Producers of Isolated Toluene from Coke-Oven Crude Light Oilsc
Plant
Location
Armco
Ashland Oil
Bethlehem Steel
CF and I
Interlake
Jones and Laughlin
Lone Star
Republic Steel
U.S. Steel
Middletown, OH
Catlettsburg, KY
N. Tonawanda, NY
Bethlehem, PA
Sparrows Pt., MD
Pueblo, CO
Toledo, OH
Aliquippa, PA
Lone Star, PA
Youngstown, OH
Cleveland, OH
Clairton, PA
Geneva, UT
Source: ADL, 1981
U-10
-------
TABLE 4-5
Producers of Isolated Toluene from Styrene By-Producta
Conpany and Location
American Hoechst - Baton Rouge, LA
Arco - Beaver Valley, PA
Cos -Mar - Carville, LA
Dow - Freeport, TX
Midland, MI
El Paso Natural Gas - Odessa, TX
'Juif - Donaldsville, LA
Monsanto - Texas City, TX
Standard Oil (Indiana) -
Texas City, TX
Sunoco - Corpus Christi, TX
U..3. Steel - Houston, TX
TOTAL
Styrene
Capacity
(105 kg)
400
100
590
660
140
68
270
680
380
36
54
3400
Isolated Toluene Produced
(106 kg)
16
4
24
26
5.5
2.7
11 .
27
15
1.4
2.2
134.8
\-;urce: ADL, 1981
4-9
-------
TABLE 4-7
Consumption of Isolated and Non-Isolated Toluene in Different Usages8
Amount , Used/year
Usage (10° kg)
Non-isolated :
Gasoline as BTX
Isolated:
Benzene dealkylation
Gasoline back-blending
Solvent for paint and coatings
Solvent for adhesives, inks,
and Pharmaceuticals
Toluene diisocyanate
Xylene
Benzole acid
Benzyl chloride
Vinyl toluene
Miscellaneous others
Net export
TOTAL
27,293
1,675
1,465
263
132
200
98
65
36
25
39
172
4,170
Percent of
Total Use in
Each Category
100
40.2
35.1
6.3
3.2
4.8
2.4
1.6
0.9
0.6
0.9
4.1
100.1
Source: ADL, 1981
4-12
-------
4.3. USERS
As mentioned in Section 4.2., most of the toluene produced as BTX mixture is
6
never isolated but remains in various refinery streams for use in gasoline.
Isolated toluene, on the other hand, is used for different purposes; the con-
sumption of isolated toluene in different usage is shown in Table 4-7. The
fluctuating, but largest single use of isolated toluene is in the production of
benzene through the hydrodealkylation (HDA) process. The fluctuation in the use
of isolated toluene exists because the HDA process is used as an effective means
of balancing supply and demand for benzene (Mara et al., 1979). The U.S. pro-
ducers of benzene through the HDA process, their capacity, and the amount pro-
duced are shown in Table 4-8.
The second largest use of isolated toluene is back-blending into gasoline
for increasing the octane ratings. Approximately 1465 million kg of isolated
toluene, representing 35.1} of 1978 consumption, were used for gasoline back-
blending.
The third largest use of toluene is in solvent applications, with the major
use being in the paint and coatings industry. Significant amounts also are used
in adhesives, inks, Pharmaceuticals, and other formulated products. With the
establishment of federal and state laws limiting the emission of aromatic sol-
vents in the workplace and in the general environment, the demand for toluene as
a solvent has declined significantly (amount unspecified) since 1975 (Mara
et al., 1979). Identification of specific users of toluene as a solvent is
difficult because the users are too widespread.
Another major use of isolated toluene is as a raw material in the production
of toluene diisocyanate (TDI), benzyl chloride, benzoic acid, xylene, and vinyl
toluene. Manufacture of phenol, cresols, toluene sulfonic acids, nitrotoluenes,
terephthalic acid, caprolactam, and styrene are some of the minor uses of
4-11
-------
isolated toluene (Mara et al., 1979). A small amount of isolated toluene
(6.6 million kg, <1$ of total) is used for the manufacture of £-cresol (ADL,
1981). The latter compound is used primarily for the manufacture of the pesti-
cide 2,6-di-tert-butyl-p-cresol (BHT). Judging from the percent of toluene used
in the manufacture of BHT, its emission from this manufacturing process should be
considered insignificant.
The identification of primary users of toluene as a chemical intermediate, ;
their production capacity, and the amount produced is shown in Tables 4-9 and
4-10. It should be .pointed out that the amount of isolated toluene used in the
United States in 1978 (excluding net export) was 4000 million kg according to
Table 4-7. However, Table 4-2 shows that the total amount of toluene available
for internal consumption during the same period (excluding net export) was only
3600 million kg. This discrepancy is due to the fact that Table 4-7 is-based on
data that are only estimates and the data in Table 4-2 were obtained from the
manufacturers who reported their net toluene production to the U.S. Inter-
national Trade Commission.
4.41. ENVIRONMENTAL RELEASE
The three primary sources of toluene release or emission to the environment
are production, usage, and inadvertent sources.
t!
4.4.1. Emission from Production Sources. Toluene can be released into the
environment during its production as process losses, fugitive emissions, and
storage losses. Process emissions are those that originate from the reaction and
distillation vents deliberately used for venting gases. Storage emissions
originate from losses during loading and handling of the product used for manu-
facturing processes and storage of the final product. Fugitive emissions are
4-14
-------
TABLE U-8
Consumers of Toluene for the Manufacture of Benzene by HDA Process3
Toluene Used Benzene Production Capacity
Company and Location (10 kg) (10 kg)
American Petrofina - Port Arthur, TX
Big Spring, TX
Ashland Oil - Catlettsburg, KY
Coastal States - Corpus Christi, TX
Commonwealth - Penuelas, PR
Crown - Pasadena, TX
Dow - Freeport, TX
Gulf - Alliance, LA
Philadelphia, PA
Monsanto - Alvin, TX
Phillips - Guayam, PR
Quintana-Howell - Corpus Christi, TX
Shell - Odessa, TX
Sunoco - Corpus Christi, TX
Toledo, OH
Tulsa, OK
59
103
91
156
298
59
65
122
52
103
103
191
18
52
163
39
77
130
120
200
380
77
84
160
67
130
130
250
23
67
210
50
TOTAL 167U 2155
aSource: Anderson et al., 1980
4-13
-------
TABLE 4-10
Other Toluene Chemical Intermediate Users in 1978s
Company and Location
Arco - Houston, TX
Sunoco - Marcus Hook, PA
TOTAL
Kalama - Kalama, WA
Monsanto - St. Louis, MO
Velsical - Beaumont, TX
Chattanooga, TN
Pfizer - Terra Haute, IN
Tenneco - Gar field, NJ
TOTAL
Monsanto - Bridgeport, NJ
Sauget , IL
Stauffer - Edison, NJ
UOP - E. Rutherford, NJ
TOTAL
Dow - Midland, MI
Production
Capacity
(10° kg)
Xylene Producers
89
92
181
Benzoic Acid Producers
64
5
23
27
3
7
129
Benzyl Chloride Producers
36
36
5
1
78
Vinyl Toluene Producers
27
Toluene Used
(10b kg)
48
50
98
33
2
12
14
1
3
65
16
16
3
0.5
35.5
25
Source: Mara et al., 1979
4-16
-------
TABLE 4-9
Producers of Toluene Diisocyanate (TDI) in 1978a
Company and Location
Allied Chemical - Moundsville, WV
BASF Wyandotte - Geismar, LA
Dow Chemical - Freeport, TX
Ou Pont - Deepwater, NJ
Mobay Chemical - Bay town, TX
New Martinsville, WV
Olin - Astabula, OH
Lake Charles, LA
Rubicon Chemical - Geismar, LA
Union Carbide - S. Charleston, WV
TOTAL
TDI Capacity
(105 kg)
36
45
45
32
59
45
14
45
18
25
364
Toluene Used
(106 kg)
20
25
25
17'
32
25
7
25
10
13
199
aSource: Mara et al., 1979
4-15
-------
TABLE U-11
Toluene Air Emission Factors from Production Sources6
Source
Catalytic reforming
Pyrolytic cracking
Styrene by-product
Coke oven by-product
Process
0.00002
0.00015
0.00001
0.00050
Emission
(kg lost/kg
Storage
0.00006
0.00060
0.00060
0.00060
Factor
produced)
Fugitive
0.00002
0.00015
0.00015
0.00015
Total
0.0001
0.0009
0.00076
0.00125
Source: Mara et al., 1979
4-18
-------
those that have their origin in plant equipment leaks. The air emission factors
used to estimate the total emission of toluene from different production sources
have been obtained from Mara et al. (1979) and the values are given in Table
4-11.
Based on the emission factors indicated in Table 1-11, the amount of toluene
emitted into the atmosphere from the four production sources has been estimated
in Table 4-12. Atmospheric releases of toluene from each source shown in
Table 1-12 are from production of both isolated and non-isolated toluene. It is
assumed that the air emission is dependent only on the manufacturing process and
is the same for both isolated and non-isolated toluene from the same process.
The manufacturing processes may lead also to toluene release in other media.
The release of toluene in water from petroleum refineries performing catalytic
reforming and pyrolytic cracking processes is assumed to be negligible because
the concentration of toluene has been determined to be below the quantification
limit in more than 90$ of discharged water from the refineries (ADL, 1981).
Coking operations, however, can lead to toluene release in other media. The
toluene-containing wastewaters from coking plants that originate from waste
ammonia liquor, final cooler blow down and benzol plant wastes have the following
distribution (ADL, 1981):
Direct discharge: 33$
Publicly Owned Treatment Works (POTW): 25*
Quenching: 40$
Deep well injection: 2%
Two-thirds of the wastewater from the quenching operation is recirculated
and actually not discharged. Therefore, only 73$ of the total wastewater con-
taining toluene is actually discharged to the environment.
4-17
-------
The average volume of effluents produced from coke-oven operation (ADL,
1981), the toluene concentration in these effluents (ADL, 1981), and the emission
factors in thesie effluents are given in Table 4-13. ''_
For a total coke production of 44 x 109 kg in 1978 (ADL, 1981), the total
Q
amount of toluene discharged in wastewater is calculated to be 44 x 10' x 4.43
x 10 x 0.73 = 142 x 10^ kg. Some toluene in wastewater may finally enter other
media, because wastewater from the quenching operation is sent to sumps that
generate only solid and gaseous wastes (ADL, 1981). Therefore, the distribution
of total released toluene in untreated wastewater can be estimated as given in
Table 4-14.
4.4.2. Emission from Toluene Usage. The emission of toluene from various usages
has been estimated from emission factors and the amounts used. The values for
the emission factors obtained from Mara et al. (1979) are shown in Table 4-15.
The atmospheric emission of toluene from its production sources, such as
gasoline in non-isolated BTX and the isolated form (for back-blending), has
already been included in Table 4-12. The emission factor for miscellaneous uses
has been assumed to be the average of other toluene usages excluding its use as a
solvent. All the toluene used in paint and coatings has been assumed to be
ultimately released to the atmosphere (Mara et al., 1979). Therefore, an emis-
sion factor of 1.0 has been estimated for this usage. Fifteen percent of the
toluene used as a solvent for adhesives, inks, and Pharmaceuticals is recovered
for fuel use (Mara et al., 1979); the remainder is emitted to the atmosphere.
Hence, an emission factor of 0.85 has been assumed for this usage.
Based on the emission factors given in Table 4-15, the estimated toluene
emissions from its various usages are shown in Table 4-16.
4-20
-------
TABLE U-12
Estimated Atmospheric Toluene Emissions from
Four Major Production Sources
Production Source
Total Amount
Produced
(million kg/yr)
Total Total
Emission Emission
Factor (103 kg/yr)
Catalytic reforming - Isolated
- Non-isolated
Pyrolytic cracking
Styrene by-product
- Isolated
- Non-isolated
Coke oven by-product - Isolated
- Non-isolated
TOTAL
3,110
27,000
324
197
135
26
96
0.0001
0.0009
0.00076
0.00125
3,011
169
103
153
3,736
U-19
-------
TABLE 4-14
Toluene Released in Different Media from Coke-Oven Wastewatera
Medium
Air
Water
Land
POTW
Percent of
Total Released
20
33
22
25
Amount released/yr
(10J kg)
28
47
31
36
toluene releases from quenching are arbitrarily assumed to be evenly distri-
buted between land and air.
4-22
-------
TABLE 4-13
Toluene Emission Factors in Wastewater from Coke Oven Operation3
Effluent
Liters of Effluent
Produced/kg Coke
Toluene
Cone.
(mg/Jl)
Emission
Factor
(kg/kg coke)
Waste ammonia liquor
Final cooler blow down
Benzol plant wastes
TOTAL
0.16
0.13
0.20
3.1
17.0
8.6
0.496 x 10'6
2.21 x 10"6
1.72 x 10
4.43 x 10
-6
-6
a
Source: ADL, 1981
4-21
-------
TABLE 4-16
Estimated Toluene Emission from Different Uses
Source
Benzene production
Solvent for paint and
coatings
Solvent for adhesives,
Pharmaceuticals , and
others
Toluene diisocyanate
t
Xylene production
Benzole acid
Benzyl chloride
Vinyl toluene
Miscellaneous others
TOTAL
Amount Used/yr
(105 kg)
1675
263
inks,
132
200
• i
98
65
36
25
39
2533
Emission
Factor
(kg lost/kg used)
0.0002
1.0
0.85
0.00128
0.0002
0.00150
0.0010
0.0010
0.0010
Total Emission/yr
(103 kg)
335
263,000
•5
112,000
256
20
98
36
25
39
375,809
4-2U
-------
TABLE 4-15
Toluene Emission Factors for Its Uses'3
Emission Factor
(kg lost/kg used)
Usage
Benzene production
Solvent for paint
and coatings
Solvent for adhesives,
ink, Pharmaceuticals,
and others
Toluene diisocyanate
Xylene production
Benzoic acid
Benzyl chloride
Vinyl toluene
Miscellaneous
Process
0.00005
NA
NA
0.00077
0.00005
0.00100
0.00055
0.00055
NA
Storage
0.00010
NA
NA
0.00032
0.00010
0.00040
0.00030
0.00030
NA
Fugitive
0.00005
NA
NA
0.00019
0.00005
0.00010
0.00015
0.00015
NA
Total
0.00020
1.0
0.85
0.00128
0.00020
0.00150
0.00100
0.00100
0.00100
Source: Mara et al., 1979
NA = not applicable.
4-23
-------
TABLE 4-17
Toluene Released in Aqueous Media from Use as a Solvent in Various Industries'
Source
Ink formulating
Textile products
Gum and wood chemicals
Paint formulating
Leather tanning
Pharmaceuticals
TOTAL
Toluene Cone.
in
Wastewater
(Mg/JO
1600
14
2000
, 990
78
515
Percent
Occurrence
87
46
78
87
25
62
Wastewater
Discharged
(10b l/d)
0.092
2000
0.11
2.8
200
250
Amount of
Toluene
Released ,
(103 kg/yr)°
0.038
3.8
0.17
0.72
1.2
2U
29.9
Source: ADL, 1981
Based on 300 operating d/yr.
4-26
-------
It can be concluded from Table 4-16 that, among the different usages of
toluene, the maximum emission (excluding inadvertent sources) occurs from
solvent application (see Section 4.4.3.).
The released toluene from the different user sources shown in Table 4-16 has
been assumed to enter only one medium, air. The use of toluene as a solvent,
however, has been found to produce toluene in wastewater (ADL, 1981). Table 4-17
shows the total estimated release of toluene to aqueous media from its use as a
solvent in different industries.
4.4.3. Emission from Inadvertent Sources. Because gasoline consumes a vast
amount of total toluene produced (Table 4-7), this use constitutes the largest
source of environmental emission of toluene. The emission of toluene from its
use in gasoline can occur from three distinct sources: evaporation from its use
in the automobile, evaporation from marketing activities (handling and transfer
of bulk quantities), and emission from automobile exhaust.
Other inadvertent sources of toluene emissions into the environment include
transportation spills into surface water and land, other manufacturing processes
not producing toluene, different combustion sources, and cigarette smoke (Table
4-18). The inadvertent release of toluene from other manufacturing processes
occurs primarily from feedstock contamination, by-product formation, and the use
of oil. An example of the latter source is in the manufacture of acrylonitrile
in which wastewater ponds are covered with oil to control the release of volatile
organics.
The release of toluene into different media from various inadvertent
sources is shown in Table 4-18. Intermedia transfers of the compound will
possibly change the emission values given in Table 4-18 because of the volatility
of toluene.
4-25
-------
4.4.4. Sum of Emissions from All Sources. The emissions of toluene into
different media from all sources are given in Table 4-19. The estimates also
include toluene emission from coke production. The emission of toluene from coke
oven operation is based on an emission factor of 0.00021 (Mara et al., 1979 and
an estimated coke production of 44 x 109 kg (ADL, 1981) for the year 1978. ;
It is evident from Table 4-19 that the toluene released into the environment
predominantly enters one medium, the atmosphere. The three largest sources of
toluene emission in descending order are auto exhaust, solvent use, and evapora-
tive loss from automobile and service stations. A large amount of toluene from
land and water spills is also likely to enter air as a result of evaporation. The
large figure for the combined release of toluene into the atmosphere explains the
reason for its presence as the aromatic hydrocarbon of highest concentration in
the ambient atmosphere (Chapter 7).
4.5. USE OF TOLUENE IN CONSUMER PRODUCTS
The consumer products shown in Table 4-20 and analyzed prior to 1969 may
contain some toluene. The percent of toluene in these products also is indicated
in the same table. The emission of toluene into the environment from this source
is already included under Section 4.4.2.
Information available through the Food and Drug Administration (FDA)
(Bolger, 1981) shows that of the 19,500 cosmetic products registered with the FDA
through August 14, 1979, 664 products contain varying percents of toluene. One
of the products contains more than 50$ toluene, 166 products contain 25 to 50%
toluene, 492 products contain 10 to 25% toluene, 1 product contains i to 5%
toluene, and 4 products contain 0.1$ or less toluene. The use of toluene is
related to nail base coats, nail enamel, nail polish removers, and other manicure
products.
4-28
-------
TABLE 4-18
Toluene Emisaion from Different Inadvertent Sources'
Environmental Release
(10-5 kg/yr)
Source
Gasoline marketing
Automobile gasoline evaporation
Automobile exhaust
transportation spills:
Oil
Gasoline
Toluene
Propylene oxide manufacture
Polychloroprene manufacture
Ethylene-propylene rubber manufacture
Ethylene-propylene terpolymer
production
Wood preserving industry
Insulation board manufacture
Hardboard manufacture
Acrylonitrile manufacture
Combustion processes:
Coal refuse piles
Stationary fuel combustion
Forest fires
Agricultural burning
Structural fires
Cigarette smoke
Others
; TOTAL
Air
19,000
18,000
640,000
NR
NR
NR
36
460
90
4,200
NR
NR
NR
59
4,400
13,000
7,000
1,000
<1,000
53
8
708,306
Water
NR
NR
NR
400
680
2.2
NR
NR
NR
NR
6.3
neg.
neg.
NR
NR
NR
NR
NR
NR
NR
NR
1,089
Land
NR
NR
NR
5.6
230
11
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
24?
Source: ADL, 1981
NR = not reported
4-27
-------
light reflex, and after-effects (muscular fatigue, nervousness, and insomnia)
that lasted for several days.
Carpenter and coworkers (1944) exposed 2 male subjects to known concen-
trations of toluene (purity not stated) for periods of 7 to 8 hours and noted
slight exhilaration at 200 ppm, and lassitude, nausea, and hilarity at 400 ppm.
Lassitude, hilarity, verbosity, and boisterousness occurred at 600 ppm (Anorexia
and listlessness were reported as after-effects.), and transitory headaches,
extreme lassitude, scotomata (areas of depressed vision), verbosity, slight
nausea, and "inebriation11 were found at 800 ppm. Marked unsteadiness was also
observed in the subjects during exposure to 800 ppm toluene. Steadiness was
determined by a test that involved holding at arms' length a wire in a hole for
3 minutes; the percentage of time the wire was actually in contact with the side
of the hole was determined, and compared with the normal value from each test
session.
Short-term experimental exposures to toluene have also elicited increases
in reaction time and reductions in perceptual speed (Ogata et al., 1970;
Oamberale and Hultengren, 1972). Ogata and coworkers (1970) reported that 23
Japanese subjects given single exposures to 200 ppm toluene showed a prolonged
eye-to-hand reaction time, but no effect on flicker fusion frequency. Exposures
were for 3 hours, or 3 hours and a 1 hour break period followed by 4 additional
hours of exposure. No changes in either reaction time or flicker value were
observed at 100 ppm. It should be noted, however, that no other information
regarding the design of these experiments was presented. ,
In a more extensive study, Gamberale and Hultengren (1972) exposed 12 male
subjects to 100, 300, 500, or 700 ppm toluene (via breathing valve and mouth-
piece) during successive 20 minute exposure periods, and measured their perfor-
mance on four tests of perceptual speed and reaction time at each level of
11-5
-------
exposure (Table 11-2). The tests were always made in the same sequence (i.e.,
Identical Numbers, Spokes, Simple Reaction Time, Choice Reaction Time) during
the final 15 minutes of each exposure period. Toluene concentrations were
increased from 100 to 300 ppm and from 500 to 700 ppm without interruption, but
the increase from 300 to 500 ppm was made following a 5 minute interval without
exposure. Menthol crystals contained in the mouthpiece tubing camouflaged the
taste and smell of the toluene. The 12 subjects were divided into two groups of
•
equal size: subjects in one group were studied individually, first under experi-
mental conditions with exposure and then under control (atmospheric air contain-
ing menthol) conditions 7 days later, while subjects in the other group were
studied under similar conditions but in the reverse order. The camouflage of the
inspiratory air with menthol made it impossible for 11 of the 12 subjects to
distinguish between exposure to toluene and exposure to pure air.
Results of the Gamberale and Hultengren (1972) study showed that both reac-
tion time and perceptual speed were impaired during exposure to toluene as
compared to exposure to pure air (Table 11-2). With respect to reaction time, a
significant effect was noted upon exposure to 300 ppm toluene in one test (Simple
Reaction Time), and a performance decrement which reportedly approached statis-
tical significance at the 0.05 level was noted for the other test (Choice Reac-
tion Time). Subject reaction time was further impaired at higher levels of
exposure (500 and 700 ppm toluene), but no impairment in either reaction time
test was noted for exposure to 100 ppm. (The 100 ppm reaction time no-effect
level is consistent with the aforementioned results of Ogata et al., 1970.) No
statistically significant impairment in subject perceptual speed was observed
until the concentration of toluene in the inspiratory air was 700 ppm. Because
perceptual speed was unaffected at concentrations below 700 ppm, the authors
11-6
-------
TABLE .11-1
Effects of Controlled 8 Hour Exposures to
Pure Toluene on Three Human Subjectsa'
Concentration Ho. of Effects
Exposures
0 ppm (control) 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.
50 ppm 2 Drowsiness with a very mild headache in 1 subject. No
aftereffects.
100 ppm 1» Moderate fatigue and sleepiness (3), and a slight
headache on one occasion (1).
200 ppm 3 Fatigue (3), muscular weakness (2), confusion (2),
impaired coordination (2), paresthesia 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 engorged. Aftereffects
included fatigue, general confusion, moderate
insomnia, and restless sleep in all 3 subjects.
300 ppm 2 Severe fatigue (3), headache (2), muscular weakness
and incoordination (1), and slight pallor of the eye-
ground (2). Aftereffects included fatigue (3) and
insomnia (1).
400 ppm 2 Fatigue and mental confusion (3), headache, pares-
thesia of the skin, muscular weakness, dilated pupils,
and pale eyeground (2). Aftereffects were fatigue
(3), skin paresthesia (1), headache (1), and insomnia
(2).
600 ppm 1 Extreme fatigue, mental confusion, exhilaration,
nausea, headache and dizziness (3), and severe head-
ache (2) after 3 hours of exposure. After 8 hours'
exposure, the effects included considerable incoor-
dination and staggering gait (3), and several
instances of dilated pupils, impaired pupillary light
reflex and pale optic discs; aftereffects included
fatigue and weakness, nausea, nervousness and some
confusion (3), severe headache (2), and insomnia (2).
Fatigue and nervousness persisted on the following
day.
11-3
-------
TABLE 11-1 (cont.)
¥
Concentration No. of Effects
Exposures
800 ppm 1 Rapid onset of severe fatigue and, after 3 hours,
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 aftereffects, last-
ing at least several days, which included severe ner-
vousness, muscular fatigue, and insomnia.
aSource: Von Oettingen et al., 1942a, 1942b
Exposures were twice i
noted in parentheses.
Exposures were twice weekly for 8 weeks. The number of subjects affected is
11-4
-------
11. EFFECTS ON HUMANS
Human exposure to toluene primarily involves inhalation, and consequently
the effect of greatest concern is dysfunction of the central nervous system. As
detailed in Chapters 9 and 10, millions of individuals are exposed to toluene via
inhalation of air from ambient atmosphere and cigarette smoke (ppb concentra-
tions), and from occupational exposures (ppm concentrations). Toxicity studies
of humans have centered, however, on evaluation of individuals exposed to toluene
in experimental and occupational settings, and from deliberate inhalation of
toluene or toluene-containing substances ("glue sniffing"). It should be noted
that occupational exposures and glue sniffing often involve complex mixtures of
solvents, and that prior to the 1950s, benzene was a common contaminant of
toluene. In evaluating the effects of toluene exposures, the purity of the
compound must be considered.
Glue sniffers inhale the vapors from a wide variety of volatile hydrocarbons
(usually poorly defined mixtures) contained in products such as glues and
thinners for their euphoric or intoxicating effects. The most popular of these
products contains toluene, and toluene is the hydrocarbon most frequently impli-
cated as the cause of the adverse effects associated with deliberate inhalation.
The practice has been reviewed extensively (Massengale, 1963; Barman et al.,
1964; Press and Done, 1967a, 1967b; Gellman, 1968; Wyse, 1973; Linder, 1975;
Faillace and Guynn, 1976; Oliver and Watson, 1977; Walter et al., 1977; Watson,
1979). Excessive levels of toluene generally are inhaled over a short time
interval, and repeated inhalation of the vapors is associated with the develop-
ment of tolerance and psychological dependence. The most common methods of
inhalation involve (1) placing the solvent in a plastic bag and inhaling the
11-1
-------
fumes, (2J.soaking a rag or handkerchief with the solvent and sniffing the rag,
and (3) sniffing the solvent from a container. The concentrations of toluene
inhaled under these conditions can approach 30,000 ppm (i.e., saturation concen-
tration at 20°C).
11.1. EFFECTS ON THE NERVOUS SYSTEM
11.1.1. Central Nervous System
11.1.1.1. ACUTE EFFECTS — Experimental exposures of up to 800 ppm toluene
have produced acute dose-related central nervous system (CNS) alterations (Von
Oettingen et al., 1942a, 19^2b; Carpenter et al., 1944). Von Oettingen et al.
(1942a, 1942b) provided what generally is acknowledged to be the most complete
description of the effects of pure toluene (benzene £0.01}) on the CNS. In
single 8 hour exposures, 3 human subjects were subjected to concentrations of
toluene in an exposure chamber that ranged from 50 to 800 ppm (Table 11-1). A
maximum of two exposures a week were conducted to allow sufficient time in
between for recovery; a total of 22 exposures were performed over an 8 week
period. Seven of the 22 exposures were to pure air, and exposures to particular
levels of toluene were replicated only 1 to 4 times. The effects that were
observed also are summarized in Table 11-1. Subjective complaints of fatigue,
muscular weakness, confusion, impaired coordination, and enlarged pupils and
accommodation disturbances were reported at levels of 200 ppm. These effects
increased in severity with increases in toluene concentration, until at 800 ppm
the subjects experienced severe fatigue, pronounced nausea, mental confusion,
considerable incoordination and staggering gait, strongly impaired pupillary
11-2
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TABLE 10-4
Exposed Population and Exposed Amount of Toluene From Dispersion Modelling
Concentration
Level Exposed Concentration
(ug/nr) rag/week
>100 >15.7
100 to 10 15.7 to 1.6
10 to 1 1.6 to 0.15
1 to 0.1 0.15 to 0.02
0.1 to 0 0.02 to 0
^Source: Slimak, 1980
10-15
-------
contact given in Table 10-3 does not represent the total exposure value as it
ignores exposure to other organs.
10.4. CIGARETTE SMOKERS
The concentration of toluene in inhaled cigarette smoke has been determined
to be 0.1 mg/cigarette (see Subsection 7.3). In assessing toluene exposure from
cigarette smoking, it was assumed that an individual smokes 20 cigarettes per
day. On the basis of these assumptions, it can be predicted from Table 10-3 that
cigarette smoking may be the second largest source of human exposure to toluene.
10.5. LIMITATIONS OF EXPOSURE ASSESSMENT BASED ON MONITORING DATA
As discussed earlier, exposure assessment on the basis of monitoring data
has the following limitations:
(1) The limited monitoring data do not provide information
for estimating exposure under different exposure
scenarios. Even when some data are available, they may
be inadequate and even susceptible to error. It is very
difficult to assess the errors in the monitoring data.
(2) The monitoring data often do not relate to the source of
emissions in terms of material balancing of the amount
emitted and the concentration measured.
(3) The population distribution around the monitoring area is
rarely provided in these data, although such data may be
available independently of monitoring.
(I) The estimate for toluene exposure to the general popula-
tion from food and drinking water as given in Table 10-3,
is very crude. Toluene has been detected in only a small
fraction of total drinking water supplies monitored (Sub-
section 7.1.2.5.). The exposure estimate does not
specify either the number of people or the locations
where people are exposed to toluene from drinking water.
The same can be said with respect to toluene exposure
from food.
10-13
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10.6. COMPARISON BETWEEN EXPOSURE DATA BASED ON THEORETICAL AND EXPERIMENTAL
VALUES
If the concentration values ranging from 0 ug/nr to greater than 100 |jg/nr
(Table 10-2) are combined with the value of 156.8 nr for inspired volume of air
per week, an inhalation exposure estimate as shown in Table 10-4 can be
developed.
A comparison of inhalation exposure data shown in Table 10-4, which are
based on dispersion equations, with inhalation exposure data in Table 10-3,
which are derived from monitored concentrations, shows reasonable agreement
between the two sets of data. The monitoring data estimate toluene inhalation by
the general population in urban areas to be 0.02 to 32 mg/week. The exposure
data developed from dispersion equations estimate this value to be in the range
of zero to greater than 15.7 mg/week. The cumulative inhalation exposure can be
calculated by multiplying the exposed concentrations from Table 10-4 with the
appropriate exposed population given in Table 10-2.
10-14
-------
In rural and remote areas, the concentration of toluene has been reported to
be in the range of a trace to 3.8 |ig/nr (Table 7-1). These concentrations were
determined in 1971; the current level may be lower than this range, as indicated
by the toluene concentration reported at Grand Canyon in 1979. The estimated
toluene exposure in rural and remote areas is shown in Table 10-3.
It should be remembered that Table 10-3 shows the amount of toluene inspired
per week by humans around certain exposure scenarios and not the amount absorbed.
0
Only a certain fraction of the toluene inhaled is absorbed by human organs.
Also, part of the absorbed toluene is rapidly excreted from the body.
10.2. INGESTION EXPOSURE BASED ON MONITORING DATA
No theoretical modeling method is available for estimating toluene exposure
from various ingestion sources. Therefore, the exposure estimate from this
source ha3 been attempted by using the limited monitoring data that are avail-
able.
10.2.1. Exposure from Drinking Water. The concentrations of toluene in drinking
water range from 0 to 19 ug/fc (Subsection 7.1.2.5.). The concentration of
toluene measured in well waters in New York State was below 10 (ig/J, (Subsection
7.1.2.4.). Therefore, a concentration range of 0 to 19 ug/A has been used for
exposure assessment shown in Table 10-3. A consumption rate of 2 2,/day has also
been assumed for exposure asessment.
1Q.2.2. Exposure from Edible Aquatic Organisms. The concentration range of
toluene in edible aquatic organisms has been assumed to be 0 to 1 mg/kg, based on
the level of toluene found in unspecified fish tissues (Subsection 7.1.4.). On
the basis of these data and the assumption that the per capita consumption of
10-11
-------
aquatic organisms in the United States is approximately 6.5 g/day (Stephan,
• • A' • .* .
1980), the exposure range of toluene from food is shown in Table 10-3.
10.3. OCCUPATIONAL EXPOSURE
Occupational exposure to toluene can primarily take place from two
scenarios, inhalation of air containing toluene and skin contact with toluene or
other solvent mixtures containing toluene. The concentration of toluene in the
air of working atmosphere has been assumed to be 377,000 ug/m. This value
corresponds to the OSHA (Occupational Safety and Health Administration) recom-
mended workroom air standard of 100 ppm toluene vapor as a time-weighted average
(TWA) exposure for an 8 hour work day (OSHA, 1973)* This value is reasonably
close to the actual occupational exposure levels discussed in Section 7.2. Based
on the above assumptions, the inhalation exposure of toluene by occupational
groups as shown in Table 10-3 far exceeds that for any other group.
Sato and Nakajima (1978) studied the absorption of toluene through human
skin. These investigators immersed one hand of 5 male subjects in pure toluene
for 30 minutes and monitored the blood levels of toluene. A peak concentration
of 170 ug/l of blood was observed after a 30 minute immersion. This maximum
concentration was maintained for 10 to 15 minutes after exposure had ended and
decreased thereafter.
Although the standard set forth by OSHA (1973) requires all workers handling
toluene to wear gloves, it is conceivable that short-term exposure of bare skin
to toluene takes place under certain circumstances. For assessment of exposure
through skin as shown in Table 10-3, a maximum concentration of 170 Mg/Z, in blood
and a blood volume of 5.9 I for an adult male have been assumed. It has also been
assumed that the skin exposure duration does not exceed 30 minutes/week. It
should also be recognized that the value for blood concentration through dermal
10-12
-------
available monitoring data were often developed for sites with various degrees of
intermixing between these exposure scenarios. Therefore, inhalation exposure
0
has been classified under three scenarios, the urban areas, areas containing the
user sites, and rural or remote areas. In this manner, the exposure estimates
developed may be representative of a broad range of the possible exposure
scenarios. It should be remembered that the urban areas may contain sites with
high automobile use, production and other manufacturing sites, and coke-oven
sites.
Human exposure to toluene through inhalation of urban air is shown in
Table 10-3- The concentration of toluene in urban areas in the United States in
recent years ranged from 0.1 ug/nr to 204 ug/m (Table 7-1). The intake estimate
is based on a breathing rate of 1.2 or/hour for an adult during waking hours and
0.4 nr/hour during sleeping hours (ADL, 1981). It is also assumed that the
sleeping period for an adult is 8 hours/day. This results in an inspired volume
of (1.2 x 16 x 7 + 0.4 x 8 x 7) = 156.8 m3/week.
i
Near user sites, the range of toluene concentration has been assumed to be
5.5 to 600 ug/m . This range corresponds to the measured value of Sexton and
Westberg (1980) near an automotive painting plant (Subsection 7.1.1.) (solvent
use constitutes about 99$ of total usage). The concentration of toluene at a
distance 18 km from the plant measured 55.5 ug/m , a value 10 times higher than
the background concentration (Sexton and Westberg, 1980). Therefore, even
workers who commute more than 18 km from the plant are susceptible to inhale
toluene concentration in the range of 5.5 to 600 ug/m for the entire 168 hours
in a week. The toluene concentrations near manufacturing sites range from 0.1 to
147 ug/m . The estimated toluene exposure range from the manufacturing and user
sites shown in Table 10-3 is based on a concentration range of 0.1 to 600 ug/m .
10-9
-------
TABLE 10-3
Toluene Exposure Under Different Exposure Scenarios*
o
i
Scenario
General Population
Inhalation
Urban areas
Rural and remote areas
Areas near manufacturing
and user sites
Ingestion
Drinking water
Pood (fish only)
Occupational Group
Inhalation
Dermal
Cigarette Smokers
Inhalation
Observed
Range of
Concentration
0.1 to 201 ug/m3
trace to 3-8 ug/m
0.1 to 600 ug/m
0 to 19 ug/fc
0 to 1 rag/kg
377,000 ug/m3
0 to 170 ug/«,D
0.1 rag/cigarette
Frequency Total Volume
of Exposed or
Exposure Amount Consumed
168 h/wk
168 h/wk
168 h/wk
2 i/d
6.5 g/d
10 h/d
0 to 30 min/wk
20 cigarettes/d
156.8 m3
156.8 nr*
156.8 ra3
11 A
15.5 g
18 m3
5.9 I
110 cigarettes
Inhalation or
Ingestion Rate
(mg/wk)
0.02 to 32
trace 0.6
0.02 to 91
0
0
18
0
11
to 0.3
to 0.15
,100
to 1.0
a
Source:
This value represents exposure to blood due to dermal contact and represent absorbed levels.
13 ttftcOSBAsrSfifl-fiWlag I&ulgfrd-
-------
TABLE 10-2
Population Distribution and Inhalation Exposure
Levels of Toluene From Different Sources3
Concentration
Level
(ug/m3)
Number of People Exposed From
Specific
Point Sources
Prototype
Point Sources
Area
Sources
>100
100 to >50
50 to >25
25 to >10
10 to >5
5 to >2.5
2.5 to >1
1 to >0.5
0.5 to >0.25
0.25 to >0.1
0.1 to 0
Subtotals
Total
Source : Anderson
0
0
34
475
1,434
6,103
19,781
39,064
95,560
269,883
34.316.299
34,748,633
et al., 1980
159
2,841
10,200
22,700
33,900
75,200
240,000
246,000
350,000
1,229,000
0
2,210,000
195,637,768
58,347
446,793
12,348,504
42,478,913
68,368,769
0
0
0
0
0
34.977.809
158,679,135
10-7
-------
ing. Any "deviations in these estimates from the true pattern (difference in
theoretical and experimental values) directly affect the exposure results.
Many assumptions were used in calculating the concentration distribution.
The exposure errors will be more severe in the case of prototype point
sources where a prototype model was used for calculating exposure from all
other similar sources. The same can be said about the exposure estimates
from area sources based on a box model method that incorporated a number of
uncertainties. .
interpolation Errors; The interpolation of population and concentra-
tion patterns used to develop patterns of exposure can introduce errors."
With the available information, it is not possible to quantify any of the
errors described above. The theoretical model may provide qualitative insights
in certain instances to predict whether the exposure estimate is either too high
or too low compared to the actual values.
10.1.2. Inhalation Exposure Based on Monitoring Data. Exposure of the general
population to toluene by inhalation can occur under a wide range of exposure
scenarios. Because it may be considered impractical to measure toluene concen-
tration from all possible exposure scenarios, an attempt has been made to develop
a few of the most prevalent ones.
The four largest sources of toluene emission, in descending order, are
automobile use (exhaust emission, engine evaporative loss, gasoline marketing
evaporative loss), industry sites using toluene as a solvent, coke oven sites,
and toluene production sites (Subsection U.4.4.). In place of dispersion model-
ing, one can use the monitoring data from each of the four sites to evaluate the
four different exposure scenarios. The difficulty with this approach is that the
10-8
-------
TABLE 10-1
Concentration of Toluene (mg/nr) at Different Distances (m)
From A Source Emitting 200 Million kg/Year Toluene3
Plume Height
(m)
10
20
100
1.36
0.003
500
O.U5
0.31
1,000
0.15
0.13
1,500
0.12
0.10
5,000
0.02
0.02
10,000
0.01
0.01
aSource: Slimak, 1980
10-5
-------
These sources included emissions from gasoline marketing, from the coke-
oven industry, and from isolated and non-isolated toluene producers (not
included in the previous categories).
Area Sources: Such sources were treated as emission per unit area over
identified areas. These sources included mobile emission, emission from
solvent use, and emissions from miscellaneous sources.
The three equations used to calculate the spatial concentration distribu-
tion of toluene from all sources are given in considerable detail in Anderson
et al. (1980); interested readers are referred to that document. The final
results of the calculations of Anderson et al. (1980) led to the estimate of
spatial concentration range of toluene around different sources of emissions.
These values are given in Table 10-2.
Anderson et al. (1980) listed the following factors that could cause uncer-
tainties in their calculated exposure levels given in Table 10-2:
Emission Estimates Errors; Some of these are (1) error in the esti-
mates of production and use of toluene, (2) the assumption that all plants
operate at the same capacity, (3) omission of certain emission sources, and
(4) error in derivation of emission factors and, in certain cases, the use
of a uniform emission factor, which implies that all these plants have
similar emission controls. It is difficult to project whether the emission
estimates used by Anderson et al. (1980) will lead to higher or lower
exposure estimates. This can be done, however, by comparing these esti-
mates with the experimentally determined concentration patterns obtained
from sources that are reasonably isolated from other sources.
Concentration Pattern Errors; The concentration patterns used in the
exposure computations were obtained through atmospheric dispersion model
10-6
-------
environmental concentration distribution in an area. Therefore, the approach
toward exposure estimation in this section has utilized both the available
ambient monitoring data and the theoretical dispersion modeling of toluene emis-
sion data.
10.1.1. Theoretical Modeling. The estimation of inhalation exposure to toluene
among different segments of the general population involves the following compu-
tational tasks: (1) estimation of annual average toluene concentration in the
air at different distances from the emission sources and (2) estimation of the
population distribution around each source of emission (available through the
U.S. Census Bureau). The latter computation has already been discussed in
Chapter 9.
The performance of the first task requires the following data: (1) emission
inventories of toluene, which are already available (Subsections 4.4.1. through
4.4.4.), (2) atmospheric reactivity of toluene, (3) meteorological data, which
are available through the U.S. or local weather bureau, and (4) a dispersion
equation to estimate concentration distribution of toluene.
Toluene concentration downwind from a source can be estimated using the
following dispersion equation (Turner, 1969):
-h
2a2
z
where
C(X,0,0) = concentration of toluene at various x coordinates and at zero y
and z coordinates (mg/m )
Q = emmission rate (mg/s)
0" = horizontal dispersion coefficient of the plume concentration
y distribution
a = vertical dispersion coefficient of the plume concentration
2 distribution
10-3
-------
U = the mean wind speed (m/s) (w = the heat of the source)
h = the effective stack height; i.e., the sum of the stack height and
plume rise (m)
:" '• '6 3
Assuming U = 5 m/s; Q = 200 x 10 kg/year = 6.34 x 10J mg/s; plume height
s 10 m and 20 m; and the values of o\ and a_ from the following equation
y z
(Anderson et al., 1980):
0, (m) s 0.06x(1 + 0.0015x)"1/2
Z
a (m) = 0.08x(1 + 0.000lx)"1/2
one can calculate the concentration of toluene at different distances from the
source, as given in Table 10-1.
The calculations of the values in Table 10-1 for toluene distribution from a
stationary source do not consider the chemical reactivity of toluene in the
atmosphere and the effect of plume temperature on the concentration distribution
of toluene. A more detailed calculation that incorporates these two variables,
as well, as building wake effect (enhanced dispersion due to buildings), has been
made for the estimation of spatial concentration of toluene from the major
stationary sources of toluene emission (Anderson et al., 1980).
The dispersion equation developed by Anderson et al. (1980) was used to
A
compute annual average concentration pattern of toluene from each point source.
A computer program was used to evaluate these concentration patterns from the
given meteorological and emission data. Because there are numerous sources of
emission, the sources were divided into three types, each of which is defined
below.
Specific Point Sources; These sources were treated using parameters
appropriate to each source. These sources included emissions from produc-
tion sources and from chemical intermediate users.
General Point Sources; For these sources, a prototype analysis was
done and the results were multiplied by the estimated number of sources.
10-4
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10. INTEGRATED EXPOSURE ANALYSIS
Exposure is the contact between a subject of concern and an agent such as a
chemical, biological, or physical entity. The magnitude of the exposure is
determined by measuring or estimating the amount of an agent available at the
exchange boundaries, that is, lung, gut, and skin, during some specified time.
Exposure assessment is the qualitative estimation or quantitative determination
of the magnitude, frequency, duration, and route of exposure. Exposure assess-
ments are often combined with environmental and health effects data in performing
risk assessments. The exposure of an agent may lead to the intake of some of the
agent. Uptake or an absorbed dose is the amount of the intake which is absorbed
by the subject.
The assessment of human health risks from exposure to any environmental
pollutant requires knowledge of (1) the dosage of the pollutant received by the
exposed human population and (2) the effect of the pollutant on human health.
Because the purpose of this section is not to develop a health effects model, no
attempt will be made to address such parameters as population characteristics
(e.g., age, sex, occupation, racial background), population habits (e.g., food
habits, recreational habits, product-use habits), and population groupings
(e.g., the aged, pregnant women, children, other high health risk groups).
Instead, this section will attempt to derive the human exposure of toluene
received from all sources of emissions.
In order to make an exposure asessment, one must consider route of entry,
magnitude of exposure, frequency of exposure, and duration of exposure. The
general population may be exposed to toluene through the following three routes:
(1) inhalation of air, (2) ingestion of water and foods, and (3) exposure through
10-1
-------
skin. The next step toward an integrated exposure analysis combines the estima-
tion of environmental concentrations with a description of the exposed popula-
tion to yield exposure profiles and exposure pathway analysis.
Certain segments of population may be exposed to toluene through occupa-
tional exposure and cigarette smoking. Because exposure of this segment of the
population falls under a special category, these scenarios will be discussed
separately. It should be mentioned that this section does not include toluene
exposure from the use of consumer products. As has been mentioned in Sub-
section 10.5., some consumer products contain high percentages of toluene.
Undoubtedly, the use of these consumer products leads to various degrees of
toluene exposure in the general population; however, no data are available from
which estimates of toluene exposure from consumer products can be derived.
10.1. EXPOSURE VIA INHALATION
Estimation of toluene exposure via inhalation can be done in two ways.
First, the exposure can be estimated from the total nationwide toluene emission
data by the use of mathematical models simulated to reflect the actual environ-
mental setting. Second, the exposure can be estimated from actual monitoring
data. Estimating exposure on the basis of monitoring data is often a preferred
method, because these data directly provide the environmental distribution of
toluene; however, this method has its own limitations. Although the monitoring
data available for toluene are more abundant than those available for many other
organic chemicals, they may not be statistically representative of all the popu-
lation exposed to toluene. The monitoring data may not provide information on
the extent of concentration variation due to chemical reactivity (e.g., photo-
reaction, oxidation in the atmosphere, etc.). These data also do not yield
relationships between materials balance of the emitted toluene and the
10-2
-------
to toluene. Toluene ranks fourth among all other agents listed in terms of the
number of people exposed to any single agent.
The number of people in the U.S. exposed to toluene through cigarette smoke
has been estimated to be 56 million during the year 1978a. This figure which
considers the exposure to the smokers only, is bound to be an underestimate since
it does not include passive smokers.
figure is based on the following assumptions: Of the total population of
225 million, 21.UJ are under age 13 (Dept. Commer., 1979) and do not smoke.
Teenagers in the age group 13 years to 17 years constitute 7.6% of the total
population (Dept. Commer., 1979). Of the 7.6% of the teenagers, only 11.7%
are assumed to be smokers (PHS, 1980). Of the remaining population, 51}
are assumed to be females and 49$ to be males (Dept. Commer., 1979)* The
percent of female and male smokers over age 17 are assumed to be 30*4$ and
37.4$, respectively (PHS, 1980).
9-3
-------
9. EXPOSED POPULATIONS
The number of people exposed to various sources of toluene can be divided
into three categories, general population, occupational group, and cigarette
smokers. The breakdown of general population subjected to inhalation exposure of
toluene from various sources of emissions can be obtained by performing a
population analysis around each source. A computer program was used by Anderson
et al. (1980) to extract site-specific population patterns from the U.S. Census
figures standardized to 1978 population levels. The number of general population
exposed to various levels of toluene from different sources of emission as
calculated by Anderson et al. (1980) is shown in Table 9-1. For an explanation
of the breakdown of the source variety shown in Table 9-1, Section 10.1.1.
The exposed population count shown in Table 9-1 is derived from the geo-
graphical coordinate of each location. Error in the geographical coordinates of
a source and population center will cause errors in population count. In addi-
tion, the population count figures obtained from U.S. Census Bureau is subject to
undercounting. The result of this undercounting will be lower population expo-
sure estimates than the actual case.
No estimate of the number of general population exposed to toluene from
ingestion of foods and drinking waters can be given. Toluene has been detected
in only a small fraction of total drinking water supplies and foods that have
been monitored. The number of people consuming the contaminated waters and foods
is not known at the present time.
According to the estimate of the Department of Health, Education, and
Welfare (1977), more than 4.8 million people per year are occupationally exposed
9-1
-------
TABLE 9-1
Population Distribution and Inhalation Exposure
Levels of Toluene from Different Sources3
Concentration
Level
>100
100 - >50
50 - >25
25 - >10
10 - >5
5 - >2.5
2.5 ~>1
1 - >0.5
0.5 - >0.25
0.25 - >0.1
0.1 - 0
Subtotals
Specific
Point Sources
0
0
31
475
1,131
6,103
19,781
39,064
95,883
269,883
34.316.299
34,748,633
Number of People Exposed
Prototype
Point Sources
159
2,841
10,200
22,700
33,900
75,200
240,000
246,000
350,000
1,229,000
0
2,210,000
From
Area
Sources
58,347
446,793
12,348,504
42,478,913
66,368,769
0
0
0
0
0
34,977,809
158,679,135
Total
195,637,768
Source: Anderson et al., 1980
9-2
-------
Lieberraan, 1967); however, one of the better methods of hippuric acid analysis in
urine was developed by Caperos and Fernandez (1977). According to this method,
the hippuric acid in acidified urine is extracted with ethyl acetate. The
extracted hippuric acid is esterfied with 1-£-tolyltriazene. The dried ester is
dissolved in chloroform and quantified by GC-FID. The recovery of hippuric acid
by this method is determined from the recovery of an added internal standard.
The sensitivity of the method with 0.5 mi urine was determined to be 5 mg/i.
8.6. FOODS
A headspace GC technique for quantification and a GC-MS technique for con-
firmation were used to determine trace amounts of toluene in plastic containers
(Hollifield et al., 1980). The sample, taken in a specially enclosed vial, was
heated at 90°C for 2 hours and 2 mi. of headspace gas. was injected into a GC
system. The principle of standard addition was used for the quantification of
toluene. Toluene present in parts per billion range can be determined by this
method.
8.7. CIGARETTE SMOKE
The concentration of toluene both in sidestream smoke (Jerimini et al.,
1976) and mainstream smoke (Dalhamn et al., 1968) has been determined. For the
determination of toluene in mainstream smoke, standard cigarettes were smoked by
machine under standardized conditions (a 2 second 35 mi puff once every minute).
The mainstream smoke is collected in a cold trap (Dalhamn et al., 1968). The
contents of the cold trap can be introduced into the GC by multiport valves and
analyzed by GC-FID for toluene determination.
Toluene determination in sidestream smoke can be accomplished by adopting
the sampling and analysis technique of Holzer et al. (1976). The sidestream
8-17
-------
smoke can be collected by drawing the smoke through a solid sorbent tube packed
' ... • . ' i
with Tenax GC. the Tenax GC sorbent tube can be thermally eluted onto a glass
capillary column for the determination of toluene content. Adoption of a cold
trap for splitless injection of the sample into the capillary column (Grob and
Grob technique) will enhance the sensitivity and accuracy of the method. Addi-
tional confirmation of the GC peaks can be done by interfacing the GC with a MS
(Holzer et al., 1976).
8-18
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a maximum capacity, the container must be tightly capped with contamination-free
lids to prevent loss of volatile components and to exclude possible oxidation.
The samples should be refrigerated (U°C) during transport and storage.
8.3-2. Analysis. Very few reliable methods are available for the analysis of
volatile organics in soil and sediment samples. Solvent extraction methods using
highly volatile solvents are not likely to be successful. The evaporative
concentration step of this method would result in the loss of volatile organics.
Headspace analysis, which has few provisions to concentrate the organics, will
produce unreasonably high detection limits.
A modification of the purge and trap method has been suggested by the U.S.
EPA (1979) for the analysis of soil and sediment samples. The modified purge and
trap apparatus used for this purpose is described by the U.S. EPA (1979). The
sample, contained in a specially-designed glass vial, is heated at 80°C and
purged with helium gas. The desorbed organics are trapped in a Tenax GC column.
At the end of trapping, the Tenax GC column is inserted in the injection port of a
GC, and the thermally desorbed organics are analyzed by GC-FID as in the case of
water and wastewater samples. The recovery of toluene was "determined to vary
between 32 and WJ when 0.1 to 3.0 ug of toluene was spiked onto a specially
prepared soil matrix. Although the recoveries were low, they were found to be
linear and reproducible (U.S. EPA, 1979). Data on spiked environmental samples
showed much higher recoveries (80 to 100$).
With the purge-trap system described, the minimum detection limit of
0.1 ppb can be attained. Thus, the method showed at least two orders of magni-
tude higher sensitivity than headspace analysis (U.S. EPA, 1979).
8-15
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8.4. CRUDE OIL AND ORGANIC SOLVENTS
Benzene and toluene concentration in petroleum crude and other fossil fuel
samples can be determined by a method developed by Grizzle and Coleman (1979) .*
In this method, the sample is directly injected into a GC system containing two*
columns in series. The effluent from the first column containing aromatics is
separated into individual fractions by the second column. Quantification of the
separated components is done by a flame ionization detector.
A combination of liquid chromatography (silica gel column) and GC-FID
method was employed by Fett et al. (1968) routinely to determine toluene in
hydrocarbon solvents.
8.5. BIOLOGICAL SAMPLES
Toluene or its metabolites have been determined both in blood and in urine
samples. These methods of analysis are discussed below.
8.5.1. Blood. Toluene in blood has been determined by GC analysis of headspace
samples (Premel-Cabie et al., 1971*; Anthony et al., 1978). According to this
method, blood is equilibriated with air in a closed container at a fixed tempera-
ture. The headspace gas is injected into a GC-FID system for detection of
toluene. The method can be used for quantification of toluene in blood by the
standard addition method as described in Section 8.2.2.2.
8.5.2. Urine. In the body, toluene is mainly oxidized to benzoic acid which,
after conjugation with glycine, is eliminated as hippuric acid in the urine.
Hippuric acid may be formed from other metabolic processes besides toluene meta-
bolism.
Hippuric acid in urine can be determined by a number of methods including.
colorimetry (Umberger and Fioresse, 1963) and UV spectrometry (Pagnatto and
8-16
-------
water samples spiked with model compounds (Vitenberg et al., 1977; Drozd et al.,
1978).
In the method of Drozd et al. (1978), a known volume (50 mi) of water is
introduced into a specially designed enclosed glass apparatus (100 mi), and the
system is thermostatically maintained at 40°C. After the system attains equi-
librium (30 minutes), a known volume of headspace vapor is introduced into a
capillary GC system via a trapping system consisting of a short cooled (-70°C)
precolumn coated with OV-101 (Grob and Grob technique). The separating colum was
coated with squalene.
The method of headspace analysis in the past had faced problems owing to the
difficulty in establishing a calibration procedure. The partition coefficient
of a component between gas and liquid phases is dependent on the total ionic
strength in solution. Therefore, the same concentrations of a component present
in two aqueous solutions of different ionic strengths but otherwise identical
conditions, will not produce the same equilibrium vapor pressure. This problem
of a calibration curve has been largely obviated through the development of a
standard addition method (Drozd et al., 1978). Water samples containing toluene
in the parts per billion range can be quantified by this method (Dro d et al.,
1978) with a reasonable accuracy; however, the method may not be applicable for
drinking water samples where the concentration may be lower than 1 ppb.
8.2.2.3. SORPTION ON SOLID SORBENTS — This method is rarely used for the
monitoring of toluene in aqueous samples. The applicability of the method was
explored by Pfaender (1976), and Ryan and Fritz (1978) used the method for
monitoring toluene in drinking water.
The method consists of passing a known volume of water through a sorbent
such as XAD-2 (Pfaender, 1976) or XAD-4 (Ryan and Fritz, 1978). The sorbed
8-13
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organics including toluene are desorbed either by solvent extraction (Pfaender,
1976) or by thermal desorption (Ryan and Fritz, 1978) and injected onto a GC-FID
system for component separation and quantification. In the thermal desorption
method of Ryan and Fritz (1978), the use of a trap consisting of a Tenax GC
precolumn to eliminate the excess water showed a good sensitivity for the method.
The recovery of toluene was nearly 90$ when the concentration in drinking water
ranged from 1 to 10 ppb. For the quantification of toluene in water by this
method, the recovery of toluene from the sorbent should be known.
8.3. SOILS AND SEDIMENTS
8.3.1. Sampling. Bottom sediment samples can be collected either by Hopper-
dredge or by clam-type dredge samplers (U.S. EPA, 1979). Hopper-dredge collected
samples generally contain more water than clam-type dredge-collected samples.
Bottom sediment samples can also be collected using a core sampler (U.S. EPA,
1979).
For volatile organic analysis, the samples should be collected in screw-
capped glass containers lined with aluminum foil (Jungclaus et al., 1978) or in
glass hypovials with crimped aluminum seals and teflon-backed septa (U.S. EPA,
1979). For best results, the container should be filled to maximum capacity to
reduce the amount of headspace and should be transported and stored at wet ice
temperature (U.S. EPA, 1979).
The method of soil sampling is given in detail by de Vera et al. (1980). The
soil samples should be taken in a grid pattern over the entire site. A scoop can
be used for collection of soil samples up to 8 cm deep. To sample beyond this
depth, a soil auger or Veihmeyer soil sampler, as described by de Vera et al.
(1980), should be used. After the sample is transferred into glass containers to
8-14
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acid. Any free chlorine should be neutralized by the addition of 35 mg of sodium
thiosulfate per 1 ppm of free chlorine (Federal Register, 1979) before the
samples are collected in glass bottles. The samples must be iced or refrigerated
during transportation and storage. All such wastewater samples should be
analyzed within seven days of collection (Federal Register, 1979).
8.2.2. Analysis. Although direct injection (Jungclaus et al., 1978) and solvent
extraction (Yukiho and Terumi, 1977; Jungclaus et al., 1976) methods have been
used to determine the concentration of organics including toluene in industrial
wastewaters, these methods are not suitable for toluene determination in other
media. Even in wastewater, both of these methods have questionable accuracy.
The direct aqueous injection method does not have good sensitivity and the
solvent extraction method is likely to provide low recovery since some of the
volatile components will be lost during the concentrative evaporating step.
The three most commonly used methods for toluene analysis in aqueous media
are (1) purge and trap, (2) headspace, and (3) sorption on solid sorbents. Each
of these methods is individually discussed below.
8.2.2.1. PURGE AND TRAP — Purge and trap is the most widely used method
for the analysis of toluene in aqueous media. It has been used for the deter-
mination of toluene in drinking waters (Bertsch et al., 1975; Lingg et al., 1977;
Ryan and Fritz, 1978), in wastewaters (Bellar and Lichtenberg, 1979; Rawlings and
Samfield, 1979; Jungclaus et al., 1978), and in rainwater (Seifert and Ullrich,
1978). The U.S. Environmental Protection Agency recommends the use of this
method for toluene analysis in wastewater (Federal Register, 1979).
In this method, an inert gas (helium) is bubbled through a water sample via
a glass frit contained in a specially designed purging chamber. The aromatics
8-11
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released into the vapor phase are swept through and trapped in a sorbent tube.
After the purging and trapping is completed, the trap is transferred to the
injection port..of a GC. The trap is heated and backflushed into a GC system,
where the separation of the volatiles takes place. Both packed (Bellar et all,
1979; Lingg et al., 1977; Federal Register, 1979) and capillary columns (Dowty
et al., 1979; Bertsch et al., 1975) employing a variety of liquid phases have
been used. The resolution of components can be expected to be better with
capillary columns.
The detection of the GC column effluents can be done either by flame ioniza-
tion detector (Dowty et al., 1979) or photo-ionization detector (Federal
Register, 1979). The use of photo-ionization detector will provide better selec-
tivity and sensitivity of detection. The confirmation of GC peaks is usually
provided by mass spectrometry aided by a computerized data system (Lingg et al.,
1977; Dowty et al., 1979; Bellar et al., 1979).
A number of variations of the purge-trap method (Grob and Zucher, 1976;
Lingg et al., 1977; Dowty et al., 1979; Bellar et al., 1979) involving the
variation of water volume, the temperature of the purging system, the stripping
rate, the duration of stripping, the nature of sorbent, and the method of desorp-
tion (thermal versus solvent) are available. Using a 5 mi sample size and flame
ionization detection, Dowty et al. (1979) determined the lower detection limit
for toluene to be 0.1 ppb by this method. The detection limit can be further
lowered if a larger volume of sample (Lingg et al., 1977) or photo-ionization
detection method is used. The purge-trap method is the preferred method for
monitoring toluene in both drinking and wastewater samples.
8.2.2.2. HEADSPACE ANALYSIS — This method has not been applied frequently
for the analysis of field samples; however, the method was standardized with
8-12
-------
8.1.2.3. PREFERRED METHOD — The preferred method for monitoring toluene in
occupational air can be either the NIOSH (1977) method of activated carbon
sorption and CS- desorption or Tenax GC sorption and thermal desorption. The
quantification of desorbed toluene by GC-FID is still the method of choice. As
in the caae of ambient air samples, N,M-bis(2-cyanoethyl)formamide liquid phase
will provide one of the best separations for the aromatics.
8.1.2.U, DETECTION LIMIT — The detection limit for toluene by carbon
sorption-CS- desorption method depends on the volume of air sampled. Concentra-
tions as low as 0.1 ppm toluene in a rubber tire manufacturing factory have been
detected by this method (Van Ert, 1980). For a 100 mi sample, the Tenax GC
sorption-thermal desorption method showed a detection limit of 0.5 ppb (Niomo
and Fiahburn, 1977).
8.1.3* Forensic Air. In suspected arson cases, the method of Twibell and Home
(1977) can be applied to speculate or even confirm the cause of fire. According
to this method, nickel wires (curie point 358°C) coated with finely-divided
activated carbon with the aid of an inert adhesive (cement binder LQ/S6) are
suspended in the atmosphere under test for 1 to 2 hours at room temperature. The
apparatus is connected to a GC-FID system, and the wires are heated by induction
heating. The resulting chromatographic profile obtained from the desorbed gases
can be compared with different fire accelerant residues (e.g., gasoline).
Although the method is not quantitative, it has been claimed to show a better
sensitivity than the method of hot headspace analysis (Twibell and Home, 1977)and
has potential for use in cases where the presence of toluene needs confirmation,
such as gasoline spills.
8-9
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8.1.4. Gaseous Products from Pyrolysis of Organic Wastes. The gaseous products
from a pilot plant burning such organic wastes as wood shavings, solid municipal
wastes, and rice hull were analyzed by Brodowski et al. (1976). The method
consisted of collecting grab samples in stainless steel sampling bulbs and
injecting 0.5 .md of the gas into a GC. The separating columns were dual stain-
less steel columns packed with Porapak QS modified with terephthalic acid.
Evidently, the method does not have high sensitivity of detection. The toluene
concentration of the pilot plant gaseous products was determined to be 0.2 to
0.3 mol % by this method (Brodowski et al., 1976).
8.2. WATER
Toluene has been determined in a number of aqueous media including surface
waters, industrial wastewaters, water from publicly-owned treatment -works
(POTW), underground water, drinking water, and rainwater.
8.2.1. Sampling. Water samples other than industrial wastewater samples are
generally collected by the grab method. In the case of industrial discharges
where the discharge parameters are dependent on the operating process, continu-
ous samples using a commercial composite sampler have been used (Rawlings and
Samfield, 1979). The preservation and handling of the aqueous samples after
collection are especially important for volatile components. The samples are
collected in glass bottles that are filled to overflow and sealed with teflon-
backed silicon rubber septa and screw caps. It has been demonstrated that simple
samples in non-reactive matrix (e.g., drinking water, ground water) collected in
the above fashion can be held under ambient conditions from 10 to 22 days without
significant loss of volatile compounds (Bellar and Lichtenberg, 1979); however,
wastewater samples should be adjusted to a pH of 2 by adding dilute hydrochloric
8-10
-------
however, this method is capable of analyzing toluene in work atmosphere at
0
concentrations of around 10 ppm (Chovin and Lebbe, 1967).
Toluene collected by scrubber methods is usually analyzed by colorimetric
methods. Despite variations, most colorimetric methods show interferences from
other chemically similar compounds (e.g., benzene, xylenes, ethylbenzenes) that
are normally cocontaminants of toluene.
The first step in the analysis of toluene collected in solid sorbents is
desorption. Two methods are usually available for desorption: thermal and
solvent. Carbon disulfide is the most frequently used solvent for the desorption
of toluene from solid sorbents (Esposito and Jacobs, 1977; Fracchia et al., 1977;
Reid and Halpin, 1968; NIOSH, 1977; Van Ert et al., 1950), although some investi-
gators have used other solvents (Ogata et al., 1975). Solvent desorption is the
method of choice when activated carbon is used as the sorbent. Activated carbon
has not only high efficiency of reversible toluene sorption, but it has almost
quantitative toluene desorption efficiency with CS2 (Fracchia et al., 1977). In
the presence of other common organic solvents found in the work atmosphere (e.g.,
n-butanol, cellosolve acetate, butyl cellosolve, etc.), the CS- extraction
efficiency decreases slightly, but addition of 5% methanol to CS_ increases the
desorption efficiency to almost quantitative value (Fracchia et al., 1977).
When Tenax GC or Chromosorb 102 is used as the sorbent, elution by thermal
process is the method of choice (Niimno and Fishburn, 1977). Although this method
may require multiport sampling valves and a cyrogenic sample trap for the trans-
fer of samples from the sorbent trap to the GC system, it has certain advantages
not available to solvent elution. Because the thermal desorption method uses the
whole sample for quantification, it has a higher degree of sensitivity than the
solvent elution method where only a small fraction of the total sample is used
for quantification.
8-7
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The quantification of toluene eluted from solid sorbents almost always is
done by the GC-FID method. A number of packed GC columns have been used for this
purpose. Dioctyl phthalate (Tokunaga et al., 1974), UCC M-982 (Nimmo arid
Fishburn, 1977), N,N-bis(2-cyanoethyl)formamide (Esposito and Jacobs, 1977),
dinonyl phthalate (Ogata et al., 1975), and Porapak Q (NIOSH, 1977) are some of
the liquid phases used for chromatographic separations.
Other methods of analysis, such as high pressure liquid chromatography
(HPLC) on a reverse phase column with methanol-water as the mobile phase and
ultraviolet (UV) detection, have been attempted (Esposito and Jacobs, 1977), but
the sensitivity of detection was poor.
Methods involving the use of detection tubes have been applied for the
determination of toluene in occupational air (Tokunaga et al., 1974). The
accuracy of the detector tubes for toluene quantification is rather poor, parti-
cularly in the presence of other organic vapor (Tokunaga et al., 1974). There-
fore, the detector tubes are suitable for the rough estimation of toluene concen-
tration in the work atmosphere.
A simple directly-combined GC-IH (infrared) system was developed to detect
low molecular weight hydrocarbons in air (Louw and Richards, 1975). In this
method, the grab sample is injected directly into a GC and the effluent from the
GC column is split in a certain ratio (1:49). The major portion of the effluent
is directed toward a cold trap (-50°C) to freeze the organics. At the end of the
trapping process, the trap is quickly heated and the released gases are allowed
to pass through a microlight pipe gas cell of an IR detector. This method has
been claimed to detect 14 to 19 Mg of each sample component present in air (Louw
and Richards, 1975); however, no field samples have been analyzed with this
system.
8-8
-------
The generation of artifacts during thermal elution with Tenax GC can be
eliminated largely by proper clean-up of the sorbent, and by following the GC
conditioning procedure (Holzer et al., 1977). The greatest advantage of the
ambient sorption-thermal elution method is its extreme simplicity and speed.
The separation and quantification of sorbent desorbed components can be
achieved by means of the GC-FID method. Although photo-ionization detectors
(PID) may have higher sensitivity than flame ionization detectors, this higher
level of sensitivity is not required when the samples are preconcentrated by
solid sorbents. High resolution capillary columns are a necessity because of the
observed complexity and low concentration of the samples. Of the different
coating materials, N,N-bis-(2-cyanoethyl)formamide and 1,2,3-tris(2-
cyanoethoxy)-propane are probably most suitable for the separation of aromatic
components.
8.1.1.4. DETECTION LIMITS — The detection limit of toluene in ambient air
depends on the volume of air passed through the sorbent trap. For a 25 I sample,
the detection limit is less than 0.1 ppb (Holzer et al., 1977) with a capillary
column and flame ionization detector. When direct injection (1 m&) and the GC-
PID method are used, the detection limit for toluene is 0.3 ppb (Hester and
Meyer, 1979).
8.1.2. Occupational Air.
8.1.2.1. SAMPLING — The concentration of toluene in occupational air is
much higher normally than in ambient air. Therefore, the collection of samples
in certain instances may not require a concentration step. The collection of
samples by the grab method has been used by a number of authors (Tokunaga et al.,
1971; Chovih and Lebbe, 1967).
8-5
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Sane of the earlier methods used liquid scrubbers for absorbing toluene from
•:;.:- '.'• •
occupational air. A number of scrubbers, including potassium iodate in dilute
sulfuric acid (Ministry of Labour, 1966), cooled organic solvents such as ethyl
cellusolve acetate, dimethylformamide, and dimethyl sulfoxide in dimethyl forma-
mide (Ogata et al.f 1975), and nitrating solution (Chovln and Lebbe, 1967) have
been used. In addition to the inherent limitations in its ability to overcome
the interferences, this method is not convenient for the collection of breathing
zone samples.
The more recent methods used solid sorbents for the collection of toluene.
Silica gel (Ogata et al., 1975; Tokunaga et al., 1974), activated carbon
(Esposito and Jacobs, 1977; Fracchia et al., 1977; Reid and Halpin, 1968; Fraser
and Rappaport, 1976; NIOSH, 1977) and Tenax GC (Mimmo andd Fishburn, 1977) are
some of the sorbents used for this purpose. Aromatic hydrocarbons such as
toluene are easily displaced from silica gel by water vapor, resulting in pos-
sible losses of toluene in humid atmospheres (NRC, 1980). Therefore, both
activated carbon and Tenax GC are the two most frequently used sorbents for the
collection of toluene from occupational air. The suitability of either of the
sorbents is dictated by the method of sample analysis. When thermal desorption
is used, Tenax GC is the preferred sorbent. On the other hand, activated carbon
is preferred when solvent desorption is the method used.
8.1.2.2. ANALYSIS — For grab samples, direct injections into a GC system
via syringes or gas sampling loops have been applied (Tokunaga et al., 1974;
Chovin and Lebbe, 1967). The separating columns used in these cases were packed
columns with stationary liquid phases of either dioctyl phthalate (Tokunaga
et al., 1974) or bis-(beta-cyanoethyl)formamide (Chovln and Lebbe, 1967). Flame
ionization detectors were used for the quantification of toluene in both cases;
8-6
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8.1.1.2. ANALYSIS — The method of analysis usually depends on the methcd
of sample collection. The earlier investigators who used plastic bags or glass
bottles for collection of grab samples used a trapping system for concentrating a
relatively large volume (1 to 10 4) of sample before analysis. In this method,
the collected sample is allowed to flow through a cryogenic trap containing
suitable sorbents. At the end of trapping, the coolant is removed from the trap
and the trap, is quickly heated to vaporize and transfer the trapped compounds
into the gas chromatographic (GC) columns. The columns used by earlier
investigators (Lonneman et al., 1968; Altshuller et al., 1971) for aromatic
separations consisted of long open-tubular columns coated with m-bis(m-phenoxy-
phenoxy)benzene combined with Apiezon grease on a packed dual column with SF-96
as the liquid phase (Pilar and Graydon, 1973).
The more recent methods, which use sorbents for trapping organics, connect
the trap to a GC systems via multiple-port gas sampling valves. The trap is
quickly heated and the desorbed organics are passed through the chromatographic
columns. Because the collected samples contain a multitude of organics,
capillary columns are normally used for the resolution of the organics. The Grob
and Grob (1971) technique, involving the passage of the thermally desorbed
organics through a small uncoated section of the capillary column cooled
crypogenically, is used. When the collection is completed, this section of the
capillary is quickly heated and the sample is separated on the remaining portion
of the analytical column. A number of coating.materials for capillary columns
including Emulphor ON-870 (Holzer et al., 1977), UCON 50 HB 2000 or 5100
(Johansson, 1978), dinonyl phthalate (Isodorov et al., 1977), Al-O- (Schneider
et al., 1978), DC-550 (Louw and Richards, 1975), OV-17 and OV-101 (Pellizzari
et al., 1976) have been used.
8-3
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In one method, thermal desorption of the organics from the sorbents was
replaced by solvent desorption (Burghardt and Jeltes, 1975). In this procedure,
the organics sorbed on activated carbon were desorbed by CS_. A part of the CS_
was injected into a packed column GC containing a long column coated with 1,2,3-
tri-(2'Tcyanoethoxy)-propane.
The quantification of toluene separated by the GC columns is done almost
exclusively by flame ionization detectors (FID). Confirmation of the
authenticity of the GC peaks often is provided by coupled mass spectrometers
(MS), with or without the aid of a computerized data system (Holzer et al., 1977;
Pellizzari et al., 1976).
A continuous automated procedure for determining toluene in the ambient air
was developed by Hester and Meyer (1979). This method needs no sample
preconcentration prior to analysis. In this method, a small diaphragm pump
activated by a timer automatically injects air into 1 mi gas-sampling (GS) loop
of a GC every 10 minutes. The separating column was packed with Chromosorb P
coated with N,N-bis(2-oyanoethyl)formamide. Since no concentration method was
employed, the detector used had about two orders of magnitude higher sensitivity
than flame ionization detectors. A photo-ionization detector was found to show
the required sensitivity.
8.1.1.3. PREFERRED METHOD — The preferred method for the monitoring of
toluene in ambient air consists of sorbent collection, thermal elution, and GC-
FID determination. Collection by trapping toluene in a solid sorbent provides a
concentration method during sample collection. .Thermal desorption is preferred
over solvent elution because of the higher sensitivity of the former method.
Tenax GC is perhaps the most suitable sorbent for sample collection. The collec-
tion and thermal desorption efficiency of toluene is excellent with Tenax GC.
8-4
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8. ANALYTICAL METHODOLOGY
Toluene has been analyzed in a number of media including the following:
(1) air, (2) waters, (3) soils and sediments, (U) crude oil and organic solvents,
(5) biological samples, (6) some foods, and (7) cigarette smoke. The analytical
methods for the determination of toluene in each of these media are individually
i
discussed below.
I
8.1. AIR
In addition to the analysis of test mixtures of toluene in air for the
evaluation of methods, toluene has also been determined in ambient air, occupa-
tional air, forensic air, and air containing the pyrolysis products of organic
wastes.
8.1.1. Ambient Air. The determination of toluene in ambient air consists of two
distinct steps: sampling and analysis.
8.1.1.1. SAMPLING — Toluene can be collected from ambient air in several
different ways including grab sampling in aluminized plastic bags (Neligan
et al., 1965), Tedlar bags (Altshuller et al., 1971; Lonneman et al., 1968), and
glass containers (Schneider et al., 1978; Pilar and Graydon, 1973). Although the
grab sampling is conceptually the simplest approach, this collection method
without subsequent concentrative technique does not provide sufficient quantity
of toluene for analytical detection and quantification. Since ambient samples
contain toluene in the parts per billion range, preconcentration steps are often
necessary.
8-1
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Sample collection by cyrogenic procedures (Seifert and Ullrich, 1978) is an
alternative method for the collection of toluene in ambient air; however, the
drawbacks of this procedure include the inconveniences in sampling and sample
regeneration. Also, unless the moisture in air is removed, it condenses in the
collection tube and may reduce or restrict the air flow through the collection
tubes. Various drying agents, such as anhydrone, anhydrous KpCO_, ascarite, LiH,
and molecular sieve can be used. It has, however, been demonstrated by Isidorov
et al. (1977) that it is impossible to find a drying agent that will preferen-
tially absorb the moisture from air without absorbing some of the trace organics.
Reversible sorption on various high surface area materials provides an
excellent method for preconcentrative collection of toluene from ambient air.
Since the moisture content in the air is normally 3 to 4 orders of magnitude
higher than the total organics (Isidorov et al., 1977), the chosen sorbents must
show little affinity toward moisture. Otherwise, the retention capacity of the
sorbents will be reached much sooner than desired.
A number of sorbents such as Tenax GC (Holzer et al., 1977), various car-
bonaceous . materials (Burghardt and Jeltes, 1975; Holzer et al., 1977; Isidorov
et al., 1977), Polisorbimid (Isidorov et al., 1977), molecular sieves and spher-
isil (Ball, 1976), and Porapak Q (Johansson, 1978) have been successfully used.
Typically, sampling is performed by drawing air through a trap containing the
selected sorbent with battery-operated diaphragm pumps. The air flow through the
trap is controlled by needle valves and measured by a previously calibrated
rotometer. The trap is kept at ambient temperature to avoid condensation of
water. At the end of the sampling, the trap-ends are closed with caps and
transferred to the laboratory in a refrigerated state, to avoid sample loss.
8-2
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TABLE 7-8
Toluene Concentrations in Selected Work Areas of Tire Manufacturing Plants3'
Work Area
Cement Mixing
Extrusion
Tire Building
Curing Preparation
Inspection and , Repair
Warehouse
No. of Plants
Surveyed
8
H
2
3
3
2
Area Toluene Concentration, ppm
Mean
2.9
1U.O
8.0
0.6
1.9
0.28
Range
0.2-7.7
3.3-50.0
2. 5-13. t
0.1-1.1
0.6-2.7
0.01-0.76
Source: Van Ert et al., 1980
3A11 of the plants, with the exception of plants where the warehouse samples
were taken, were surveyed during 1973-77. The warehouse samples were collected
in 1977.
7-19
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TABLE 7-7
Toluene Concentrations in Work Areas of
Leather Finishing and Rubber Coating Plantsa
; Toluene Concentration, ppm
Industry Work Areas Range Average
TM<-»«», ifi „<«>,<„- Finishing Area 19-85 53
Leather Finishing washingtnd Topping Area 29-195 112
Rubber Coating Spreading Machines 34-120 73
Source: Pagnotto and Lieberman, 1967
7-17
-------
et al., 1973). The origin of toluene in this atmosphere was attributed to mine
casings..
A more recent study (Fraser and Rappaport, 1976) designed to determine the
health effects associated with the curing of synthetic rubber simulated the vul-
canization process in the laboratory. Toluene emission in the vulcanization area
from this experiment amounted to 1.1 ppm. The actual field survey of different
work areas of 10 large tire manufacturing plants across the United States was
conducted by Van Ert et al. (1980). The toluene concentrations in different work
areas measured by these investigators is shown in Table 7-8.
It can be concluded from Table 7-8 that the extrusion process area and the
tire building process area are the two areas of tire manufacturing plants that
account for the major toluene emissions from these plants.
7.3- CIGARETTE SMOKE
The concentration of toluene in inhaled cigarette smoke is approximately
0.1 mg/cigarette (NBC, 1980; Dalhamn et al..,, 1968). Jerimini et al. (1976)
determined the concentration of toluene in the sidestream smoke of cigarettes.
When 30 cigarettes were inhaled in a 30 m room and the concentration of toluene
in room air was determined, it was found to be 0.23 ppm. This value corresponds
to 0.87 mg of toluene in the sidestream smoke of each cigarette. Holzer et al.
(1976) determined the toluene concentration in a 60. nr room and found an ambient
toluene concentration of UO ppb. When 1 cigarette was smoked in the room, the
concentration of toluene rose to 45 ppb. This corresponds to 1.1 mg of toluene
contribution from each cigarette. It seems from this discussion that the main-
stream smoke of 1 cigarette contributes 0.10 mg toluene to the smoker. The
sidestream smoke, on the other hand, may contain a higher amount of toluene.
7-18
-------
TABLE 7-5
Toluene Concentrations in Different Work Areas
of a Rotogravure Plant in Milan, Italy*
Toluene Concentration, ppm
Work Area
Range
Annual Mean
Center of Room
Folding Machines
Between Machine Elements
1UO-239
56-277
306-824
203
203
Source: Forni et al., 1971
.7-15
-------
TABLE 7-6
Toluene Exposure Levels for Different Occupational Groups
Exposure Level
Type of Occupation
Reference
100-1100 ppma
150-1900 ppmb
3-214 ppm
30.6 ppm (mean)0
80-300 ppm .
15-200 ppm (mean)
50-1500 ppm
200-400 ppm
300-430 ppm
200-400 ppm
18-500 ppm
56-824 ppm
100-200 ppm (TWA)
occasional rises
to 500-700 ppm
16-164 ppm
21-187 ppm
7-112 ppm (TWA)
Airplane painting
Paint and pharmaceutical
industry
Automobile painting
Automobile painting
V-belt manufacturing
Shoemakers
Not stated
Rotogravure printing
Rotogravure printing
Rotogravure printing
Rotogravure pringing
Rotogravure printing
Rotogravure pringing
Rotogravure pringing
Rotogravure printing
Rotogravure printing
Greenburg et al., 1942
Parmeggiani and Sassi, 1954
Ogata et al., 1971
Hanninen et al., 1976
Capellini and Alessio, 1971
Matsushita et al., 1975
Wilson, 1943
Banfer, 1961
Munchinger, 1963
Suhr, 1975
Szadlowski et al., 1976
Forni et al., 1971
Funes-Craviota et al., 1977
Ovrum et al., 1978
Vaulemans et al., 1979
Maki-Paakkanen et al., 1980
Paint contaminated with other volatile components (Table 11-9)
3Concomitant exposure to butyl acetate (Section 11.2.1)
"Concomitant exposure to other organic solvents (Table 11-3)
Concomitant exposure to 20-50 ppm (mean gasoline in a few working places
(Section 11.1.2)
7-16
-------
toluene. However, these investigators could not detect the presence of toluene
in the river sediment.
i
7.I.U. Edible Aquatic Organisms. Of the 59 monitored tissue samples that were
recorded in the STORE! system (U.S. EPA, 1980), 95$ of the data showed toluene
concentrations of less than 1 ppm. The maximum toluene concentration detected in
1 fish tissue was 35 ppm. It could not be determined whether these concentra-
tions were determined in edible flesh or in whole fish. Toluene was also
detected in fish caught from polluted waters in the proximity of petroleum and
petrochemical plants in Japan (Ogata and Miyake, 1973). A concentration of 5 ppm
was measured in the muscle of 1 such fish.
7.1.5. Solid Wastes and Leachates. Toluene has been detected in the air samples
at a few landfill sites (U.S. EPA, 1980a) and in well water near a few landfill
sites (U.S. EPA, 1980). However, no data regarding the level of toluene in solid
wastes and their leachates could be found in the literature.
7.2. OCCUPATIONAL CONCENTRATIONS
Several reports describing the presence of toluene in occupational atmos-
pheres were found in the literature. A toluene level of 10,000 to 30,000 ppm was
reported in a merchant ship after it was internally sprayed with a toluene-
containing insecticide (Longley et al., 1967). Two hours after the initial
monitoring, concentrations ranging from 5000 to 10,000 ppm were still present in
the atmosphere of the ship.
A monitoring program was instituted in response to a report of an epidemic
solvent poisoning in a rotogravure plant in Milan, Italy. Solvent containing
toluene was largely used in this plant as an ink solvent and diluent. The
7-13
-------
results of the monitoring showed that the concentration of toluene ranged from 0
to 277 ppm in different parts of the work areas (Forai et al., 1971). The
determined toluene concentration at different parts of the plant during the
period 1957 to 1965 is shown in Table 7-5.
In 1966, the above rotogravure plant was moved to a different location and
the ventilation system of the plant was improved. Subsequent analysis for
toluene showed annual mean concentrations at 156 and 265 ppm near the folding
machines and between the machine elements, respectively (Forni et al., 1971).
Toluene exposure levels for other occupational groups are shown in
Table 7-6. Many of the levels given in this table originate either from exposure
evaluation in foreign countries or the data may be too old to have relevance in
contemporary working atmospheres. Accidental exposures to toluene are discussed
in Sections 11.1.1.1. and 11.1.1.2.1.
A study of 8 Japanese factories operating polychromic rotory processes for
photogravure printing reported toluene concentrations in the range of U to
240 ppm in different work areas of the plants (Ikeda and Ohtsuji, 1969).
Toluene exposures to an unspecified number of workers in 11 leather-
finishing and rubber-coating plants have also been reported (Pagnotto and
Lieberman, 1967). Toluene is used as lacquer thinners and stain removers in the
leather finishing industry. In rubber-coating plants, the major source of
toluene emission is the fabric-spreading machine areas. The concentration of
toluene in work areas of these industries is shown in Table 7-7.
Toluene has been detected in other occupational atmospheres. For example, a
toluene concentration of 0.13 ppm has been reported in a submarine atmosphere
(Chiantella et al., 1966). The origin of toluene in this atmosphere has been
speculated to be paint solvents and diesel fuel used in the submarine. Toluene
has been detected in the atmosphere of M15 'and M19 antitank mines (Jenkins
7-1U
-------
The frequency of toluene occurrence at this' plant was 76$ for the influent and
T\% for the final effluent sample.
The state of Ohio (U.S. EPA, 1977) conducted a survey of toxic substances in
2 municipal wastewater treatment plants. The toluene concentration in the waste-
water of the plant dealing primarily with domestic wastewater ranged between
1 and 5 ppb. The treated effluent from the same plant, on the other hand, showed
a concentration of 1 ppb. About 87$ of the influent from the other plant which
treated industrial-domestic wastewater showed the presence of toluene in the
concentration range of 8 to 150 ppb. The frequency of toluene detection in the
treated effluent from the same plant amounted to 36$. The toluene concentrations
in these treated effluents ranged from 1 to 10 ppb.
7.1.2.4^. UNDERGROUND WATER — The New York State Department of Health and
the United States Geological Survey examined 39 wells in 1978 for organic con-
tamination in groundwater (ADL, 1981). Toluene was detected in 85$ of the wells
tested. However, the toluene concentration in these waters was below 10 ppb.
Toluene concentration in well water can be obtained from the data recorded
in STORET (U.S. EPA, 1980). Eighty seven percent of the monitored data showed
less than 5 ppb (detection limit) toluene. Of the 143 monitored data, only 3
indicated the presence of toluene in the concentration range of 42 to 100 ppb.
All of these 3 wells were in the vicinity of landfill sites.
7.1.2.5,. DRINKING WATER — Toluene has been detected in raw water and in
finished water supplies of several communities in the United States. Levels of
up to 11 ppb were found in finished water from the New Orleans area (U.S. EPA,
1975a). In a nationwide survey of water supplies from 10 cities, 6 were dis-
covered to be contaminated with toluene (U.S. EPA, 1975b). Concentrations of 0.1
7-11
-------
and 0.7 ppb were measured in 2 of these water supplies and were detected but not
quantified in the rest. Toluene was detected but not quantified in 1 of 111
finished drinking waters during a second nationwide survey (U.S. EPA, 1977). In
& .
a subsequent phase of this survey, toluene was found in 1 raw water and: 3
finished waters out of 11 supplies surveyed (U.S. EPA, 1977). A level of 19 ppb
measured by gas chromatography/mass spectrometry was found in 1 of these finished
waters, and 0.5 ppb was found in another.
Nineteen volatile organic compounds, including toluene, were detected at
concentrations below 5 ppb in District of Columbia drinking water (Saunders
et al., 1975). These investigators also found that the concentrations of the
various contaminants in tap water varied by unspecified amounts from .week to
week, but the chemical composition remained the same. , ;
7-1.2.6. RAINWATER — Toluene has been detected in rainwater from Berlin,
West Germany (Lahmann et al., 1977). The toluene content in the rainwater varied
with sample collection points. The rainwater from a residential area, airport,
and a busy traffic intersection showed toluene concentration of 0.13 ppb,
0.70 ppb, and 0.25 ppb, respectively.
7.1.3- Sediment. Toluene concentrations in sediment samples as recorded in
STORE! (U.S. EPA, 1980) show that 91% of the samples contain less than 10 ppb of
toluene. The concentration of toluene exceeded 500 ppb in only 7% of the
samples. Samples with higher concentrations (greater than 500 ppb) of toluene
were obtained from the vicinity of an industrial area in San Francisco.
C
Jungclaus et al. (1978) monitored the sediment from a river receiving indus-
trial effluent from a specialty chemicals manufacturing plant containing
7-12
-------
TABLE 7-3
Percent Distribution of U.S. Wastewaters Within
a Certain Toluene Concentration Range3
Effluent
Discharged
Northeast
North Atlantic
Southeast
Tennessee River
Ohio River
Upper Mississippi
Lake Michigan
Missouri River
Colorado River
Western Gulf
Pacific Northwest
TOTAL
Number of
Observations
103
48
100
28
70
64
6
16
1
1
45
482
Percent
<10
84
88
87
96
84
69
100
100
100
100
91
85
Sample in the
Range,
10.1-100
9
6
10
4
11
30
7
11
Toluene Concentration
PPb
100.1-1000
4
6
3
3
2
2
3
>1000
3
1
1
Source: U.S. EPA, 1980
7-7
-------
of less than 10 ppb. Fifteen of the reporting stations showed toluene concentra-
tion in excess of 100 ppb.
Wastewaters from a speciality chemicals manufacturing plant were analyzed
by Jungclaus et 41. (1978). The concentration of toluene in the wastewater was
reported to be in the range of 13 to 20 ppm. Similarly, wastewater from one tire
manufacturing company was analyzed by Jungclaus et al. (1976) and was found tp
contain approximately 10 ppm of toluene. Both of these values are among the
highest values reported in Table 7-3.
An analysis of raw wastewater and secondary effluent from a textile manufac-
turing plant was reported to contain toluene as one of the predominant compounds
(Rawlings and Samfield, 1979). The toluene concentrations in 22 wastewater
samples and 22 secondary treated effluent samples were in the range of 0.5 to
300 ppb (Rawlings and Samfield, 1979). Effluents from a paper mill in Hiro Bay,
Japan, were analyzed for organic matter. It was determined that toluene consti-
tuted 1} of the total chloroform extractables from the effluent (Yamaoka and
Tanimoto, 1977).
Toluene has also been detected in a variety of industrial wastewaters.
Table 7-4 shows the frequency of toluene detection in industrial wastewaters
(U.S. EPA, 1980).
7.1.2.3. PUBLiar-OWMED TREATMENT WORKS (POTW) — A pilot study of two
POTWs, one handling more organic pollutant than the other, was conducted for the
U.S. EPA (1979). Toluene was detected in 100$ of the influent samples and 95$ of
the final effluent samples from the plant containing more organic pollutants.
The maximum and median toluene concentrations in the influent sample from this
plant were 440 and 13 ppb, respectively. The influent sample at the other plant
had maximum and median toluene concentrations of 37 and 10 ppb, respectively.
7-8
-------
TABLE 7-4
Detection Frequency of Toluene in Industrial Wastewaters"
Industry
Frequency of Detection
(No. Found/No. Samples)
Soap and Detergents
Adhesives and Sealants
Leather Tanning
Textile Products
Gum and Wood Products
Pulp and Paper
Timber
Printing and Publishing
Paint and Ink
Pesticides
Pharmaceuticals
Organics and Plastics
Rubber
Coal Mining
Ore Mining
Steam Electric Power Plants
Petroleum Refining
Iron and Steel
Foundries
Electroplating
Nonferrous Metals
Coil Coating
Photographic
Inorganic Chemical
Electrical
Auto and Other Laundries
Phosphates
Plastic Processing
Procelain Enameling
1/20
2/11
19/81
56/121
14/18
4/98
58/285
50/109
48/94
23/147
38/95
306/723
15/67
53/249
6/72
32/84
18/76
43/431
2/54
5/18
21/173
2/12
9/25
10/107
1/35
9/56
1/33
1/1
2/19
7-9
-------
TABLE 7-4. (cont.)
Frequency of Detection
Industry (No. Found/No. Samples)
Landfill . 3/17
Mechanical Products 23/35
Pubicly-Owned Treatment Works 11AO
aSource: U.S. EPA, 1980
7-10
-------
publicly-owned treatment works (POTW), (4) underground waters, (5) municipal
drinking waters, and (6) rainwater. The toluene levels in each of the media have
been discussed separately.
7.1.2.1. SURFACE WATERS — Information regarding toluene levels in surface
water has been obtained primarily from the STORE! system as given by ADL (1981).
Table 7-2 shows the toluene levels for major river basins in the United States.
It is evident from Table 7-2 that 835& of all the monitored surface water contains
toluene levels below a concentration of 10 ppb. The concentration of toluene in
surface waters of the central region (Lake Erie, upper Mississipi, Lake Michigan,
etc.) are higher than surface waters from other regions. This higher level of
toluene cannot be attributed to the emission from production sites since the
central region contains only 8 of the 38 major production sites. Surface waters
from Texas, which contain 20 of the 38 production sites, showed lower levels of
toluene. This indicates that production processes may not be the major source of
toluene emission in surface waters.
Recent studies of the coastal waters of the Gulf of Mexico have shown that
aromatic hydrocarbons comprise 80 to 90$ of the total dissolved volatile hydro-
carbons (
-------
TABLE 7-2
Distribution of U.S. Surface Waters Within a Certain Toluene Concentration Range
a
Northeast
North Atlantic
Southeast
Tennessee River
Ohio River
Lake Erie
Upper Mississippi
Lake Michigan
Missouri River
Lower Mississippi
Colorado River
Western Gulf
Pacific Northwest
California
Great Basin
Puerto Rico
Unlabeled
TOTAL
Number of
Observations
1
14
110
16
54
2
18
30
34
8
3
15
80
5
1
1
1
393
Percent Sample in the Toluene Concentration
Range, ppb
<10
100
93
81
98
67
20
44
88
100
100
99
100
100
100
100
83
10.1-100 100.1-1000 >1000
100
4 4
666
2
100
22 11
77 3
53 3
13
1
14 3 IA
aSource: U.S. EPA, 1980
IA = insignificant amount.
7-6
-------
TABLE 7-1. (cont:)
Concentration, ppb
Location
Rural and Remote Areas:
Brethway-Gunderson Hill, WA
"Camel's Hump, VT
Hell's Canyon, ID
Moscow Mt . , ID
Point Reyes, CA
Grand Canyon, AZ
Talladega Natibna Forest, AL
Global:
Zurich, Switzerland
Toronto, Canada
Berlin, W. Germany
Stockholm, Sweden
The Hauge, Netherland
Year
1971
1971
1971
1971
1971
NR
1977
NR
1971
1975-76
NR
1974
Average
0.11
1.01
0.31
0.21
0.21
Trace
0.4
39m
30n
27°
NRP
18C
Highest, or Range
NR
NR
NR
NR
NR
Trace
0.2-1.3
NR
188
2.4-94.2
0-2.7
54
?NR: Not reported.
°Pellizzari, 1979.
.Leonard et al., 1976.
Lonneman et al., 1968.
plltshuller et al., 1971.
Kopcznski et al., 1972. (A single measurement was made).
*Singh et al., 1979.
.Stephens, 1973.
^Russell, 1977.
^Atwicker et al., 1977.
Robinson et al., 1973.
Grob and Grob, 1971.
^Pilar and Graydon, 1973-
_Lahmann et al., 1977.
pJohansson, 1978.
Hester and Meyer, 1979.
J!G. Holzer et al., 1977.
Burgardt and Jeltes, 1975.
7-3
-------
concluded also from Table 7-1 that the concentration of toluene has declined
significantly in' the past 15 years in Los Angeles, presumably as a result of
automotive emission controls. The concentration of toluene in many urban areas
in the United States in recent years ranged from less than 0.1 ppb to as much as
50 ppb, averaging approximately 1 to 10 ppb. In remote locations of the United
States, the value averaged approximately 0.3 ppb in 1971 (Table 7-1), but the
', **
current level (data reported in 1979) may be lower as indicated by the toluene
concentration at Grand Canyon.
Sexton and Vestberg (1980) monitored the air near an automotive painting
plant at Janesville, Wisconsin, to investigate the effect of emission from paint
solvents on atmospheric toluene level. The toluene concentration downwind
within 1.6 km of the plant was 160 ppb. The concentration of toluene was still
20.5, 22.9, 17.5, and 15.1 ppb at distances 6, 10.5, 13.5, and 16.5 km,
respectively, downwind from the plant. These concentrations are about 10 to
15 times higher than the background toluene concentrations of 1.5 ppb determined
*
at a distance of 1.6 km upwind of the plant. These concentrations are also
comparable to or higher than most of the values given in Table 7-1.
In response to numerous complaints from residents about illness and odors in
the vicinity of a chemical solvent reclamation plant in Maryland, Smoyer et al.
(1971) monitored the valley air surrounding the plant. A toluene concentration
as high as 11 ppm was registered in the valley air. Both this result and the more
recent investigation of Sexton and Westberg (1980) indicate that processes
involving solvent use of toluene may result in high emission of toluene in the
vicinity of these sources.
7.1.2. Aqueous Media. Toluene has been monitored in a number of aquatic media
including: (1) surface waters, (2) industrial wastewater, (3) water from
7-4
-------
7. ENVIRONMENTAL AND OCCUPATIONAL CONCENTRATIONS
Monitoring data for the concentration of toluene has been divided into two
subsections, one pertaining to the environmental levels and the other to the
occupational levels.
7.1. ENVIRONMENTAL LEVELS
Toluene has been detected in the following environmental media: (1) air,
(2) aqueous media, (3) sediments, CO solid wastes and leachates, and (5) edible
aquatic organisms.
7.1.1. Air. Toluene is the most prevalent aromatic hydrocarbon present in
ambient air. Atmospheric levels of toluene in different locations in the United
States and other parts of the world are given in Table 7-1. The quantification
of toluene levels in the atmosphere has exclusively been done by GC-FID,
especially with capillary columns (Section 8.).
From the experimental measurements of the toluene-to-benzene ratio, Pilar
and Graydon (1973) concluded that the major source of toluene in urban air with
high traffic volume is automobile emission. Recently, Pellizzari (1979) has
measured toluene levels near manufacturing and refining sites in the United
States. The ratio of toluene to benzene in these sites indicates that besides
automobile emission, manufacturing processes are probably a factor in ambient
toluene concentration at many of the sites.
It can be inferred from Table 7-1 that the atmospheric concentration of
toluene in urban areas not containing toluene manufacturing or gasoline refining
sites are in the same range as the sites containing these industries. It can be
7-1
-------
TABLE 7-1
Atmospheric Concentrations of Toluene
Concentration, ppb
Location
Manufacturing or Refining Sites:
Baton Rouge, LA
Birmingham, AL
El Dorado, AR
Elizabeth, NJ
El Paso, TX
Houston, TX
Magma, UT
S. Charleston, WV
Upland, CA
Other Urban Areas:
Los Angeles, CA
Azusa, CA
Riverside, CA
Denver , CO
Phoenix, AZ
Oakland, CA
Albany, NY'
Troy, NY
Newbury Park CA
Tuscaloosa, AL
Year
NRa
NR
NR
NR
NR
NR
NR
NR
NR
1963-65
1966
1967
1968
1971
1973
1979
1967
1970-71
1973
1979
1979
NR
NR
1978
1977
Average
O.!4b
2.0
11. Ob
17.0b
4.9"
1.6b
0.35b
0.05b
7.3b
59°
37 d
30e
39f
50e
22°
11. 7g
i4e
NRh
91
8.6g
3.1s
1.3k
1.0k
NRr
38
Highest, or Range
0.03-0.23
0.21-4.7
2.5-13.6
1.9-39.1
0.05-18.8
0.21-2.93
0.23-0.43
0.04-0.07
0.78-14.8
NR
129
50
NR
NR
NR
1.1-53.4
23
9-18 : '
74
0.54-38.7
0.15-16.9
NR
NR
0.7-13
24-S53
7-2
-------
CH,
0
•OLUENI
X X
TOLUENE
CH,OH
BENZYL ALCOHOL
1
6
MNZAlOEHVDg
•ENZOICACJO
I
*
CATECHOL
\
l^toOH
I^^OOH
MUCONICAOO
(il-2. 3-OH-2.1-OOH TOL
CM,
CH,
1-MSTHVLCATCCHOL
/
/
*
MeTMVLHVOROXVMUCONIC
SCMIALOCHVDE
METMVIWUCONIC
2-OH-t-OXO-Z. ca-4. ca-HA
HVDROXVMUCONIC
SEMIALDEHYDE
ACETALOEHVOE
ACETATE
PYRUVATE
CO, » ENERGY
FIGURE 6-2
Microbial Metabolism of Toluene
6-15
-------
pyruvate, and acetalydehyde and to C02 and energy (Bayley et al., 1966). The
conversion of toluene to compounds that can be used as sources of carbon and
energy suggests that toluene will be degraded rapidly by these oicrobial species
proliferating at the expense of the compound.
The enzymes responsible for toluene degradation are carried on plasmids
(Williams and Worsey, 1976; Saunders, 1977). Williams and Worsey (1976) isolated
13 bacteria from soil, all of which carried the toluene-degrading plasmids,
i
suggesting that the plasmid-borne gene responsible for toluene degradation is
wide spread in the soil microbial population. The plasmid can also be transposed
into other hosts, further increasing the number of toluene-degrading bacteria
(Broda et al., 1977; Jacoby et al., 1978). The toluene plasmid in Pseudomonas
* "^™""^^^^^™—""^"""
putida coded for the metabolism of toluene to the corresponding alcohol and
aldehyde via the meta pathway, to the semialdehyde and further products (Worsey
and Williams, 1975; Worsey et, al.r 1978). A plasmid coding for both toluene and
xylene degradation in a Pseudomonas sp. has been isolated recently and charac-
terized (Yano and Nishi, 1980). Broda et al. (1977) have speculated that the
ortho pathway of toluene degradation probably is chromosomally coded.
6-16
-------
degradation of toluene after 180 minutes. It should be noted that phenol is the
metabolic degradation pathway of toluene. In another study, Declev and Damyanova
(1977) grew sludge cultures in either 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 cells showed greater versatility in
their ability to oxidize phenol and xylene.
6.4.1.2. PURE CULTURES — Although pure cultures do not occur in nature, a
discussion of biodegradation in these media may provide insight to degradation in
more complex media occurring in a natural environment. Fungi and bacteria have
i
been shown to use toluene (Smith and Rosazza, 1974). In the course of studying
the effects of toluene on microbial activity, Kaplan and Hartenstein (1979)
discovered that 6 of 7 fungi imperfect!, 7 of 13 basidiomycetes, and 6 of 14
bacteria grew with 0.1 or 0.05$ toluene as the sole carbon source. The addition
of yeast extract increased the amount of toluene-utilizing microorganisms. In
contrast, no oil-use or hydrocarbon-degrading fungi grew on toluene as the sole
carbon source (Davies and Westlake, 1979). Using an oxygen electrode to measure
oxidation, Buswell and Jurtshuk (1969) found that resting cells of an ri-octane-
utilizing Corynebacterium sp* oxidized only 7% of the available toluene compared
to 100$ oxidation of ri-octane. Toluene did not serve as a growth substrate in
this experiment. Kapraleck (1954) isolated a Pseudomonas-type bacteria from the
soil of a petroleum deposit that used toluene. Pseudomonas and Achromobacter
spp. from soil used toluene as the sole carbon source for growth (Glaus and
Walker, 1964; Gibson and Yeh, 1973). Smith and Rosazza (1974) reported that
bacteria and yeast hydroxylated toluene. In contrast, Nei et al. (1973) found
little oxidation of toluene by phenol-using yeast.
6-13
-------
The metabolic pathway for the bacterial oxidation of toluene has been
studied with soil microorganisms (Figure 6-2) and reviewed by Gibson (1971) and
Subramanian et al. (1978). On the basis of simultaneous adaptation studies,
Kitagawa (1956) concluded that Pseudomonas aeruginosa oxidized toluene via
benzyl alcohol and benzaldehyde to benzole acid and then to catechol. This
pathway was supported by the investigations of Nozaka and Kusunose (1968). A
Mycobaeterium sp. also produced benzoic acid from toluene (Atkinson and Newth,
1968), as did a methanotrophio bacterium (Methylosinus trichosporium) (Higgins
et al., 1980).
An alternative pathway was proposed by Glaus and Walker (1964) using a
Pseudomonas sp. and an Achromobaeter sp. isolated from soil that used toluene as
a sole carbon source for growth. These investigators found that washed cell
suspensions oxidized toluene to 3-methylcatechol, indicating that the methyl
moiety was not oxidized, as occurred in the pathway proposed by Kitagawa (1956).
A similar oxidation product was found , by Nozaka and Kustnose (1969) using
Pseudomonas mildenbergii cell-free extracts. Gibson et al. (1968a) also
reported the detection of 3-methylcatechol from toluene by Pseudomonas putida.
An oxidation product preceding 3-methylcatechol was found in cultures of a mutant
strain of £. putida (strain 39/D) (Gibson et al., 1968b, 1970). This new product
was identified as (+)-cis-2.3-dihydroxy-1-methylcyclohexa-4.6-diene ( cis-2.3-
dihydro-2,3-dihydroxytoluene) ( cis-2,3-DH-2,3-DOH TOD (Kobal et al., 1973).
The catechol and 3-methylcatechol then can be cleaved by ortho cleavage to yield
the corresponding muconic acids or by meta cleavage to yield the corresponding
hydroxymuconic semialdehydes (Bayly et al., 1966). Methylmuconic acid was
formed from toluene oxidation by a soil bacterium Nocardia corallina (Jamison
et al., 1969). The semialdehydes are further converted to 2-hydroxy-6-oxo-
2.cis-4,cis-heptadienoic acid (2-OH-6-OXD-2.cis-4.cis-HA) and then to acetate,
6-14
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system could be eluted through a column of 140 cm height. The leaching of
toluene from landfill sites that contain soil originated partly from municipal
sludges can be expected to be even lower. The higher organic content of these
soils may retard the aqueous elution process due to higher sorption properties of
the soils toward toluene.
6.4. ENVIRONMENTAL PERSISTENCE
6.4.1. Biodegradation and Biotransformation
6.4.1.1. MIXED CULTURES — The study of the disappearance of toluene in
soil began nearly 75 years ago. Stormer (1908) and Wagner (1914) showed that
toluene was susceptible to bacterial decomposition in the soil. Gray and
Thornton (1928) and Tausson (1929) isolated soil bacteria that used toluene as a
sole carbon source. Glaus and Walker (1964) found that the half-life of toluene
in isolated bacteria from soil inhabited with toluene-degrading bacteria was 20
to 60 minutes. Wilson et al. (1980) indicated that from 20 to 60% of toluene
eluted through 140 cm of sandy soil biodegraded. The authors stated that the
process was probably very sensitive, to the soil type and, therefore, may or may
not be an important removal process of toluene from a particular soil system.
More literature, however, exists on the bi©degradation of toluene in aqua-
tic environments. In a report prepared by the Arthur D. Little Company (1981),
the biodegradation of toluene in lakes, rivers, and ponds was discussed using an
extension of the U.S. Environmental Protection Agency's (U.S. EPA) multicompart-
ment EXAMS. The report stated that the biodegradation of toluene accounted for
0.31| 4.81, 0.36, 0.09i and 18.47? of the total toluene loss in oligotrophic
lakes, eutrophic lakes, clean rivers, turbid rivers, and ponds, respectively.
6-11
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Using the standard dilution method and filtered wastewater effluent as the seed
to determine the biochemical oxygen demand (BOD), the biodegradability (per-
centage bio-oxidized) of toluene ranged from 63 to 86} after up to 20 days (Price
et al., 1974; Bridie et al., 1979).
Matsui et al. (1975) found, that in activated sludge acclimated to various
organic compounds, the total organic carbon (TOO removal efficiency for toluene
was 60% while the chemical oxygen demand (COD) was 72% for 24 hours. The authors
concluded, however, that although toluene was a readily biodegradable compound,
in this experiment disappearance was due mainly to evaporation. Using the
Warburg technique, Lutin et al. (1965) reported a 40} degradation of toluene in
activated sludge after 144 hours. In comparison, 63% of the benzene was degraded
in the same time. The degradation of toluene in benzene-acclimated activated
sludge reached 17.2} of the theoretical BOD after 6 hours and 48} after 192 hours
(Malaney and McKinney, 1966). Toluene was the most biodegradable of a number of
alkylbenzenes tested by these authors, who also found that the introduction of a
methyl group to benzene retarded the initial (6 hour) rate of oxidation of
toluene but not the extent of degradation compared to benzene. Marion and
Malaney (1964) exposed activated sludge to 500 mg/2, of toluene from 3 municipal
plants and reported that unacclimated sludge showed little ability to oxidize
benzene and toluene after 6 hours and that after 72 hours, less than 11} oxida-
tion had taken place (compared to 44.7} reported by Malaney and McKinney, 1966).
One sludge sample, however, acclimated to benzene, oxidized greater than 30} of
the toluene after 180 hours. It should be noted that the high concentration of
toluene used in this study probably was toxic to the organisms in the sludge.
The degradation of toluene has also been studied in mixed cultures of
bacteria. Chambers et al. (1963), using phenol-adapted bacteria, reported 38}
6-12
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Water to Soil: "The importance of this transport process can be evaluated by'
experimentally determining the toluene content in sediments of surface water
contaminated with toluene. Theoretical modeling can also be used for this
purpose. Using the U.S. EPA's multicompartment Exposure Analysis Modeling
System (EXAMS), ADL (1980) has determined that bottom sediments account for over
90$ of the total toluene discharged into surface waters under steady-state con-
ditions. The values for the distribution of toluene between surface water and
sediment as determined by the EXAMS modeling do not agree with experimental
results of Jungclaus et al. (1978). Jungclaus et al. (1978) determined the
toluene content in the water and sediments of a river receiving wastewater
containing toluene. Although toluene was detected in the river water, it was
found not to accumulate in the sediments. More research in this area is needed
to explain this discrepancy between the EXAMS modeling and the experimental
results.
6.3. SOIL
6.3-1. Fate. Toluene probably exists in soils in the sorbed state. The
sorption of toluene by clay minerals (bentonite and kaolinite) was studied by
El-Dib et ali (1978) and was found to follow Freundlich's adsorption isotherm.
These authors also found that the adsorption capacity increased as the pH value
decreased.
The fate of toluene in soil has not been thoroughly investigated. It can be
anticipated, however, that a portion of toluene in soil will undergo intermedia
transfer to air and water, and a portion will undergo intramedia transfer. The
part that stays in soil may participate in chemical reactions (including photo-
chemical reactions) and biological degradation and transformation. The relative
6-9
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importance of intermedia transfer and chemical and biological reactions of
toluene in soils is not known.
Investigations by Wilson et al. (1980) indicate that volatilization, bio-
degradation, and biotransformation processes dominate the fate of toluene in
soils. The intermedia transfer of toluene from soil to water probably is not an
important pathway. No data could be found in the literature searched that would
support a hypothesis for any role of chemical reactions in determining the fate
of toluene in soils. The intermedia transport of toluene and its biological fate
in soils have been discussed separately below.
6.3-2. Transport.
6.3-2.1. SOIL TO AIH — Laboratory experiments of Wilson et al. (1980) show
that UO to 80> of an unspecified amount of toluene applied'to the surface of
sandy soils will volatilize to air. The volatilization rate is dependent on the
nature of soil. The volatilization rate may be significantly lower for soils
with high organic contents due to their sorption properties (ADL, '1980). This
phenomenon may be especially important with respect to municipal sludges that
normally contain high organic substances.
6.3.2.2. SOIL TO WATER — The transfer of toluene from soil to ground or
surface waters can be of importance with regard to the possibility of contamina-
tion of these water bodies and their subsequent use as sources of drinking
waters. Unfortunately, very little information is available about this subject.
From the investigations of Wilson et al. (1980), it can be concluded that the
transport of toluene from soil to water is probably not a major transfer pathway.
These investigators showed that 0 to 20% of the applied toluene on a sandy soil
6-10
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measured octanol-water partition coefficient of 2.51 (U.S. EPA, 1980c) (as
opposed to the theoretical value for log BCF of 2.69 [Chiou et al., 1977]), the
U.S. EPA (1980c) has estimated the BCF as 27.1. A factor of 3.0/7.6 = 0.395 has
been used to adjust the estimated BCF from the 7.6% lipids on which the Veith
et al. (1979) equation is based to the 3% lipids that is the weighted average for
consumed fish and shellfish in the United States. Thus, the weighted average BCF
for toluene from edible aquatic organisms consumed by Americans has been calcu-
lated to be 27.1 x 0.395 = 10.7.
In one experiment (Roubal et al., 1978), coho salmon (Oncorhynchus kisutch)
and starry flounder (Platichthys stellatus) were exposed to a soluble fraction of
a crude oil containing aromatic hydrocarbon in a flowing seawater. It was found
that alkylated aromatics accumulated in tissues to a greater degree than unsub-
stituted derivatives. In both species, accumulations of substituted benzenes
increased with increased alkylation. The tissues were not analyzed for toluene
because of inadequate analytical procedures. It was determined, however, that
the bioconcentration factors in starry flounder for Cj. and C_ substituted ben-
zenes were as high as 2600 and as low as near zero (concentration in fish tissue
was below detection limit of 0.05 ppm) for xylenes. Substantial variations in
BCF for individual hydrocarbons were found in both species. The muscle of coho
salmon, which has a higher lipid content than starry flounder, showed a lower
BCF. It was concluded (Roubal et al., 1978) that factors other than lipid
content were more important in the observed species differences in the BCF
values.
6.2.2. Transport. The primary fate-determining processes of toluene in aqueous
media appear to be its intermedia transport processes (U.S. EPA, 1979). The
details of the transport processes are discussed below.
6-7
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Water to Air: Although there are no experimentally determined evaporation
rates of toluene from water, there are theoretical models available for predict-
ing the rate of evaporation of slightly-soluble materials from aqueous solution
(Mackay and Wolkoff, 1973; Lisa and Slater, 1974; Mackay and Leinonen, 1975;
Dilling, 1977). The most accurate of these is based on the mass transfer
coefficients for the liquid and vapor phases reported by Liss and Slater ( 1 974 )
and the Henry's law constant for a solute as calculated by its solubility, vapor
pressure, and molecular weight (Mackay and Leinonen, 1975). Based on these,
Mackay and Leinonen (1975) reported the calculated evaporation half-life for
toluene from 1m deep water to be 5.18 hours.
^
The intramedia transfer of toluene in water can be calculated from this
half-life value. If the t. ,? and the current velocity are assumed to be
5.18 hours and 1 m/sec, respectively, the distance downstream that water in a
river would flow before the volatilization of 50$ toluene is:
5.18 hour x 1 m/sec x 3600 sec/hour = 18,648 m
Similarly, Henry's law coefficient (H) can be used to determine toluene
concentration in air phase over seawater. If the height of the air and water
columns are assumed to be the same, the Henry's law coefficient can be given as:
[toluene]
H = [toluene] = 0.349 for seawater (NRC, 1980)
Thus, if equilibrium were attained, only 26% of toluene would be present in the
gas phase above seawater. This calculation does not consider stratification.
In natural shallow or deep waters where stratification is expected to occur,
it is likely that the atmospheric mixing layer is 10 to 100 times deeper than the
aquatic mixing layer (NRC, 1980). In such water, 78 or 97?, respectively, of the
toluene would exist in the gas phase.
6-8
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Other reaction products also are formed from toluene reactions under simu-
lated atmospheric conditions. Some of the ring fragmentation products formed are
acetylene, acetaldehyde, and acetone. The total yield of these products is much
less than 1$. Formaldehyde and formic acid are also formed, but their yields are
not known. A measurement of the total gas phase carbon showed that 60$ of the
oxidation products from the photodecomposition of toluene left the gas phase and
deposited on the walls of the reaction vessel or formed an aerosol (NRC, 1980).
The distribution of the products between gas and condensed phases (aerosol) in
the open atmosphere (as opposed to the reaction in a vessel) is still not clear.
In addition to the above photooxidation products, photolysis of toluene in
polluted atmospheres (containing NO ) yields ozone and fairly high amounts of
peroxyacetylnitrate (PAN) (5 to 30$ nitrogen yield) and peroxybenzoylnitrate
(PBzN) (0 to 5% nitrogen yield) (NRC, 1980). The mechanism of PAN formation is
either by the fragmentation of the aromatic ring or by the secondary reactions
involving products of toluene photolysis. PBzN is formed by the photooxidation
of benzaldehyde produced from the photooxidation of toluene (NRC, 1980). The
formation of the peroxy compounds is significant because these products are
strong eye irritants, oxidizing agents, and may induce plant damage (NRC, 1980).
For an excellent review of the photochemical fate of toluene in the atmosphere,
the reader is referred to a recent NRC document (NRC, 1980).
6.1.2. Transport. The volatility of toluene and its low solubility in water
permit it to volatilize from water surfaces to the atmosphere (MacKay and
Wolkoff,^ t973). Studies of actual and simulated oil spills in seawater indicate
that virtually all hydrocarbons smaller than C15 will be lost to the atmosphere
within a few days (McAuliffe, 1977). The reverse process, that is, transfer of
toluene from air to hydrosphere through rain, is also known to occur (Walker,
6-5
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1976); however, washout should not be considered to be a significant removal
process for toluene from air (NRC, 1980).
6.2. AQUATIC NEDIA
6.2.1. Pate. Sauer et al. (1978) concluded from their studies of the coastal
waters of the Gulf of Mexico that toluene and other alkylbenzenes are persistent
in the marine environment. The probable modes of toluene loss or transformation
from the aquatic environment are discussed below.
Oxidation: Reaction of toluene in water with hydroxy radicals generated
from the irradiation of hydrogen peroxide produces benzaldehyde, benzyl alcohol,
and cresols (Jefcoate et al., 1969). No data were found in the literature from
which a relevant rate of oxidation of toluene in the aquatic environment could be
determined.
It has been observed (Carlson et al., 1975) that toluene may form small
amounts of chlorine-substituted products during chlorination under conditions
used for water renovation. The extent of chlorination increases with the
decrease of pH and increase of contact time. At a water temperature of 25"C and a
_ji
chlorine concentration of 7 x 10 M, the percent chlorine uptake was determined
to be 11.1 and 2.9$ at water pH of 3 and 7, respectively (Carlson et al., 1975).
With other conditions remaining the same, no chlorine uptake was observed at
water pH of 10.1. Therefore, chlorination of renovated water which is usually
carried out at pH levels near 7 may not be of significant environmental concern.
Hydrolysis: No data have been found that would support any role of hydroly-
sis in the fate of toluene in the aquatic medium.
Bioaccumulation: No measured steady-state bioconcentration factor (BCF) is
available for toluene but, using the equation of Veith et al. (1979) and the
6-6
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TABLE 6-1
Rate Constants for Reactions of Toluene with
Reactive Species in the Atmosphere3
Estimated Average Rate of
Daytime Annual Toluene
Concentration Rate , Constant, Removal,
Species ppm
Hydroxyl ~
radical *• x 10"°
Atomic Q
oxygen 3 x 10
Peroxy „
radical 1 x 10
Ozone 3 x 10~
ppm" min" ppm/min
9.5 x 103 3.7 x 10"4
1.1 x 102 3-3 x 10~7
2.5 x 10~7 2.5 x 10"11
5 x 10~7 1.5 x 10"8
Fraction of
Hydroxyl Rate
1
ID"3
4 x 10"8
5 x 10~5
aSource: NRCj 1980
6-3
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{=3
?H3
•OH
addition
OH
OH
5=3
OH
NO,
CH,
OH
0,
H20
CH.,
•CH.
.OH abstraction ^
rao
NO ^
H02*
FIGURE 6-1
Proposed Reaction Pathways of Toluene Under Atmospheric Conditions
Source: NRC, 1980
6-4
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6. ENVIRONMENTAL FATE, TRANSPORT, AND PERSISTENCE
The environmental fate, transport, and transformation of toluene in three
different media—air, water, and soil are individually discussed below.
6.1. AIR
i
6.1.1. Fate in Air. Toluene can persist in the atmosphere. It is, therefore, a
prime candidate for short- and long-range transport away from urban emission
sources. The dispersion of toluene from a point source to the ambient atmosphere
can be modeled theoretically by using dispersion equations. One such modeling
method has been used in the Integrated Exposure Analysis Section (Section 10) to
determine the transport characteristics of toluene.
The atmospheric toluene concentration downwind from one of the largest U.S.
automobile manufacturing plants was measured by Sexton and West burg (1980). At a
point 6 km from the plant site, the toluene concentration was found to be
20.5 ppb. The concentration of toluene was still 15.1 ppb at a point 18 km
downwind.
Toluene itself does not absorb light at wavelengths longer than 295 nm. The
solar spectrum in the troposphere does not contain much light of wavelengths
shorter than,295 nm. Therefore, toluene can absorb only insignificant amounts of
sunlight in the lower atmosphere, but a charge-transfer complex between toluene
and molecular oxygen absorbs light of wavelengths to at least 350 nm. According
to Wei and Adelman (1969), it is the photolysis of this complex that may be
responsible for some of the observed photochemical reactions of toluene.
Toluene apparently is removed from the atmosphere primarily through free
radical, chain processes (NRC, 1980). Of the free radicals in the atmosphere,
6-1
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hydroxy (-OH), atomic oxygen (0), and peroxy ('H02 or -ROg. where R is an alkyl
or acyl group) radicals are potential initiators for the removal of toluene. An
additional reactive species is ozone. The rate constants for the reaction of
these species with toluene and their relative significance for toluene removal
are given in Table 6-1.
It is obvious from Table 6-1 that reactions with hydroxy radicals are the
most important processes for the removal of toluene from the atmosphere. Based
upon an estimated daytime hydroxy concentration given in Table 6-1 and a rate
—12 ^ —1
constant for the reaction of *OH radicals with toluene of 6.4 x 10 cnr mol
see' (Perry et al., 1977), the chemical lifetime of toluene in daylight hours
has been estimated to be 43 hours. This value is subject to considerable
uncertainty and may vary on a day-to-day basis by as much as an order of magni-
tude depending on solar intensity, temperature, and local trace gas composition
of the atmosphere.
The reaction products formed from toluene under simulated atmospheric con-
ditions are not known with certainty. According to the study of O'Brien et al.
(1979), the gaseous products of the reaction are£-cresol, m- and £-nitrotoluene,
benzyl nitrate, and benzaldehyde. Of these products, o-cresol and benzaldehyde
are the major components, each composing about Q% of the total product yield.
The mechanisms by which these products are formed are shown in Figure 6-1.
It is assumed that the reaction proceeds via addition of *OH radicals to the
ring or by abstraction of hydrogen from the methyl side chain. Several investi-
gators have determined the relative importance of both reaction pathways. From
the amounts of reaction products formed, it was determined that the addition
mechanism is of much greater significance than the abstraction mechanism (Kenley
et al., 1978; O'Brien et al., 1979; Hoshino et al., 1978).
6-2
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solvent vapors can be adsorbed in activated carbon as a method of controlling
toluene vapor emissions into the atmosphere.
5.3- ABATEMENT FOR COKE OVEN EMISSIONS
Hydrocarbon emissions result from the burning of the stripped coke oven gas
for the under-firing of the coke batteries. The combustion exhaust gases from
each oven are combined together and vented through a common stack. Improving the
combustion efficiency of the coke batteries would be a proper method of control
(U.S. EPA, 1980b).
5.4. ABATEMENT FOR EMISSIONS FROM MANUFACTURING SITES
Current technology for the control of gaseous hydrocarbon emissions from
manufacturing sites takes the form of charcoal adsorption, direct flame or cata-
lytic incineration, chemical sorbents, vapor condensation, process and material
change, and improved maintenance (U.S. EPA, igSOb). The feasibility of sorbing
organics by the wet scrubbing method, using selected aqueous surfactant systems
as opposed to plain water, has been demonstrated (Matunas et al., 1978). Organic
removal as high as 90 to 95$ can be attained by using this method. Condensation
of organics by the removal of heat may be an expensive method since refrigeration
must be used for the removal of heat from gases (Matunas et al., 1978).
5.5. ABATEMENT PRACTICES FOR RAW AND FINISHED WATERS
No information could be found on this subject. Treating water with acti-
vated carbon, however, is expected to remove toluene from drinking waters.
5-3
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5.6. ECONOMIC BENEFITS OF CONTROLLING TOLUENE EMISSIONS
There is no significant geographical area in the United States in which
ambient concentrations of alkylbenzenes are known to be harmful to plants or
animal lives (NRC, 1980); however, as reactive hydrocarbons, they can contribute
to the formation of photo-chemical smog that is known to be harmful to life and
property. Brookshire et al. (1979) selected residential properties in six pairs
of selected neighborhoods and found the property value could increase on the
average of $504 annually if the air quality were improved. The authors ascribed
about one-half of the enhanced value to respondent-perceived aesthetic benefits
(visibility) and the other half to perceived health benefits. Thayer and Schulz
(1980) extrapolated the results of Brookshire et al. (1979) to the entire south
coast air basin of California and concluded that the urban benefits from improved
air quality amounted to between $1.6 billion and $3 billion in the basin. The
benefits that an improved air quality would provide for commercial agriculture in
southern California can be added to the urban benefits described above. Adams
et al. (1980) examined the economic impact of ambient oxidants upon 14 selected
crops in the region. They extrapolated their results of these 14 crops to all
southern California commercial agricultural products and predicted a
$250 million benefit to be derived from control of oxidants in the air.
All of the cost benefits discussed above are based on total pollutants in
air. It is not possible to project the portion of these benefits that may be
attributable to the control of toluene pollution alone. For a detailed descrip-
tion of the cost benefits of controlling alkylbenzene pollution, interested
readers are referred to a recent NRC (1980) document.
5-4
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5. ABATEMENT PRACTICES IN INDUSTRY
The four major potential sources of toluene release to the environment, in
order of importance (Table 4-19), are (1) inadvertent sources, such as vehicular
emissions and losses during gasoline transfer, (2) solvent use in paint, coating
adhesives, and inks, (3) coke production, and (4) manufacturing sites such as
petroleum refineries and chemical plants. Therefore, the institution of pollu-
tion control devices for these four major sources can be expected to produce a
large impact on the overall toluene level in the environment.
5.1. ABATEMINT PRACTICES FOR INADVERTENT SOURCES
The two major sources of vehicular emissions of toluene in the atmosphere
are exhaust emissions and evaporative emissions from the gas tank and the car-
buretor. Crankcase emissions have been eliminated essentially through the use of
positive crankcase ventilation technologies (U.S. EPA, 1980b).
The installation of catalytic converters on automobiles has resulted in a
significant reduction of hydrocarbon emissions from automobiles. Generally,
tailpipe catalysts control systems remove unsaturated and aromatic hydrocarbons,
including toluene, more efficiently than paraffinic hydrocarbons (U.S. EPA,
1980b). Therefore, both the photochemical reactivity and the mass of hydro-
carbons emitted are reduced by the catalytic converter systems.
Evaporative emissions from automobiles have been reduced through the use of
adsorption regeneration carbon canister technologies (U.S. EPA, 19dOb). Such
systems are more effective, however, for regular grade gasoline containing 25 to
27% aromatics than for premium grade unleaded gasoline containing 43$ aromatics
(U.S. EPA, 1980b).
5-1
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Most of the current diesel exhaust emission studies are concerned with
emission controls through either engine design or the use of fuel additives.
Other control -options, such as catalytic reactors, appear to be viable
(Santodonato et al., 1978).
Other major sources of automobile emissions are losses from spilled gaso-
line and losses during fuel transfer. The former can be reduced by educating the
public about the necessity of restricting spillage both for economic and environ-
mental reasons. The loss of gasoline during fuel transfer is already controlled
in many areas of the country by incorporating vapor recovery systems (NRC, 1980).
5.2. ABATEJCNT PRACTICES FOR SOLVENT USAGE
Solvent vapors originating from industrial use of toluene in coatings and
thinners can be controlled or recovered by applying condensation, compression,
adsorption, or combustion principles. Control efficiencies of 90$ or greater are
possible by activated carbon adsorption, provided that participates are removed
from the contaminated airstream by filtration before the airstream enters the
carbon bed (U.S. EPA, 1980b).
When recovery of the vapor is not desired, an incineration method can be
used for controlling emissions. The choice between direct flame and catalytic
incineration methods must be based on economic factors and on local emission
standards.
Control of toluene emissions from gravure printing can be done in a number
of ways (U.S. EPA, 1980b). Process modifications involving microwave, infrared,
electron beam, or ultraviolet drying and subsequent recovery of organic vapors
will reduce emissions. Another alternative is to replace inks containing organic
solvents with aqueous or solventless inks. Incineration of the exhaust gases by
thermal or catalytic methods provides another method of emission control. Last,
5-2
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TABLE 4-19
Total Yearly Release of Toluene into Different Media
Environmental Release
(10-* kg/yr)
Source
Production (see Tables
4-12 abd 4-14)
Usage (see Tables 4-16
and 4-17) :
Inadvertent (see Table
4-18
Coak production
TOTAL
Air
3,764
375,809
708,306
10,560
1,098,439
Water
47
30
1,089
NA
1,166
Land
31
NA
247
NA
278
POTW
36
NA
NA
NA
36
NA = not available
4-29
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TABLE 4-20
Consumer Product Formulations Containing Toluene0
Product
Percent Toluene Content
China cement, solvent type
Contact rubber cement
Microfilm cement, cotton base
Model cement
Plastic cement, polystyrene
Shoe cement
Tire repair, bonding compounds
Paint brush cleaners
Stain, spot, lipstick, rust removers
Nail polish
De-icers, fuel antifreeze
Fabric dyes
Indelible inks
Marking inks
Stencil inks
Solvents and thinners
20 to 30
may contain toluene
27 to 30
up to 20 to 25
24
may contain toluene
>80
contain 25 to 90 BTX
may contain toluene
35
30
<60
may contain toluene
80 to 90
40 to 60
may contain toluene
aSource: Gleason et al., 1969
4-30
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suggested that the simpler CNS functions may be affected at lower levels of
toluene exposure than the more complex functions.
Wineke et-al. (1976) noted, in an abstract published in the Proceedings of
the 2nd International Industrial and Environmental Neurology Congress (Prague,
Czechoslovakia), that experimental exposure to 98 ppm toluene for 3 hours did
not affect psychophysiological performance in 20 subjects. The parameters
evaluated in this study included performance in a bisensory (auditory and visual)
vigilance task, psychomotor performance, critical flicker frequency, and audi-
tory evoked potentials. The available abstract did not provide any additional
information on the experimental design, the nature of the psychophysiological
tests, or the results of this study.
Gusev (1965) examined the effects of acute low-level toluene exposure on the
electroencephalographic (EEC) activity of four human subjects who were trained
to develop synchronous and well-marked alpha rhythms when stimulated by light.
Toluene exposures of 1 mg/m (approximately 0.27 ppm) for 6 minutes were
reported to cause statistically distinct changes in EEC activity from the left
temporal-occipital region in all subjects; these changes persisted through a 6
minute recovery period. It should be noted that the 1 mg/m concentration is
slightly lower than the odor threshold determined for toluene in the same experi-
ment (1.5 mg/m ; see subsection 11.7.2.). Toluene concentrations of 0.6 mg/m
caused no variations in the electric potentials of the EEGs. Exposure sessions
consisted of 10 separate observation periods in which inhalation of toluene
(5 periods) alternated with inhalation of pure air (5 periods). A single period
consisted of 18 one-minute cycles. Every cycle included the sequential presenta-
tion of a sound stimulus (10 seconds), a wait for the light stimulus (7 seconds),
the presentation of the light stimulus (18 seconds), and an interval of active
physical exercise (25 seconds) for recovery of normal EEC rhythm. Of the
11-8
-------
TABLE 11-2
Effect of Toluene Exposure on the Performance of Perceptual Speed and Reaction Tine Teats3'
Mean Test Scores
Performance Teat
Identical Nunbera0
(minutes)
Spokead
(seconds)
Reaction Time - Simple6
(meters/second)
Reaction Time - Choice
(meters/second)
Concentration
(ppm)
too
300
500
700
100
300
500
700
100
300
500
700
100
300
500
700
Experimental
Conditions
5.62
5.25
5.13
5.19
50.5
46.7
13.6
05. 1
228
236
246
253
425
429
432
442
Control (ilr)
Conditions
5.53
5.29
5.04
4.80
50.8
43.7
40.2
36.9
230
222
219
214
422
416
400
408
t-Value
+0.50
-0.39
+ 1.34
+2.65»
-0.08
+ 1.18
+1.28
+2.5I*
-0.31
+2.35*
+3.88"
+4.81"
+0.34
+1.99
+2.91"
+3.59"
aSource: Qamberale and Hultengren, 1972
12 male subjects were expoaed to toluene concentrations of 100, 300, 500, and 700 ppm during four successive 20-
mlnute periods. The teats were performed at each concentration sequentially in the order Hated. The number of
times each test sequence was repeated was not stated.
°Peroeptual speed: Identical Numbers. Subjects were instructed to underline the 3-digit numbers, from a total of
60 columns, that was identical to the number at the head of each column. Performance waa measured as the time
taken to complete the teat.
Perceptual speed: Spokes. Subjects were instructed to connect circles located at random on four pages and
numbered from 1 to 20 In the correct numerical order using a pen. Performance was measured aa the mean time taken
for the four assignments.
Simple Reaction Time. Subjects were instructed to respond to a signal from a lamp by pressing a pushbutton.
Stimuli were administered at Intervals of approximately 10 seconds, an acoustic warning signal was given 3
seconds prior to onset of stimuli, and 30 stimuli were given in each trial. Performance was measured aa the mean
reaction time for the last 20 stimuli administered.
Choice Reaction Time: Stlmulua/reply test as above, but there were three pushbuttons equipped with matching
stimulus lamps. Stimulus administration followed a random sequence with the number of light signals evenly
distributed among the lamps, but the trial and performance measurements were otherwise the same as for simple
reaction time.
Degrees of freedom * 11; "P < 0.05} "P < 0.01; ""P < 0.001
-------
symptoms indicative of CMS depression become evident: confusion and disorienta-
tion, headache, blurred vision and reduced speech, drowsiness, muscular incdbr-
dination, ataxia, depressed reflexes, and nystagmus. In extreme cases, loss of
consciousness, possibly with convulsions (Helliwell and Murphy, 1979), occurs.
The duration and severity of these effects vary greatly, depending upon the
intensity of exposure; the duration may range from 15 minutes to a few hours
(Press and Done, 1967b). Also, all of the symptoms described have not been
exhibited in any single sniffer, nor in any single episode of sniffing.
Winek et al. (1968) published partial results of an autopsy on an adolescent
who' had died as a result of sniffing model airplane glue containing toluene. At
autopsy, the cut surfaces of the lungs of this individual were found to be
extremely frothy and congested, with diminished amounts of crepitation through-
out the lung tissue. Other gross observations that were noted included some
petechial hemorrhages in the larynx and upper trachea, firmness and congestion in
the spleen, and a dark red brown color and congestion in the liver. No hemor-
rhages, obstructions, or ulcerations were seen anywhere in the gastrointestinal
tract, and all other organs were unremarkable. The results of toxicological
analyses of various body tissues for toluene are presented in Section 13.2.
Congestion in various organs, swelling of the brain, subseromucous petechiae,
and pulmonary edema were associated with 19 other cases of acute death from
*%'
thinker intoxication (Chiba, 1969); the English abstract of this Japanese study
indicated that toluene was the major component of the inhaled thinner. Nomiyama
and Nomiyama (1978) described an instance in which U adolescents were found dead
after sniffing 99% pure toluene in a car, but post-mortem results other than
levels of toluene (blood and alveolar air) and hippuric acid (urine) were not
presented. Sudden death due to solvent sniffing has been reported in at least
122 cases (Bass et al., 1970; Alha et al., 1973). The sudden deaths have been
11-10
-------
18 minutes allotted for EEC recording in each period, 3 minutes were used for
training, the next 3 minutes for background observations, the following
6 minutes for the toluene exposure, and the final 6 minutes for recovery. It
should be noted that no other studies have reported any effect of toluene on the
CNS at such low levels of exposure, and that the purity of the toluene used was
not stated.
Narcosis is the primary result of acute toluene exposure at high concentra-
tions. A number of accounts of workers who were rendered unconscious by toluene
vapor have been published in the medical literature (Lurie, 19^9; Browning, 1965;
Longley et al., 1967; Reisin et al., 1975). Most of these cases have involved
the entry of workmen into confined areas with poor ventilation and subsequent
exposure to high levels of toluene during maintenance operations. Longley et al.
(1967) described two episodes of acute toluene intoxication involving 26 men who
were exposed in the holds of cargo ships. Toluene concentrations were estimated
to have ranged from 10,000 ppm at waist level to 30,000 ppm at floor level, but
it was emphasized that this estimate was purely conjectural. Effects at these
concentrations ranged from exhilaration, lightheadedness, and cluminess and
dizziness to collapse and unconsciousness. No deaths occurred and recovery was
quite rapid, with no after-effects following removal from the contaminated
atmosphere. The durations of the exposures were not indicated, but loss of
consciousness occurred within minutes.
Episodes of toluene abuse are characterized by the progressive development
of CNS symptoms. 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 and
Done, 1967a, 1967b; Wyse, 1973; Lewis and Patterson, 1971*; Hayden et al., 1977;
Oliver and Watson, 1977; Barnes, 1979). As duration of exposure increases,
11-9
-------
years in preparing a toluene-containing mixture for use in the manufacture of
V-belts. The mean atmospheric concentration of toluene in the mixing department
was 250 ppm, with extremes of 210 ppm and 300 ppm. No CNS effects were observed,
however, in 17 other workers who were exposed to 125 ppm toluene (range, 80 to
160 ppm) while engaged in the manufacture of the belts.
In a more extensive study, Suhr (1975) found no evidence of adverse neuro-
logical effects in a group of 100 rotogravure printers with at least 10 years of
exposure to 200 to 400 ppm pure toluene (<0.3/& benzene). Subjective complaints
indicative of CNS toxicity (headache, giddiness, nervousness, irritability,
sleeplessness, bodily fatigue and incoordination), abnormal reflex reactions,
and abnormal Sphallograph test results were not found to occur significantly more
often in the printers than in an unexposed control group of equal size. The
Sphallograph is an instrument that is used to detect slight disturbances of
muscular coordination by sensing variations in the balance of two metal plates; a
t
test person stands on the plates, and balance disturbances are detected by strain
gauges.
The Suhr (1975) conclusion that chronic occupational exposure to 200 to
HOO ppm toluene did not cause adverse neurological effects in the rotogravure
workers is equivocal for several reasons. First, the nature of the control group
used in this study is not defined, other than that they "were from the same firm
and not exposed to toluene." Additionally, the worker and control groups were
only roughly matched by groups for age distribution, years of exposure, and
nature of workshift (i.e., 2 or 3 shift work). Second, the venous blood levels
measured in the printing room workers at the end of their shifts indicate expo-
sure to toluene levels of at least 300 ppm and possibly as high as 600 ppm.
These levels are consistent with the reported air concentration measurements,
which were made with a "measuring cell" device. It is not clear, however, when
11-12
-------
attributed, however, to severe cardiac arrhythmia, and are discussed in Sub-
c
section 11.5. (Effects on the Heart).
11.1.1.2. SUBCHRONIC AND CHRONIC EFFECTS — Wilson (1943) described the
effects of exposure to commercial toluene vapor on 100 workers (out of a total of
1000 workers) who showed symptoms severe enough to seek examination at a hospi-
tal. The workers were exposed daily to toluene concentrations ranging from 50 to
1500 ppm for periods of 1 to 3 weeks, but the composition of the commercial
formulation and the type of industry were not described. Also, it is unclear
whether the remaining 900 workers evidenced any symptoms of toluene exposure.
The concentration of toluene was determined shortly after any exposed person
appeared at the hospital with symptoms, and the patients were classified into
groups by degree of exposure. The following effects were reported:
50 to 200 ppm (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.
200 to 500 ppm (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.
500 to 1500 ppm (approximately 10/S of the patients) - nausea, headache,
dizziness, anorexia, palpitation, and extreme weakness. Loss of coordination
was pronounced and reaction time was definitely impaired.
Characteristic CNS alterations have also been described in foreign reports
of workers exposed for longer durations to moderate levels of toluene.
Parmeggiani and Sassi (1954) found signs of "nervous hyperexcitability" in 6 out
of 11 paint and pharmaceutical industry workers who were exposed to 200-800 ppm
toluene vapor for "many" years. Capellini and Alessio (1971) noted symptoms of
stupor, nervousness, and insomnia in one worker who was employed for "diverse"
11-11
-------
I
workers were examined for reflex reactions and Sphallograph measurements. If it
was after or before the workshifts (as the data for the 33 Sphallograph groups
would indicate), then blood levels of toluene may have declined significantly.
Astrand et al. (1972) have shown major drops in levels within minutes after the
removal of human subjects from exposure. Third, the Sphallograph appears to be a
very infrequently used device in the United States; several behavioral toxicolo-
gists who were contacted by Syracuse Research Corporation (SRC) indicated that
they have never heard of the instrument, and the device does not appear to have
been described in standard texts. Suhr (1975) also cites the work of Pohl and
Schoidle (1973), who tested the effects of "extreme" concentrations of 11 fre-
quently used organic solvents in humans with the Sphallograph and found only
minimal effects. This would argue that the Sphallograph is not a sensitive test
for determining CMS effects of solvents. Last, until more is known concerning
the exposures of the control group, the significance of the reportedly negative
results of the subjective symptom survey is questionable.
Chronic occupational exposure to toluene has also been associated with
behavioral changes. Munchinger (1963) diagnosed an "organic psychosyndrome" in
21$ of a group of printers exposed on the average to 300 ppm toluene for 18 years
(mean age, U2 years), and in 40$ of a group of printers' helpers exposed to
430 ppm for 12 years (mean age, 44 years). A total of 110 workers were examined,
but the number of printers and printers' helpers was not stated and testing on
control subjects was not performed. The syndrome was characterized by subjective
memory, thinking, and activity disturbances. Results of Rorschach testing were
consistent with the psychosyndrome diagnosis in 83$ of the cases. In combina-
tion, Rorschach Test and Knoepfel's 13-Error Test results agreed with the diagno-
sis in 95$ of the cases.
11-13
-------
More recently, several groups of investigators have shown that long-term
exposure to combinations of toluene and other common organic solvents caused
impairments in visual intelligence and psychomotor performance of workers. In
1973, Lindstrom compared the psychological test performances of a group of 168
male workers who had been exposed to hydrocarbon solvents for 0.1 to 30 years
(mean, 6 years) to those of an unexposed control group (N = 50). Twenty-six of
the workers had been exposed primarily to toluene and 25 others to a combination
of toluene and xylene; the remaining workers (numbers in parentheses) were
exposed primarily to trichloroethylene (44), tetrachloroethylene (8), "thinners"
(44), and miscellaneous solvents (21). Exposure concentrations were not
reported. Results showed that the solvent-exposed workers were inferior in
performance to the controls in sensorimotor speed performance, psychomotor per-
formance, and visual accuracy as determined by standardized test procedures
(e.g., Bourdon-Wiersma vigilance test, Santa Ana dexterity test, Mira psycho-
motor test). The performance of the workers on the Rorschach personality test
was comparable to that of the control group.
Hanninen et al. (1976) compared the behavioral responses of a group of 100
car painters with those of 101 age-matched nonexposed subjects. The painters
(mean age 35+11 years) were exposed to different organic solvents for 1 to
40 years (mean, 14.8 ± 8.5 years), but, as detailed in Table 11-3. toluene was
present in the greatest amount (30.6 ppm). A battery of tests included 1 test
for verbal intelligence, 3 visual testa, 5 memory or learning tasks, 4 tests of
psychomotor performances, and the Rorschach test for measuring personality
Changes (Tables 11-4 and 11-5). Results of this study showed significant dif-
ferences between the exposed and reference group in almost all intellectual
performances and memory tasks. Impairments in visual and verbal intelligence and
in memory, as well as a reduction of emotional reactivity as indicated by the
11-14
-------
TABLE 11-4
Performance Teats: Means, Standard Deviations, and Significances Between the Group Means (Age-Hatched) Groups3
Teat , .
WAIS* Slallarities teat0
MAIS Picture Completion4
'MIS Block Design'
Figure Identification f
WAIS and VMS'5 Digit Spanh
WHS Logical Memory1
WHS Associate Learning-*
Benton Teat for 7isual Reproduction
Benton Teat for Visual Retention
SADT - right hand"
SAOT - left hand1'
SADT - coordination with both hands"
Finger Tapping - right hand1
Finger Tapping - left hand1
Reaction Time (Slaple) - right hand
Reaction Tine (Simple) - left hand
Reaction Time (Choice)
Nira Teat*
Mlra Teat"
Means and I
Exposed (H a 100)
19.4 * 3.1
14.9 * 2.9
34.6 * 7.0
32.0 * 9.0
10.6 a. 1.6
11.7 * 3.7
15.3 * 3.6
21.1 * 3.1
8.2* 1.5
44.7 * 5.7
42.3 * 5.4
29.0 * 5.4
202.5 * 29.2
186.7 * 28.5
12.4 * 2.9
12.1 * 3.0
9.1 * 1.8
18.3 * 3.3
2.2* 1.0
J^flH'frrd Deviations
Honexoosed (H a 150)
2.9 * 2.1
16.2 * 2.3
39.6 * 5.6
36.7 * 9.8
11.5 * 1.8
13.9 * 3.1
17.1 * 2.6
22.6 * 2.3
8.7 * 1.3
47.5 * 5.8
43.6 * 5.1
31.5 * 5.7
209.6 * 23.8
196.4 * 22.4
11.9 * 1."
11.7* 1.4
9.1 * 1.2
20.3 * 4.6
2.0 * 0.8
Significance
of Differences .
(t-test)
•ee
M*
•M
Me
Me
M*
.MM
M«
t
ie
M
i
•««
*
aSouroe: Hannlnen et al., 1976
bWechaler Adult Intelligence Scale.
°Meaaurea verbal intelligence and abstraction.
Measures visual intelligence and obaerration.
"Measures visual intelligence and abstraction.
Measures speed of perception and raemory for visual details.
3Vechaler Memory Scale.
Measures memory for digits.
Htoaaures verbal memory.
•^Measures verbal aeaory and learning.
t>
Santa Ana Dexterity Teat; measures payehoootor speed.
Measures motor speed.
'"Teat for paychonotor behavior and paychoaotor ability; two variables tested.
"Paired t-teat.
•P < 0.05; »*P < 0.01; M«P < 0.001
11-16
-------
TABLE 11-3
Mean Concentrations of Organic Solvents
in the Breathing Zone of 40 Car Painters3'
Mean
Solvent Concentration
(ppm)
Toluene 30.6
Xylene 5.8
Butyl Acetate 6.8
White Spirit 4.9
Methyl Isobutyl Ketone 1.7
Isopropanol 2.9
Ethyl Acetate 2.6
Acetone 3.1
Ethanol 2.9
Source: Hanninen et al., 1976
Sampling Period = 1 hour; Number of Car Repair Garages = 6;
Number of Samples = 54.
11-15
-------
Rorschach test, were the predominant effects of solvent exposure (Tables 11-4
and 11-5). Differences in psychomotor performances between the exposed and
control subjects were less consistent; impairments were seen only in some of the
Santa Ana dexterity and finger tapping test scores, and reaction times were
unaffected by exposure. It should be noted that in other studies, reaction time
increased as a result of acute (Ogata et al., 1970; Gamberale and Hultengren,
1972) and subchronic (Wilson, 1973) exposures to toluene concentrations in
exces*s of 200 ppm. The possible influence of differences in initial intelligence
levels on the performance scores was controlled in the Hanninen et al. (1976)
study by a separate comparison of the test results of 33 pairs of exposed and
unexposed subjects who were matched for age and intelligence.
In a related study, Seppalainen et al. (1978) examined the same cohort of
car painters studied by Hanninen and coworkers (1976) for neurophysiological
effects. Results of EEC analysis on 102 solvent-exposed car painters and 102
nonexposed control subjects showed no increase in abnormalities (Abnormal EEGs
were encountered in 32 painters and 37 controls.). It was noted, however, that
the incidence of abnormal EEGs in both groups was higher than expected (approxi-
mately 10}) on the basis of EEC literature. It was further reported that 26 of
the car painters had a complex of four subjective symptoms indicative of CNS
disturbance (interrupted sleep, absentmindedness, easy to fall asleep when
watching television, frequent headaches); this symptom complex was found only in
12 controls. EEC testing on the workers with these symptoms showed abnormalities
in 46J (12/26) of the cases, but 26% (20/76) of those without the symptom complex
also displayed EEC abnormalities. This difference was not statistically signi-
ficant (Chi squared = 2.68).
Rouskova (1975) did observe changes in EEG response to photic stimulation in
a group of 20 workers with a 13.5 year (average) history of exposure to higher
11-18
-------
TABLE 11-5
Rorschach Personality Test Variables: Means, Standard Deviations, and
Significances Between the Group Means (Age-Matched Groups)3
u .„..._.... Significance
Means and Standard Deviations _„ °, M
Variable
Number of responses
Number of rejections
Average latency time of responses
Adaptability
Emotionality
Spontaneity
Rational self-control
Originality of perception
Hostility
Anxiety
Bodily Preoccupation
Exposed (N = 100)
13.6
0.7
16.4
11.6
8.8
11.8
8.6
1.6
1.6
3.9
0.4
± 6.4
± 1-1
± 8.5
± 3.1
± 3.3
± 2.4
± 2.8
± 1-7
± 1.6
+ 2.0
± 0.8
Nonexposed (N = 101) (t-test)
13.8 ±
0.4 +
16.5 ±
12.1 +
10.4 +
11.9 ±
7.3 ±
1.5 ±
2.4 ±
3.8 ±
0.8 +
4.5
1.0 »«b
8.1
3.1
3.2 «•»
2.6
2.8 »»»°
1.2
1.7 »»»
2.2
1.1 »b
Source: Hanninen et al., 1976
Paired Chi Square-test for dichotomized scores
Paired t-test
»P < 0.05; "P < 0.01; »*«P < 0.001
-------
concentrations of toluene (>250 ppra) and 1,1,1-trichloroethane (concentration
not stated). Photic stimulation was applied in a series of rhythmic flashes,
each lasting 10 seconds with intervals of 10 seconds between each flash series;
frequences ranged from 1 to 30 per second. Evaluated as a normal response was
the occurrence of EEC activity of the same frequency as stimulation or of a
harmonic or a subharmonic multiple of that frequency lasting at least one second.
Results showed that abnormal EEC responses were found in 18 of the 20 workers
(90$), but in only 1 of 20 unexposed control subjects.
Residual effects indicative of cerebellar and cerebral dysfunction have
been observed in a number of persons who had abused toluene or solvent mixtures
containing toluene over a period of years (Grabski, 1961; Satran and Dodson,
1963; Knox and Nelson, 1966; Kelly, 1975; Boor and Hurtig, 1977; Heisenberger,
1977; Keane, 1978; Sasa et al., 1978; Tarsh, 1979; Malm and Lying-Tunell, 1980).
Boor and Hurtig (1977) also described a case of cerebral involvement in an
optician who regularly used toluene occupationally to clean eyeglasses and con-
tact lenses in a small, unventilated room. Clinical signs in these individuals
included ataxia, intention tremors, nystagmus, equilibrium disorders, positive
;Babinski reflex, impairment of speech and hearing, reduced vision, disturbance
of concentration and memory, emotional lability, and psychosis. These reports,
which are summarized in Table 11-6, indicate that the severity of the encephalo-
pathic effects generally varied with the intensity and duration of exposure and
that the effects were largely reversible, particularly when the exposures were
not too extreme. Prolonged toluene abuse had, however, on occasion led to
permanent encephalopathy and brain atrophy as evidenced by EEG and neuroradio-
logical (pneumoencephalogram, angiogram) changes (Knox and Nelson, 1966; Boor
and Hurtig, 1977; Sasa et al., 1978).
11-19
-------
TABLE 11-6
Enoephalopathlo Effects or Chronic Toluene Abuse
Subject (Age)
Exposure History
Effects and Diagnosis
Reference
Hale (33 years)
Hale (30 years)
IV)
O
Female (19 years)
Hale (25 years)
Regularly sniffed toluene for II years.
Subject purchased a gallon of pure
toluene every 1-6 weeks, and Inhaled the
toluene on an aloost dally basis at fre-
quent Intervals throughout the day.
10-year history of toluene abuse.
Almost dally sessions of prolonged paint
sniffing for 1-1/2 years. Ingredients
not specified but It was Indicated that
toluene was a conmon Ingredient In all
the brands sniffed. Previous 4-year
history of multiple drug and solvent
abuse.
10-year history of lacquer thinner (99)
toluene) abuse; during the last 5 years he
had spent virtually all his waking hours
inhaling the vapors (1 gallon used every
2 weeks)
Patient Initially examined after 6 years by
Orabakl; signs Included ataxla, Intention
tremors, pyramidal signs and psychosis which
were concluded to be consistent with oerebellar
degeneration. After 8 anre yeara of abuse, Knox
and Nelson reexamlned the patient and concluded
that the syndrome was primarily a diffuse
cerebral disorder based on findings of ataxla,
tremors, limb inooordlnatlon, emotional lability,
narked anout reflex, and positive Bablnakl toe
reflex; cerebral atrophy was confirmed by EEQ
and pneumoenoephalography.
Recurrent headaches, "Inappropriate" speech,
brief episodes of memory loaa, Increased
Irritability, and exaggerated swings In mood.
Unremarkable clinical and neurological exam,
but nonspecific EEQ changes were found that
were regarded as consistent with diffuse
enoephalopathy.
Ataxla, intention tremors of hands and feet,
Inooordlnatlon, hallucinations. Normal EEQ,
brain aoan, arterlography, and pneumoenoephalo-
graphy. The diagnostic impression was
oerebellar dysfunction secondary to aome toxic
factor In the paint. Objective neurological
Improvement 5 months after sniffing was
discontinued.
Ataxla, mildly slurred speech, nystagmus, and
bilateral Bablnakl signs. Normal BEG, nuollde
brain scan, eleotronyogram, and nerve oonduotion
studies, but a computerized brain aoan showed
diffuse widening of the cortical and oerebellar
aulcl. Subjective Improvement In condition
following abstinence from exposure, but a
neurological exam after 9 months was
essentially unchanged.
Grabakl, 1961;
Knox and Nelson, 1966
Satran and Dodson, 1963
Kelly, 1975
Boor and Hurtlg, 1977
-------
Table 11-6. (oont.)
Subject (Age)
Exposure History
Effects and Olagnoala
Reference
Hale (59 years)
Male (age not stated)
Hale (27 years)
N>
Hale (20 years)
Hale (25 years)
Female (18 years)
Optician who frequently but Inter-
mittently used 99t toluene in a small
unventllated room to clean eyeglasses
and contact lenaes. Unable to smell
toluene because of chronic anosmia.
Duration of exposure not stated.
Habitual Inhalation of paint thinner
(toluene) on the job. Duration not
stated.
Sniffed unspecified glues and paint
thlnners for 10 years. Proa age 25,
toluene was involved 1-5 times per week
(200-300 ml/week usod), and from age 26,
he inhaled 4-7 times per day (100 ml/day
used.
3-year history of dally aerosol spray
paint Inhalation. Product contained
copper, toluene, and xylene as solvents
and isobutane propane and raethylene
chloride as propellants.
Sniffed toluene for 4 months, starting
while on the job using toluene as a
solvent in the rubber processing
Industry.
Inhaled pure toluene since age 12,
regularly since age 16 (2 liters used
per month). Sniffed more heavily than
usual during the last 2 months.
Fatigue and olunalneas of the left aide which
got progressively worae. Occasional staggering
and mildly slurred speech, disturbed concen-
tration and memory. Normal neurological exam,
ECO, and brain soana. Daily Improvement without
apeolfio treatment following oeaaatlon of exposure.
Blzzare behavior prior to hospital admission.
Admitted In an agitated, violent, nearly catatonic
state.
Arm and neck tremors, ataxla, Incoordlnatlon,
and equilibrium disorders. No abnormal
psychiatric aymptoma. Pneumoencephalographlo
and angiographloal evidence of nidbrain and
cerebrum atrophy. Degeneration of the
cerebellum suspected.
Reduced vision, poor color perception, con-
stricted visual fields, normal optic fundl, im-
paired papillary response, ataxla, and nystagmus.
Symptoms slowly subsided following cessation
of paint sniffing.
Delusions and unpredictable behavior.
Largaotll prescribed because he waa thought to
have a schizophrenic illness. Symptoms dis-
appeared and did not recur following termina-
tion of enlfflng.
Personality changes (apathy, Irritability,
emotional lability, oareleaanesa), vomiting,
difficulty in walking, and slurred speech
1-2 weeks before admission. Gait ataxla,
Incoordlnatlon, dysarthrla, downbeat nystagmus,
bilateral positive Bablnski sign, vlaual and
color sense loss, impaired concentration and
abstracting ability upon admission. Symptoms
consistent with mainly cerebellar-braln stem
Involvement and possibly optio neuritis.
Symptoms decreased when she did not Inhale
toluene, and disappeared after 8 months.
Boor and llurtlg, 1977
Helsenberger, 1977
Sasa et al., 1978
Keane, 1978
Tarsh, 1979
Malm and Lylng-Tunell, 1980
-------
11.1.2. Peripheral Nervous System. Matsushita et al. (1975) found evidence of
peripheral neuropathy in a group of 38 female shoemakers (mean age 20.7 +
5.2 years) who had been exposed to a glue containing mainly toluene and "slight"
gasoline for an average duration of 3 years and 4 months. The results of neuro-
logical and muscular function tests reportedly showed abnormal tendon reflexes,
reduced grasping power of the dominant hand, and decreased finger tapping tempo
in the exposed workers relative to a group of 16 unexposed control women
(Table 11-7), but descriptions of the tests were not provided. A significant
decrease in finger agility was also noted in the exposed shoemakers; agility of
the fingers was estimated by measuring the time needed to move 25 "bulbs'* using
glass chopsticks. The average toluene concentration in the air varied with time
of year from 60 to 100 ppm (range 15 to 200 ppm); in a "few" working places,
gasoline ranged from 20 to 50 ppm. An increased urinary hippuric acid level
among the exposed women (3.26 + 0.82 mg/ml versus 0.35 i 0.24 mg/ml for controls)
is consistent with an exposure to toluene.
Electroneuromyographic measurements were made in the Seppalainen et al.
(1978) study (described in Section 11.1.1.) on 59 of the toluene-exposed car-
painters and 53 referents with a similar age distribution for any indication of a
possible peripheral neurotoxic effect from exposure. Maximum motor conduction
velocity (MCV), conduction velocity of the slower motor fibers (CVSF), maximal
sensory conduction velocity (SCV), and motor distal latencies were recorded from
nerves in the upper and lower extremities (median, ulnar, deep peroneal, pos-
terior tibial, and sural nerves). Results of these measurements showed that the
mean conduction velocities and motor distal latencies of the car painters were
almost identical to those recorded for the unexposed control group. In several
instances, however, individual nerve conduction velocities were found to be
slower than the normal historical value (not stated) for Seppalainen's
11-22
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TABLE 11-7
Results of Neurological and Muscular Function Tests
of Toluene-Exposed Female Shoemakers3
Testb
Abnormal tendon reflex:
Biceps and triceps
Patellar
Ankle
Pathological reflex
Grasping power (dominant hand)
Tapping tempo (M + S.D.)C
Cold pressure test
Postural hypotension
Cuff test (upper arm)
Dermatographism
Blocking test (M + S.D.) (seconds)
Numbers investigated
Exposed Group
6(16)
11(37)*
7(18)**
K 3)
11(29)"
162.9 ± 16.6
6(16)
2( 5)
5(13)
5(13)
68.2 + 13.3
38(100)
Control Group
3(19)
K 6)
0( 0)
0( 0)
K 6)
168.6 + 17.3
2(13)
K 6)
K 6)
K 6)
61.8 ± 13.7
16(100)
aSource: Matsushita et al., 1975
Numbers of subjects with abnormal scores reported. The percentage of
subjects affected is indicated in the parentheses.
Q
Unit of measurement not stated.
Statistical significance (Chi Square- and t-tests): *P < 0.05; **P < 0.1;
M = mean; SD = standard deviation.
11-23
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laboratory. When the conduction velocities of the study group were compared with
the historical values, abnormally slow MCVs or SCVs and/or prolonged motor distal
latencies were found in 12 of the 59 .painters, but in none of the 53 controls.
Although the two previous reports (Matsushita et al., 1975; Seppalainen
et al., 1978) indicate a possible effect of toluene on the peripheral nervous
system, toluene's role in the causation of human peripheral neuropathies has not
been clarified. Reports of polyneuropathies in abusers exposed to excessive and
prolonged concentrations of glues and solvents have appeared in the Japanese and
American literature, but have in all cases involved mixtures of toluene and other
solvents (Matsumura et al., 1972; Takenaka et al., 1972; Goto et al., 1974>;
Shirabe et al., 1974; Suzuki et al., 1974; Korobkin et al., 1975; Oh and Kim,
1976; Towfighi et al., 1976; Altenkirch et al., 1977>. The cases described in
these reports were characterized by the sudden onset and rapid progression of a
symmetric, predominantly motor polyneuropathy (although sensory nerve involve-
ment of the glove and stocking type has been reported), even after exposure has
ceased. Symptoms included extremity weakness, numbness, paresthesia, marked
amyotrophy, and occasional flaccid paresis. Collective results of eleetro-
myographic studies have shown delayed nerve conduction velocities and signs of
denervation, and biopsies of nerves have revealed axonal degeneration, demyelin-
ation, and enlargement of some axons with focal accumulation of neurofilaments.
Muscle biopsies revealed extensive neurogenic atrophy.
The earlier reports regarded either ri-hexane alone (Korobkin et al., 1975;
Towfighi et al., 1976) or a combination of n-hexane and toluene (Matsumura
et al., 1972; Goto et al., 1974; Shirabe et al., 1971; Suzuki et al., 1974) as
the cause of glue sniffers' neuropathy. The following observations have been
offered as evidence to indicate that ti-hexane plays an important role in its
etiology: (1) in many of the reported cases, neuropathy did not develop until
11-24
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the patients began to sniff glue products that contained ji-hexane, and (2) it is
known that continuous occupational exposure to ri-hexane under poor ventilation
conditions produces a neuropathy among workers that is clinically and patho-
logically similar to that observed among the glue sniffers. From a recent
outbreak of polyneuropathy among 18 glue thinner sniffers in West Germany, how-
ever, Altenkirch et al. (1977) presented data that implicate methyl ethyl ketone
(MEK) as the causative agent and argues against ri-hexane and toluene as the
causes. These data are summarized as follows (Altenkirch et al., 1977):
1. In a number of sniffing adolescents (1000 to 2000), no
adverse neurological effects were observed during the
abuse of a thinner with a high ri-hexane (31$) and
toluene (30$) content over a period of 7 years.
2. The clinical picture of neuropathy occurred when the
ri^-hexane fraction had been decreased by approximately
one-half (16$) and MEK (11$) had been added; the amount
of toluene was not significantly changed (29$).
3. Individuals who had discontinued sniffing prior to the
introduction of the new formulation or who had used
only the old composition were not affected. Neuro-
pathies occurred, however, after 3 to U months in
sniffers who had used only the new mixture.
4. Sniffing even a relatively small amount of the MEK-
containing composition led to neurotoxic damages, while
comparatively large amounts of the old composition were
tolerated for a long time without consequences.
5. After the MEK-containing thinner was taken off the
market, new cases of the disease were not observed.
Altenkirch and coworkers (1977) further noted that the exact composition of the
glues that contained n-hexane and toluene cited in many of the aforementioned
reports is incompletely characterized, and concluded that it remains open to
question whether ri-hexane was the sole causative agent in those cases. It should
be emphasized that no report in which peripheral neuropathy is attributed to the
inhalation of toluene alone was located in the literature. Further, no sensory
or neuromuscular involvement was detected in a patient who experienced permanent
11-25
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cerebral dysfunction following prolonged inhalation of 99$ pure toluene (Boor
and Hurtig, 1977).
11.2. EFFECTS ON THE BLOOD AND HEMftTOPOIETIC TISSUE
11.2.1. Bone Marrow. The action of toluene on human bone marrow has been the
subject of persistent controversy. Early reports of occupational exposures
(generally prior to the 1950s) ascribed myelotoxic effects"to toluene (Ferguson
et al., 1933; Greenburg et al., 1942; Wilson, 19**3), but the majority of recent
evidence indicates that the chemical is not toxic to the blood or bone marrow.
The myelotoxic effects previously attributed to toluene are generally regarded
by recent investigators to have been the result of concurrent exposure to ben-
zene, which was present as a contaminant. Banfer (1961) noted that it first
became possible to supply industry with adequate quantities of "pure" toluene
(
-------
TABLE 11-8
Results of Blood Examinations Performed on Toluene-Exposed Airplane Painters
a,b
Toluene-Exposed
Workers
Unexposed
Workers
•firythrocytes , _
counts <5.2 x 10 /mm
Lymphocytes _
counts >5000/mm
Mean Corpuscular Volume
13.1* (N = 61)
20.4$ (N = 59)
21.3$ (N = 61)
5.2$ (N =
7.7$ (N = 395)
7.2$ (N = 111)
Hemoglobin
>_l6g/100 ml
Mean Corpuscular Hemoglobin
£35 picograms
Mean Corpuscular Hemoglobin
Concentration
% of cases £35g/100 md
29.5$ (N = 61)
13.1$ (N = 61)
34.4$ (N = 61)
2.4$ (N = 81)
0$ (N = 73)
2.5$ (N = 81)
Source: Greenburg et al., 1942
Percent abnormal cases reported.
11-27
-------
benzene. However, the contamination of the toluene vehicle in the paint with
benzene cannot be precluded (NIOSH, 1973), because these blood changes are con-
sistent with those of benzene poisoning. Volatile Components SUCtl 33 ethyl
alcohol, ethyl acetate, butyl alcohol, and petroleum naphtha were also present in
quantity in the lacquers, dopes, and brushes used by the workers (Table 11-9).
In 19^3» Wilson reported ° that of approximately 1000 industrial workers
(industry not stated) exposed to 50 to 1500 ppm of commercial toluene vapor for 1
to 3 weeks, 100 showed symptoms attributable to toluene intoxication. Ten of the
100 workers had been exposed to concentrations in excess of 500 ppm and showed
signs of serious CNS toxicity (Section 11.1.1.2.). In most of these 10 cases,
0
all blood elements remained normal except for the red cell count, which was
"usually" reduced («2.5 x 10 /mm3). In 2 of the 10 "cases, leukocytes (2500 to
3000 /mm ) and platelets were reduced as well, and differential counts showed
decreased polymer phonuclear cells and reticulocytes, and increased monocytes.
Sternal bone marrow biopsies in these two cases showed partial degeneration of
the blood-forming elements, which resulted in a diagnosis of aplastic anemia. No
«
clinical blood changes were seen in the workers who had been exposed to the lower
concentrations of toluene (i.e., <500 ppm).
Von Oettingen et al. d9M2a, 19l2b) were the first workers to document the
effects of essentially pure toluene on human subjects. The toluene used was
shown, on spectrophotometric analysis, to contain not more than 0.01$ benzene.
In this study, no significant changes in the total or differential white cell
count were found in 3 volunteers following controlled 8 hour exposures to various
concentrations of toluene within the range of 50 to 800 ppm. Not more than 2
exposure sessions were performed per week to provide sufficient time for recovery
in between exposures, and the experiments were conducted over a period of 8 weeks
(Section 11.1.1.1.). Erythrocyte counts were not made.
11-28
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TABLE 11-9
Analysis of Paint Used by Painters3
Percentage
in Mixture
Spray painters
Primer (75$ of paint used):
Zinc chroraate 10.8
Magnesium silicate 0.7
Synthetic resin 12.8
Driers (lead and cobalt compounds) 0.3
Xylene . 5.8
Toluene 69.6
Lacquer 1 (15$ of paint used):
Volatile portion:
Ethyl alcohol
Ethyl acetate
Butyl alcohol
Butyl acetate
Petroleum naphtha
Toluene
Nonvolatile:
Nitrocellulose, synthetic resin,
titanium oxide, ferrocyanide blue,
iron oxide, carbon black, zinc oxide,
etc. No lead compounds
Lacquer 2 (10$ of paint used):
Volatile portion:
Toluene
Xylene
Petroleum naphtha
Nonvolatile:
Resin, titanium oxide, zinc oxide,
ultramarine blue, ferrocyanide
blue, iron oxide, diatomaceous
earth, amorphous silica, carbon
black
100.0
100.0
11-29
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TABLE 11-9 (cont.)
Percentage
in Mixture
Brush painters
Dope:
Volatile portion:
Ethyl acetate
Ethyl alcohol
Butyl acetate
Butyl alcohol
Petroleum naphtha
Toluene
Nonvolatile:
Nitrocellulose, glycol sebacate,
aluminum, cadmium sulfide, barium
sulfate
Brush wash:
Acetone
Ethyl alcohol
Toluene
100.0
100.0
aGre.enburg et al., 1942
Dip painters used a primer only of the same composition as given
for spray painters.
11-30
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Parmeggiani and Sassi (1954) concluded from a clinical study of 11 paint and
pharmaceutical workers exposed to 200 to 800 ppm toluene and 13 others with expo-
sure to a combination of toluene (150 to 1900 ppm) and butyl acetate (150 to
2400 ppm) that toluene had no particular injurious action on the bone marrow (or
other organs). The English summary of this study indicated that the workers were
exposed for "many" years, but the purity of the toluene was not reported. Among
the workers in the two groups, 3H% reportedly showed slight anemia (<4,000,000
erythrocytes/mnr), 15$ had a mild neutropenia (<3500/mm^), 26% were lympho-
cytotic (>2000/nmr), and 45$ showed a decrease in blood platelets (<150,000/mm^)
not accompanied by evident signs of capillary fragility.
In a more recent investigation, Banfer (1961) examined 889 rotogravure
printers and helpers who were exposed to the vapors of toluene-containing print-
ing inks for at least 3 years. Four hundred and seventy eight non-exposed
persons from two groups served as controls; one group was composed of 155 manage-
ment workers from the same plant, and the second group was composed of 323
persons from outside the plant. The available commercial toluene used in these
inks reportedly contained only traces of benzene (<0.3$); when 5 samples of the
toluene were examined by Banfer, no traces of benzene were found, but the method
of analysis and detection limits were not stated. Analysis of the room air for
toluene was performed by infrared spectroscopy, but limited to 5 samples taken
from different sites on a single day. Ambient toluene concentrations were not
specified, but three of the samples were determined to be below the "MAK-Wert,"
the fourth sample was at the "MAK-Wert," and the fifth sample, taken near one of
the presses, exceeded the "MAK-Wert" by 400 ppm. A translation of this study by
NIOSH (1973) indicates that the "MAK-Wert" was 200 ppm. Hematologic examina-
tions of the workers and controls did not reveal any significant changes in the
total number of leukocytes, lymphocytes, granulocytes, or erythrocytes, or hemo
11-31
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globin levels (Table 11-10). Sternal biopsies from 6 printers with white cell
counts of less than 5000/mm were normal.
Capellini and Alessio (1971) performed hematological examinations on 17
workers who had been exposed for "diverse" years to 125 ppm toluene (range, 80 to
•<
160 ppm) in a plant manufacturing V-belts for industrial machinery. Results
showed that the hemoglobin values, red cell counts, white cell counts, and
platelet counts of the workers were within the same limits as those of 19 non-
exposed control subjects from the same plant. The benzene content of the toluene
was not reported. Blood findings were also within normal limits in another
worker employed in a different department who was exposed to mean toluene concen-
trations of 250 ppm (range, 210 to 300 ppm) and who demonstrated symptoms of CMS
toxicity and conjunctival irritation.
In 1975, a report by the West German Association of Gravure Printers (Suhr,
1975) identified a study population of 100 printers with at least 10 years of
exposure to pure toluene (
-------
TABLE 11-10
Hematologic Examination of 889 Rotogravure Workers0
Printers
(N = 889)
Controls,
Group 1
(N = 155)
Controls,
Group 2C
(N = 323)
Erythrocytes '
counts <4 x 10 /mnr
16 (1.79$)
3 (1.93$)
7 (2.10$)
Leukocytes, total
counts > 8500/mnr
counts <5000/mn£
counts 2000/mm-'
25 (2.81$)
889 (100$)
3 (4.16$)
155 (100$)
4 (1.32$)
323 (100$)
889 (100$) 155 (100$) 323 (100$)
Hemoglobin
value <13g/100mA
4 (0.45$)
4 (2.58$)
4 (1.23$)
Source: Banfer, 1961
Unexposed management workers from the same plant
"Unexposed individuals not employed at the plant
11-33
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were observed in the neutrophils of the exposed workers. Thirteen of the 38
workers showed an abnormal appearance of the granules (mean number per neutro-
phil, 7.6 i 5.6)..compared with 1 of 16 controls (mean number per neutrophil, 3-8
± 3.4).
Further evidence of the relative non-toxicity of toluene to the hematopoie-
tic system was presented by Francone and Braier (1954). Toluene, because of its
presumed myelotoxic action, was administered orally as a treatment for leukemia.
It was found that daily doses of up to 10 g of toluene in olive oil for 3 weeks
(to a total of 130 g) were tolerated by leukemia patients without complaints or
evidence of side effects, but the treatment had no clinical effect on the
leukemia process.
Hematological abnormalities have been infrequently reported in sniffers of
toluene-based glues. In a total of 90 cases surveyed by 4 groups of investi-
gators (Christiansson and Karlsson, 1957; Massengale et al., 1963; Barman et al.,
1964; Press and Dona, 1967b), there were no instances of anemia or lymphopenia, a
single report of neutropenia, and 6 cases of eosinophilia of greater than 5%.
Christiansson and Karlsson (1957) also performed bone marrow examinations on 17
individuals; 10 of these showed changes suggestive of disturbances in maturation
of leukocytes, although these changes were not reflected in the peripheral blood
of the same individuals. The individuals examined in the .Christiansson and
Karlsson (1957) study were habituated to the inhalation of toluene-based paint
thinners, rather than model glues as were the subjects in other surveys. In a
fifth clinical survey of 89 glue sniffers, however, Sokol and Robinson (1963)
found abnormalities of the blood in 68 of the cases. An effect on the white blood
cells was indicated by findings of eosinophilia (25 subjects), leukocytosis (12
cases), and lymphopenia (4 subjects). Sokol and Robinson (1963) also reported
low hemoglobin values in 20 subjects and basophilic stippling of erythrocytes in
11-34
-------
42 of the patients, and noted the frequent occurrence of poikilocytosis (25
cases), anisocytosis (20 cases), hypochromia (14 cases), and polychromesia (10
cases). There is no obvious explanation for the discrepancy between the hemato-
logical findings of Sokol and Robinson (1963) and those of the other investi-
gators. However, since none of the aforementioned cases deal with exposure to
pure toluene, the abnormalities observed should be considered to be the possible
result of contamination of the toluene by benzene or some other organic solvent.
Powers (1965) diagnosed five cases of acute aplastic anemia that were asso-
ciated with glue sniffing in black adolescents with pre-existing sickle-cell
disease. The 5 children had apparently used 3 different glues, 2 containing
toluene and 1 containing acetone. All of these patients recovered following
transfusion and cessation of sniffing. A case of fatal aplastic anemia, uncom-
plicated by the presence of sickle-cell disease, was described in a sixth indi-
vidual with a 3 year history of glue sniffing.
11.2.2. Blood Coagulation. Pacseri and Emszt (1970; cited in NIOSH, 1973)
reported that an increase in prothrombin time was found in 191 printers exposed
to 170 to 340 ppm toluene (duration of exposure not stated). Two of the sub-
jects showed a reduced number of red blood cells, but no other hematologic
abnormalities were found in these workers. The benzene content of the toluene
was not reported.
11.2.3. Phagocytic Activity of Leukocytes. It has been reported that the
phagocytic activity of leukocytes from printing-plant workers exposed to toluene
vapors was significantly reduced relative to a control population (Bansagi,
1968). There was no relationship, however, between the decrease in activity and
the concentration of toluene in the air. The Chemical Abstracts summary of this
11-35
-------
Hungarian study did not detail any of the exposure information or mention the
benzene content of the toluene.
Friborska (1973; cited in NHC, 1980) noted increased concentrations of
alkaline phosphatase and lactic acid dehydrogenase .in leukocytes and increased
acid phosphatase in both leukocytes and lymphocytes from workers who were rou-
tinely exposed to toluene. The authors associated these alterations with
increased functional capacity of the cells.
11.2.4. Immunocompetence. Serum immunoglobulin level (Lange et al., 1973a) and
leukocyte agglutinins (Lange et al., 1973b) were studied in a group of 35 workers
with a history of exposure to benzene, toluene, and xylene. The duration of
exposure ranged from 1 to 21 years and the concentration of these compounds in
the air ranged from 0.011 to 0.17 mg/J,, 0.08 to 0.23 mg/i, and 0.12 to 3.0 mg/l,
.respectively. Serum IgG and IgA levels were found to be significantly lower in
the solvent-exposed workers than in non-exposed controls, although IgM levels
tended to increase (Lange et al., 1973a). Lange and coworkers (1973b) also found
that 10 of the 35 workers had leukocyte agglutinins for autologous leukocytes,
and demonstrated an increase of leukoagglutination titer in human sera after
incubation with benzene, toluene or xylene; this suggested that some workers
exposed simultaneously to these aromatic compounds may exhibit allergic blood
dyscrasias. In another group of workers (N = 79) with a similar history of
exposure to benzene, toluene, and xylene (i.e., levels and durations of exposure
comparable to those of the workers examined by Lange et al.), Smolik et al.
(1973) found a decreased level of serum complement. It should be noted that in
all of the aforementioned studies, the specific solvent(s) responsible for the
changes was not identified.
11-36
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11.3. EFFECTS ON THE LIVER
Greenberg et al. (19^2) found enlarged livers in 13 out of 61 airplane
*
painters (21$) who were exposed to 100 to 1100 ppm toluene for 2 weeks to more
than 5 years. Toluene was the major solvent used in the paints, although
significant quantities of other volatile components were present (Table 11-9);
these workers reportedly had no history of inhalation exposure to any other toxic
volatile solvents, including benzene. This incidence of liver enlargement was 3
times that observed in a control group of 430 workers who had never been exposed
to toluene, but it cannot be correlated with exposure level, because only the
numbers of workers exposed at different exposure levels (and not hepatomegaly
incidences) were reported. The liver enlargement was diagnosed by palpitation,
and in no cases were the livers tenderi There was also no correlation between
the enlarged livers and either clinical or laboratory (blood and urine analyses)
evidence of disease, and it was suggested that the enlargement might have been
compensatory in nature.
Greenburg and coworkers1 (19^2) finding of hepatomegaly has not been sub-
stantiated in subsequent studies of workers with histories of occupational
toluene exposure. Parmeggiani and Sassi (1951*) found a comparable incidence
(27$) of enlarged livers in a group of 11 paint and pharmaceutical production
workers who were exposed to 200 to 800 ppm toluene for "many" years and in a
control group of unexposed workers from the same plant. Normal liver function,
as determined by electrophoresis, serum colloid stability testing, and galactose
tolerance testing, was also observed in the exposed workers. Capellini and
Alessio (1971) observed no changes in "the function of the liver" in 17 workers
exposed for "diverse" years to mean atmospheric concentration of 125 ppm toluene
(range, 80 to 160 ppm) in a plant manufacturing V-belts for industrial machinery.
11-37
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Liver function in this study was evaluated by determinations of total serum
protein and protein electrophoresis.
More recently, Suhr (1975) similarly found comparable, but high, incidences
of enlarged livers and elevated liver enzymes in a group of 100 gravure printers
with at least 10 years' exposure to 200 to 400 ppm pure toluene (benzene £0.39),
and in a control group of 100 workers from the same company who had not been
exposed to toluene. It should be noted that the nature and history of the
control group was not defined in any greater detail. Enlargement of the liver
was established in 22$ of the printers and 20$ of the control group, and liver
enzyme assays showed that about half of all test persons (5051 of the printers,
51$ of the controls) had increases in serum glutamic oxalacetic transaminase
(SCOT), serum glutamic pyruvic transaminase (SGPT), glutamic dehydrogenase
(GLDH), or gamma glutamyl transferase levels. It was concluded that because of
the equal distribution of affected persons in both groups, the deviations in
these parameters could not be attributed to toluene exposure. The cause of the
hepatomegaly and liver enzyme deviations was not further investigated. Blood
alcohol determinations before and after the workshifts indicated comparably
elevated levels in both the printers and control group, but less than half of the
100 subjects in each group were tested; approximately half of the tested subjects
had levels between 0.01 and 0.1$. The significance of the elevated blood alcohol
levels is unclear, however, because of the small number of subjects tested,
because only single blood alcohol determinations were performed on each subject,
and because the data was presented ambiguously.
Other studies have reported significant effects on indices of liver func-
tion in groups of toluene-exposed workers. In an examination of 91* rotogravure
printers with a history of exposure to 18 to 500 ppm toluene and of a reference
group of 30 municipal clerks, Szadlowski et al. (1976) found significant reduc-
11-38
-------
tion in bilirubin and alkaline phosphatase in the exposed group, but no dif-
ference from controls in SCOT, SGPT, leucinamino-peptidase, or cholinesterase
levels. The 9^ rotogravure workers were categorized into four groups by
intensity of exposure to toluene. The mean exposure levels, durations of expo-
sure and ages of the groups were, respectively (Szadkowski et al., 1973): Group
1 (N = 68) - 300 ppm, 7.3 ± 5.3 years, 32 years; Group 2 (N = 1) - 126 ppm, newly
appointed on day of investigation, 24.3 years; Group 3 (N = 11) - 82 ppm, 5.6 +
5.2 years, 42.9 years; Group 4 (N = 11) - 18. ppm, 8.5 ± 4.4 years, 35.8 years.
Blood alcohol levels ranged from 0.02% to 0.07? in the exposed workers.
Trevisan and Chiesura (1978) performed the following hepatic function tests
on 47 subjects who were exposed occupationally to toluene via inhalation:
bilirubin, SCOT, gamma glutamyl transpeptidase (GGT), alkaline phosphatase (AP),
ornithine-carbamyl transferase (OCT), Quick's test, and protein measurement.
All tests gave normal results with the exception of GGT, which was reportedly
above normal (28 ji/mS,) in 34? of the cases. In a group of 12 subjects controlled
before and after toluene entered in the working operation, mean GGT activity
increased 2-fold after exposure. Although GGT has proved to be a very sensitive
screening enzyme for slight changes in liver function (Dragosics et al., 1976),
it should be noted that the data from this study was published in abstract form,
and that information on exposure or type of occupation and detailed results of
the hepatic function tests were not presented.
English summaries of two Polish studies of women with histories of occupa-
tional exposure to toluene indicated abnormalities in the glycoprptein, serum
mucoid and haptoglobin patterns of 53 women (Kowal-Gierczak et al., 1969), and
changes in the serum levels of iron and copper, and urinary excretion of
porphyrin in 51 women (Cieslinska et al., 1969). Clinical signs of liver func-
tion impairment were not observed in these subjects, but the changes were
.11-39
-------
interpreted by the investigators to indicate a hepatotoxic effect of toluene.
The concentrations of toluene, durations of exposure, and the possibility of
exposure to other chemicals were not discussed in the summaries.
Intensive exposure to toluene via glue or thinner sniffing appears to have a
minimal effect on the liver. Results of hepatic function tests (SCOT, SGPT, AP,
bilirubin, sodium sulfobromophthalein excretion, serum proteins, cephalin floc-
culation) on a total of 179 sniffers who were examined in early clinical surveys
were essentially unremarkable (Christiansson and Karlsson, 1957; Massengale
et al., 1963; Sokol and Robinson, 1963; Barman et al., 1964; Press and Done,
1967a, 1967b). Christiansson and Karlsson (1957) apparently did detect liver
enlargement in 5 out of 32 Swedish lacquer thinner sniffers, but other signs of
liver function were normal. More recently, Litt and coworkers (1972) found
elevated SGPT and AP levels in 2 and 5%, respectively, of a group of 982 glue
sniffers.
Grabski (1961) described an individual who had abused pure toluene for six
years and showed signs of cerebellar degeneration, hepatomegaly, and impaired
liver function. Complete series of liver function tests were normal, however, in
an optometrist and a glue sniffer exposed independently to 99? pure toluene, both
of whom also exhibited encephalopathic effects (Boor and Hurtig, 1977). Rever-
sible hepatorenal damage was diagnosed in an individual with a 3 year history of
inhaling a cleaning fluid that contained 80/1 toluene (other components not known)
coupled with alcohol ingestion (O'Brien, 1971); the hepatic effect was indicated
by elevated serum bilirubin and AP.
11.4. EFFECTS ON THE KIDNEYS
Urinary findings were normal in 91 specimens from a group of 61 airplane
painters (number of donors not stated) who were exposed to 100 to 1100 ppra
11-40
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toluene for 2 weeks to 5 years (Greenburg et al., 19^2). Urinalysis consisted of
specific gravity, albumin, and sugar determinations, and examinations for formed
elements. Exposure to mean concentrations of 60 to 100 ppm toluene and 20 to
50 ppm gasoline in a "few" working places for an average duration of 3 years and
U months did not result in abnormal urinalysis findings as determined by standard
methods (protein, sugar, urobilinogen, bilirubin, occulted blood, keton body),
except for excretion of hippuric acid, in 38 female shoemakers (Matsushita
et al., 1975). Proteinuria and hematuria were noted, however, in a worker who
was exposed to concentrations of toluene sufficient to cause unconsciousness
while cleaning the inside of a tank that was coated with an emulsion of 45$
toluene and 27$ DDT (Lurie, 1949).
Reisin and coworkers (1975) published a report regarding the development of
severe myoglpbinuria and non-oliguric acute renal failure in a paint factory
laborer 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 a
loss of consciousness for 18 hours and subsequent development of chemical pneumo-
nitis and 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
hemodialysis led to complete recovery.
Pyuria, hematuria, and proteinuria have been the most frequently observed
signs of renal dysfunction associated with the deliberate inhalation of toluene-
j
based glues (Christiansson and Karlsson, 1957; Massengale et al., 1963; Sokol and
Robinson, 1963; Barman et al., 1964; Press and Done, 1967a, 1967b). The clinical
findings observed in 159 cases surveyed between 1957 and 1967 are tabulated in
Table 11-11. These indications of renal dysfunction have not been universally
-------
TABLE 11-11
Renal Function Investigations of Glue Sniffers
a,b
(0
Number of
Patients
32
27
89°
15
16
Pyuria Hematuria
All 32 urine ND
samples "normal";
details not given
0 2
32 14
0 0
6 3
Proteinuria Clearances
ND ND
0 ND
12 ND
1 PSPd
0/13
5/13 Urea
1/7
Azotemia
ND
0
ND
0/7
0/9
Reference
Christiansson and
Karlsson, 1957
Massengale et al.,
1963
Sokol and Robinson,
Barman et al., 1964
1963
Press and Done, 196?b
Source: Press and Done, 1967b
Exposure were to toluene-containing plastic cements except in the Christiansson and Karlsson (1957) study,
in which the subjects examined had sniffed paint thinner.
°Urinary abnormalities were found in 67 of the 89 glue sniffers.
Phenosulfonphthalein clearance in 2 hours.
ND = not determined
-------
observed in glue sniffers, are generally transient, and follow closely the inten-
sive exposures (Press and Done, 1967b).
O'Brien et al. (1971) more recently described a case of reversible hepato-
renal damage in a 19 year old male who had a 3 year history of glue sniffing while
employed in the sign-painting trade. Prior to hospital admission, the subject
had spent 6 hours inhaling a cleaning fluid that contained 80? toluene (the other
components were not identified). Upon admission, the patient was vomiting and
anuric, and after 8 hours, periorbital edema and subconjunctival hemorrhages
developed. Blood concentration of toluene was determined to be 160 ppm. In
addition to diminished urine output, evidence of renal damage included hema-
turia, proteinuria, and elevated serum creatinine. The effects of these expo-
sures on hepatic function are discussed in Section 11.3. (Effects on the Liver).
Although serious involvement of the kidney with human intoxication by
toluene has not been stressed in the early literature, several reports have
recently appeared that associate deliberate inhalation of toluene with metabolic
acidosis (Taher et al., 1971; Fischman and Oster, 1979a; Kroeger et al., 1980;
Bennett and Forman, 1980; Moss et al., 1980). The cases of acidosis described by
these investigators (Table 11-12) are characterized by serious electrolyte
abnormalities (hypokalemia, hyperchloremia), and are related primarily to
toluene's ability to impair hydrogen ion secretion in the distal renal tubule
(distal renal tubular acidosis). In addition to findings compatible with distal
renal tubule acidosis, Moss et al. (1980) found pathologically increased excre-
tion of amino acids, glucose, phosphate, uric acid, and calcium that indicated
proximal tubule dysfunction consistent with Fanconi's syndrome. Kroeger et al.
(1980) reported the case of a patient with toluene-induced renal tubular acidosis
who developed recurrent urinary calculi. It should be noted that each of the
subjects who developed acidosis had a history of "multiple toluene abuse and,
11-43
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TABLE 11-12
Toluene- Induced; Metabolla Actdosis
Subject (Age)
Exposure History
Sympto
Clinical Findings
Reference
Hale (23 yr)
Female (30 yr)
Female (17 yr)
Female (21 yr)
Female (25 yr)
Hale (23 yr)
Female (27 yr)
Four Individuals
(ages and aexea
not atated)
Male (22 yr)
Sniffed glue and pure toluene
Intermittently for 6 yr.
Two 3 to 5 d episodes of sniffing
aerosol paint containing 60$
toluene within 1 wk.
Sniffed transmission fluid con-
taining 100) toluene for 5 d.a
Inkernlttently sniffed trans-
mission fluid containing 1001
toluene for at least 5 yr.
Frequent sniffing of transmission
fluid containing 100$ toluene
during a 5 yr period.8
Sniffed toluene on a "regular"
basis for 5 yr. form not
specified.
Daily inhalation of glue for
9 mo.
Olue or paint sniffers (details
not atated).
Abused a lacquer thinner (99)
toluene) for 8 yr.
Several episodes of musole
weakness following prolonged
(e.g.. H to 7 d) Inhalation
sessions. One instance
of flaccid paralysis.
Nausea.
Persistent vomiting.
Hospitalized on 6 occasions
within a 16 mo. period. Severe
weight loss (18 kg) at first
admission. Becurrent
syaptoms of vomiting, musole •
weakness, and lethargy. After
the 6th episode, patient died
of cardlopulmonary arrest.
Persistent vomiting, lethargy,
and muaole weakness.
Hospitalized * times within
15 mo. History of vomiting,
flank pain, and paralysis of the
lower extremities.
Lethargy, weakness, and ataxia.
Microscopic hematurla and
sterile pyurla.
Hot stated.
Abdominal pain, vomiting,
generalized weakness, and
diminished reflexes.
Hypokalemla with hyperohloremlo
metabolic acldosia. Elevated
urinary pH. Toluene detected in
blood.
Hyperohloremlo aoldoals.
Elevated urinary pH. Toluene
detected In blood.
High anlon gap metabolic
aoldoals.
Hypokalemla. Hyperohloremlo
metabolic aoldosla and high
urinary pH on 1st and 6th
admissions. High anlon gap
metabolic aoldoais on the
other admissions.
Normal anlon gap hyperohloremlo
metabollo aoldoals with severe
hypokalemla.
Recurrent uretal and renal
calculi d atones total).
Hyperohloremlc metabolic
aoldosis and hypokaleola.
Aoldlo urine.
Hyperchloremlo metabollo
aoldoals, hypokalemla,
hypooaloemla, hypophosphatemla
and hypourloemla. Increased
excretion of It amlno acids
and glucose.
Hyperohioremlo metabolic
aoldosis with hypoblcar-
bonatemla.
Hypokalemla and hypochloremlc
metabolic aoldosis.
Taher et al., 1974
Taher et al., 1971
Flschman and Qatar,
1979a
Flsohman and Oster,
1979a
Fiaohman and Oster,
1979a
Kroeger et al., 1980
Moss et al., 1980
Moss et al., 1980
Bennett and Foroan,
1980
Toluene is not ordinarily a component of transmission fluid (Flachman and Oster, 1979b).
Anlon gap is defined as serum Na - (Cl » IICO ) in mlllleqiilvalents
yr s year; d * day; wk = week; mo. = month
per liter.
-------
although the acute consquences of renal tubular acidosis associated with toluene
sniffing were on occasion life threatening, these effects were completely rever-
sible with abstinence from toluene exposure. These symptoms also responded
promptly to electrolyte repletion therapy with potassium chloride and sodium
bicarbonate.
Fischman and Oster (1979a) found a high anion gap metabolic acidosis with
hypokalemia in two patients who had sniffed 100* toluene; this condition is
reportedly indicative of an increased production of acid by the body. Although
it was noted that renal failure, ketonemia, and elevated lactate levels could
have accounted in part for the abnormal increases in anion gap, it was suggested
that the acid metabolites of toluene (e.g., benzoic and hippuric acids) may have
caused the high anion gap metabolic acidosis.
Clinical manifestations associated with the reported metabolic alterations
included nausea, lethargy, ataxia, muscular weakness, and paralysis
(Table 11-12). The National Research Council has noted that some of these
manifestations may mimic those usually attributed to the effects of toluene on
the CNS, and that altered pH and electrolyte balance may be more commonly
i
responsible for the manifestations of toluene abuse than is usually recognized
(NEC, 1980). In particular, hypokalemia often produces significant muscular
weakness including flaccid paralysis.
11.5. EFFECTS ON THE HEART
Ogata et al. (1970) found an apparent decrease in the pulse rate of 23
volunteers who were exposed to 200 ppm toluene for periods of 3 hours, or for
3 hours and a 1 hour break period followed by 4 additional hours, but no effect
at 100 ppm. Systolic and diastolic blood pressure were not affected by exposure.
Exposure to 100 and 200 ppm toluene for 30 minutes did not, however, have any
11-45
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effect on the heart rates OP electrocardiograms of 15 other subjects during
either rest or light exercise (Astrand et al., 1972). Other studies have shown
that experimental exposure to toluene at levels of 100 to 700 ppm for 20 minutes
(Gamberale and Hultengren, 1972) or 50 to 800 ppm for 3 hours (Von Oettingen
et al., 1942a, 1942b) did not cause any definite effects on heart rate or blood
pressure. Suhr (1975) noted that the pulse rates and blood pressures of a group
of 100 printers with a 10 year history of exposure to 200 to 400 ppm toluene and
those of an unexposed control group of identical size were similar at the
beginning and end of work shifts.
Sudden deaths that were not due to suffocation secondary to solvent
sniffing, but rather, were attributed to a direct effect of the solvent itself
have been reported in at least 122 cases (Bass, 1970; Alha et al., 197,3).
Toluene, benzene, and gasoline have been individually implicated in a small
number of these deaths (10, 6, and 4 cases, respectively), but the volatile
hydrocarbons most frequently involved were trichloroethane and fluorinated
aerosol propellants. Severe cardiac arrhythmia resulting from light plane
anesthesia was offered as the most likely explanation for the cause of the sudden
sniffing deaths. Bass et al. (1970) noted that stress, vigorous activity, and
hypoxia, in combination with sniffing, appear to increase the risk of death.
11.6. EFFECTS ON MENSTRUATION
Dysmenorrhea was reported by 19 out of 3d Japanese female shoemakers (mean
age, 20.7 years) who were exposed to mean toluene concentrations of 60 to 100 ppm
for an average duration of 3 years and 4 months (Matsushita et al., 1975). In an
unexposed control group of 16 women from the same plant, this effect was noted in
3 individuals (19$). It should be noted that these women were concomitantly
exposed to 20 to 50 ppm of gasoline in a "few" working places.
11-46
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Michon (1965) reported disturbances of menstruation in a group of 500 women
(age 20 to 10 years) who had been exposed to a mixture of benzene, toluene, and
xylene in the air of a leather and rubber shoe factory. The concentration and
component distribution of this mixture were not specified, but it was stated in
the English summary of this Polish study to be within permissible occupational
limits established at the time in Poland (100 mg/nr (31 ppm) for benzene,
250 mg/nr (67 ppm) for toluene, and 250 mg/nr (58 ppm) for xylene). When the
menstrual cycles of the exposed women were compared with those of 100 women from
the same plant with no exposure to these hydrocarbons, prolonged and more intense
menstrual bleeding was found in the exposed group. The regularity of the cycle
was not affected.
It has also been noted in the English summary of a Russian study that
occupational exposure to average concentrations of 25 to 350 mg/nr (6 to 93 ppm)
toluene and other solvents, through the use of organosiliceous varnishes in the
manufacture of electric insulation materials, caused a high percentage of
menstrual disorders (Syrovadko, 1977). The newborn of these women were
reportedly more often underweight and experienced more frequent fetal asphyxia
and "belated" onset of nursing.
11.7. EFFECTS ON THE RESPIRATORY TRACT AND THE EYES
11.7.1. Effects of Exposure. Carpenter et al. (194M) observed that 2 male
subjects who were exposed to toluene for 7 to 8 hours experienced transitory mild
throat and eye irritation at 200 ppm, and lacrimation at 400 ppm. Parmeggiani
and Sassi (1951*) found irritation of the upper respiratory tract and conjunctiva
in 1 of 11 paint and pharmaceutical product workers who were exposed to 200 to
800 ppm toluene for "many" years. In the studies of Von Oettingen et al. (19^2)
11-47
-------
and Wilson (1913')', however, no complaints of respiratory tract discomfort were
recorded in volunteers or workers exposed to levels of toluene as high as 800 to
1500 ppm for 8 hour periods (Section 11.1., Effects on the Nervous System). In 2
episodes of accidental poisoning on ships that involved estimated short-term
exposures to 10,000 to 30,000 ppm toluene, Longley et al. (1967) recorded no
complaints of respiratory tract or eye irritation among 26 men.
Transient epithelial injury to the eyes that consisted of moderate conjunc-
tival irritation and corneal damage, with no loss of vision, was observed in
three workers who were accidentally splashed with toluene (McLaughlin, 1916;
Grant, 1962). Complete recovery generally occurred within 48 hours. The results
of opthalmologic examinations of 26 spray painters who were exposed to toluene at
levels of 100 to 1000 ppm for 2 weeks to more than 5 years were reported to be
negative (Greenburg et al., 1912); results were not published, but it was noted
that the examinations in each case consisted of a "history of ocular complaints,
visual acuity, fundus, pupil and slit lamp investigation of the media of the
eye."
Raitta and coworkers (1976) found lens changes in a group of 92 car painters
who were exposed to a mixture of organic solvents for 1 to 40 years (mean 15 +
9 years). Of the organic solvents detected in the breathing zones of the
workers, toluene was present in the greatest amounts (30.6 ppm); the mean concen-
trations of the other solvents present in the air are included in the summary of
the Hanninen study (Table 11-3). This study was part of a large investigation
performed to evaluate the effects of chronic solvent exposure on the nervous
system of the car painters (Hanninen et al., 1976; Seppalainen et al., 1978)
(Section 11.1.1.2.). Among the 92 car painters (mean age 34*9 ± 10.4 years,
range 21 to 64 years), 2 had been operated on for a cataract and 46 had ocular
changes that consisted mainly of lens opacities and/or nuclear sclerosis. To
11-48
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eliminate the influence of age on the development of the lens changes, the
painters were compared with age-matched unexposed railroad engineers; 69 age-
matched pairs were generated for comparison. Results showed that, in 27
instances, more lens changes were present in the car painters than in the age-
matched engineers, and that in 4 instances, there were more changes in the
engineers (Table 11-13). In the remaining 38 pairs, both the painters and the
unexposed engineers had similar lens changes. The lens changes were further
found to occur with increased frequency after 10 years of exposure (Table 11-13).
11.7.2. Sensory Thresholds. Gusev (1965) investigated the olfactory threshold
for toluene in 30 subjects with a total of 744 observations. The minimum
perceptible concentration was found to be within 0.40 to 0.85 ppm (1.5 to
3-2 mg/nrj and the maximum imperceptible concentration within 0.35 to 0.74 ppm
(1.3 to 2.8 mg/m3). In sniff tests with 16 subjects (8 male, 8 females), May
(1966) determined the minimum perceptible concentration to be a much higher
37 ppm (140 mg/m ); toluene was found to be clearly perceptible at 70 ppm. In
the latter study, the number of observations used to establish the average values
were not stated.
Odor thresholds and sensory responses to inhaled vapors of Toluene Concen-
trate were more recently determined by Carpenter et al. (1976b). Toluene Concen-
trate is a hydrocarbon mixture containing 45.89$ toluene, 38.69$ paraffins,
15.36$ naphthenes, and 0.06$ benzene. The most probable concentration for odor
threshold, determined in two trials with 6 subjects, was 2.5 ppm. Based on
sensory thresholds for irritation (eye, nose, throat), dizziness, taste, and
olfactory fatigue, 6 of 6 volunteers indicated their willingness to work for
8 hours in a concentration of 480 ppm (corresponding to 220 ppm of toluene).
Only 3 subjects thought they could work in an atmosphere containing 930 ppm
(corresponding to about 427 ppm toluene).
11-49
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TABLE 11-13
Frequency of Lens Changes and Distribution by Exposure Time
in 69 Age-Matched Pairs of Car Painters and Railway Engineers3
Result
Car painters had fewer
changes than the engineers
No noticeable difference
between the pairs
Car painters had more
changes than the engineers
Frequency of
Lens Changes
(no. pairs)
4
38
27
Distribution
by Years
< 10 11
3
22
6
of
of
to
1
13
17
Lens Changes
Exposure
20 >21
0
3
4
Source: Raitta et al., 1976
11-50
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11.8. EFFECTS ON THE SKIN
Toluene appears to be absorbed less readily through the skin than through
the respiratory tract, but percutaneous absorption of liquid toluene may be
significant (Section 13.1.). When toluene is applied to the skin, its degreasing
action will remove natural lipids, possibly causing dryness, fissures, and
contact dermatitis (Gerarde, I960; Browning, 1965).
Malten et al. (1968) found that exposure of human forearm skin for 1 hour on
6 successive days to toluene (volume and conditions not stated) resulted in
injury to the epidermal stratum corneum (horny layer). The skin damage was
assayed by measurements of water vapor loss, and daily measurements following the
exposures indicated that regeneration took about 4 weeks.
Koilonychia and hapalonychia of the fingernails (conditions in which the
nails are, respectively, concave and uncornified (soft)) were observed in 6 of 16
cabinet makers who were dermally exposed to a thinner mixture that contained 30$
toluene, 30$ xylene, and 40$ methyl alcohol (Ancona-Alayon, 1975). These defor-
mities involved primarily the thumb, index, and middle fingernails, and were
attributed to the practice of cleaning metal parts on furniture with solvent-
soaked rags and unprotected hands. Most of the affected workers had an average
exposure of two years.
11.9. SUMMARY
Toxicity studies in humans have primarily involved evaluation of indivi-
duals exposed to toluene via inhalation in experimental or occupational settings
or during episodes of intentional abuse, and the health effect of greatest
concern is dysfunction of the central nervous system.
Single 8 hour experimental (Von Oettingen et al., 1942a, 1942b; Carpenter
et al., 19^) and subchronic occupational (Wilson, 19^2) exposures to toluene in
11-51
-------
the range of 200 to 300 ppm have elicited subjective symptoms indicative of CNS
toxicity (e.g., fatigue, nausea, muscular weakness, mental confusion, and
impaired coordination). These effects were generally dose-dependent and
increased in severity with increasing toluene concentration. Acute experimental
exposures to toluene have also caused objective increases in reaction time at 200
to 300 ppm (Ogata et al., 1970; Gamberale and Hultengren, 1972) and decreases in
perceptual speed at 700 ppm (Gamberale and Hultengren, 1972). Gusev (1965)
observed disturbances of EEG activity in several subjects exposed to 0.27 ppm
toluene for 6 minute intervals, but this effect does not have any apparent
toxicological significance.
Short-term accidental workplace (Lurie, 1949; Browning, 1965; Longley
et al., 1967; Reisin et al., 1975) and deliberate (Press and Done, 1967a, 1967b;
Wyse, 1973; Lewis and Patterson, 1974; Hayden et al., 1977; Oliver and Watson,
1977; Barnes, 1979; Helliwell and Murphy, 1979) inhalation exposures to exces-
sive levels of toluene (i.e., levels approaching air saturation concentrations
of 30,000 ppm) have initially resulted in CNS stimulatory effects such as
exhilaration, lightheadedness, dizziness, and delusions. As exposure durations
increase, narcotic effects characteristic of CNS depression progressively
develop, and, in extreme cases, collapse, loss of consiousness, and death (Winek
et al., 1968; Chiba, 1969; Nomiyama and Nomiyama, 1978) have occurred.
Chronic occupational exposure to toluene has been associated with "nervous
hyperexcitability" (Parmeggiani and Sassi, 1954) and subjective memory, think-
ing, and activity disturbances (Munchinger, 1963) in workers exposed, respec-
tively, to concentrations of 200 to 800 ppm and 300 to 430 ppm. No evidence of
adverse neurological effects have been reported, however, in other studies of
printers exposed to 200 to 400 ppm toluene (Suhr, 1975) or manufacturing workers
exposed to 80 to 160 ppm toluene (Capellini and Alessio, 1971), although the
11-52
-------
negative findings in the former study are equivocal and symptoms of stupor,
nervousness, and insomnia were noted in one worker exposed to higher concentra-
tions (210 to 300 ppm) of toluene in the latter study. Exposure to mixtures of
vapors from an organic solvent containing predominately low-levels of toluene
(approximately 30 ppm) for an average of 15 years has produced a greater inci-
dence of CMS symptoms and impaired performance on tests for intellectual and
psychomotor ability and memory in car painters (Hanninen et al., 1976;
Seppalainen et al., 1978). Matsushita et al. (1975) reported impaired per-
formance in neurological and muscular function tests in female shoemakers who had
been exposed to '15 to 200 toluene for an average duration of over 3 years, but
these workers were also exposed to "slight" levels of gasoline. Changes in EEC
response to photic stimulation were reported by Rouskova (1975) in workers
exposed to >250 ppm toluene and unspecified levels of 1,1,1-trichloroethane for
an average of 13-5 years.
Residual effects indicative of cerebellar and cerebral dysfunction have
been observed in a number of persons who had abused toluene or solvent mixtures
containing toluene over a period of years (Grabski, 1961; Satran and Dodson,
1963; Knox and Nelson, 1966; Kelly, 1975; Boor and Hurtig, 1977; Weisenberger,
1977; Keane, 1978; Sasa et al., 1978; Tarsh, 1979; Malm and Lying-Tunell, 1980).
These effects were largely reversible upon cessation of exposure, but prolonged
toluene abuse has, on occasion, led to permanent encephalopathy and brain atrophy
(Knox and Nelson, 1966; Boor and Hurtig, 1977; Sasa et al., 1978). Reports of
polyneuropathies in abusers of glues and solvents have also appeared in the
literature, but have in all cases involved mixtures of toluene and other solvents
such as n-hexane and methyl ethyl ketone (Matsumura et al., 1972; Takenaka
et al., 1972; Goto et al., 1974; Shirabe et al., 197^; Suzuki et al., 197K;
11-53
-------
Korobkin et al., 1975; Oh and Kim, 1976; Towfighi et al., 1976; Altenkirch
et al., 1977).
Early reports of occupational exposures (generally prior to the 1950s)
ascribed myelotoxic effects to toluene (Greenburg et al. 1942; Wilson, 1943), but
the majority of recent evidence indicates that toluene is not toxic towards the
blood or bone marrow (Von Oettingen et al., 1942a, 1942b; Panneggiani and Sassi,
1954; Banfer, 1961; Capellini and Alessio, 1971; Suhr, 1975; Matsushita et al.,
1975). When administered orally to leukemia patients, it has been further
reported that toluene was nontoxic and had no effect on the leukemic process
(Francone and Braier, 1954). Hematological abnormalities have been infrequently
reported in sniffers of toluene-based glues and thinners (Christiansson and
Karlsson, 1957; Massengale et al., 1963; Sokol and Robinson, 1963; Barman et al.,
1964; Press and Done, 1967b). Other investigators have noted increases in
prothrombin time (Pacseri and Emszt, 1970), decreases in phagocytic activity of
leukocytes (Bansagi, 1968), and increased enzyme concentrations in leukocytes
and lymphocytes (Friborska, 1973) of workers who were exposed to toluene.
Decreases in serum immunoglobin and complement levels (Lange et al., 1973a;
Smolik et al., 1973) and leukocyte agglutinins (Lange et al., 1973b) have been
reported in workers exposed simultaneously to benzene, toluene, and xylene.
Liver enlargement was reported in an early study of painters with exposures
to 100 to 1100 ppm toluene for 2 weeks to more than 5 years (Greenburg et al.,
1942), but this effect was not associated with clinical or laboratory evidence of
disease or corroborated in subsequent studies of workers (Panneggiani and Sassi,
1954; Suhr, 1975). Chronic occupational exposure to toluene has generally not
been associated with abnormal liver function (Greenberg et al., 1942;
Panneggiani and Sassi, 1954; Capellini and Alessio, 1971; Suhr, 1975), although
reductions in serum bilirubin and alkaline phosphatase (Szadlowski et al., 1976)
11-54
-------
and increases in gamma glutamyl transpeptidase (Trevisan and Chiesura, 1978)
have been noted. Intensive exposure to toluene via glue or thinner sniffing
appears to have a minimal effect on liver function indices (Christiansson and
Karlsson, 1957; Grabski, 1961; Massengale et al., 1963; Sokol and Robinson, 1963;
Barman et al., 1961; Boor and Hurtig, 1977; Press and Done, 1967a, 1967b).
Exposure to mean concentrations of 100 to 1100 ppm toluene for 2 weeks to
5 years (Greenburg et al., 19^2) or 60 to 100 ppm toluene for over 3 years
(Matsushita et al., 1975) did not result in abnormal urinalysis findings in
airplaine painters or female shoemakers, respectively, but clinical case reports
have described proteinuria and hematuria (Lurie, 19^9; O'Brien et al., 1971) and
myoglobenuria and renal failure (Reisin et al., 1975) in workers who were acci-
dentally overexposed to toluene. Pyria, hematuria, and proteinuria have been the
most frequently observed signs of renal dysfunction associated with the deli-
berate inhalation of toluene-based glues, but these effects have not been uni-
versally observed in glue sniffers (Christiansson and Karlsson, 1957; Massengale
et al., 1963; Sokol and Robinson, 1963; Barman et al., 1964; Press and Done,
1967a, 1967b). Several reports have recently appeared that associate deliberate
inhalation of toluene with metabolic acidosis (Taher et al., 1971*; Fischman and
Oster, 1979a; Koeger et al., 1980; Bennett and Forman, 1980; Moss et al., 1980).
Acute experimental exposure to toluene within the range of 50 to 800 ppra
have not caused any definite effects on heart rate or blood pressure
(Von Oettingen et al., 19*»2a, 19l»2b; Ogata et al., 1970; Astrand et al., 1972;
Gamberale and Hultengren, 1972). Toluene has been implicated in a small number
of sudden deaths due to solvent sniffing Which appear to result from cardiac
arrhythmias (Bass, 1970; Alha et al., 1973), but trichloroethane and fluorinated
aerosol propellants have most frequently been associated with these deaths.
11-55
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Oysmenorrhea has been reported in a significant number of female shoemakers
exposed to 60 to 100 ppm toluene and concomitantly to 20 to 50 ppm gasoline in a
"few" working places fop an average duration of 3 years and 4 months (Matsushita
et al., 1975). Disturbances of menstruation have also been reported in women
exposed concurrently to toluene, benzene, and xylene in the workplace (Michon,
1965), and in women exposed occupationally to toluene and other unspecified
solvents (Syrovadko, 1977).
Minimum perceptible concentrations of toluene have been determined to be
0.40 to 0.85 ppm (Gusev, 195) and 37 ppm (May, 1966), but the reasons for this
discrepancy are not apparent. Toluene has been reported to cause transitory eye
and respiratory tract irritation as a result of 8 hour exposures in the range of.
200 to 800 ppm (Carpenter et al., 1944; Parmeggiani and Sassi, 1954; Capellini
and Alessio, 1971), but no complaints of respiratory tract discomfort were
recorded in volunteers or workers exposed to levels as high as 800 to 1500 ppm
for 8 hour periods in other studies (Von Oettingen et al., 1942; Wilson, 1943).
No complaints of respiratory tract or eye irritation were recorded in men acci-
dentally exposed to 10,000 to 30,000 ppm toluene for brief durations (Longley et
al., 1967).
Transient epithelial injury to the eyes that healed with. 48 hours was
observed in workers who were accidently splashed with toluene (McLaughlin, 1946;
Grant, 1962). Opthalmologic examinations of spray painters who were exposed to
100 to 1000 ppm toluene for 2 weeks to more than 5 years were normal (Greenburg
et al., 1942), but Ratta et al. (1976) found lens changes in a group of car
painters exposed concurrently to approximately 30 ppm toluene and much lower
concentrations of other solvents for an average of 15 years. The little informa-
tion that is available on the dermal toxicity of toluene indicates that moderate
11-56
-------
contact may cause skini damage due to its degreasing action (Gerarde, 1960;
Browning, 1965; Moleten et al., 1968).
11-57
-------
12. ANIMAL TOXICOLOGY
fS
12.1. SPECIES SENSITIVITY
Information on the toxic effects of chronic exposure to low levels of
toluene may be more relevant to greater numbers of people than information on
acute toxicity from the viewpoint of industrial health (see Sections 10.3 and
10.1!). However, for those rare exposures to high levels, e.g., "glue sniffing",
data obtained from acute toxicity studies are valuable. In the sections to
follow, consideration will be given to acute, as well as chronic, studies.
Inhalation has been a principal route of exposure in humans; therefore,
animal studies have centered on intoxication by this route. In all species
studied, the progressive symptoms typically found after increasingly higher
doses were irritation of the mucous membranes, incoordination, mydriasis, nar-
cosis, tremors, prostration, anesthesia, and death. Cats appeared to be more
resistant than dogs and rabbits; rats and mice were less resistant than dogs or
rabbits (Tables 12-1 and 12-2).
12.1.1. Acute Exposure to Toluene
12.1.1.1. ACUTE INHALATION — Carpenter et al. (1976b) reported 100J mor-
tality in rats exposed to 1 hours of inhalation of 12,000 ppm of "toluene concen-
trate" comprising a mixture of paraffins, naphthenes, and aromatics (^5.956
toluene and 0.06$ benzene). Tremors were seen in 5 minutes and prostration in
15 minutes. At 6300 ppm, inhalation produced head tremors in 1 hour and prostra-
tion in 2 hours, while only slight loss of coordination was seen after 1 hours at
3300 ppm. A calculated LC_Q of 8800 ppm for a U hour period of inhalation was
12-1
-------
ro
inhalation rats
inhalation rats
inhalation rats
inhalation rats
inhalation mice
inhalation mice
inhalation Swiss mice
TABLE 12-1
Acute Effects of Toluene
Route
inhalation
inhalation
inhalation
inhalation
inhalation
Species
rats
rats
rats
rats
rats
Dose
4
24
12
13
12
,000
,400
,200
,269
,000
ppm
ppm
ppm
ppm
ppm
for
for
for
4 h
1.5 h
6.5 h
1/6
60$
50$
Effect
dead
mortality
mortality
Lethal dose
for
4 h
Lethal dose
Reference
Smyth et al. ,
Cameron et al
Cameron et al
Paustov, 1958
Carpenter et
1969a
., 1938
., 1938
al., 1976b
("toluene concentrate")
6,300 ppm for 4 h
("toluene concentrate")
3,300 ppm for 4 h
("toluene concentrate")
1,700 ppm for 4 h
("toluene concentrate")
8,800 ppm for 4 h
("toluene concentrate")
24,400 ppm for 1.5 h
12,200 ppm for 6.5 h
5,320 ppm for 7 h
(less than 0.01)
benzene present)
Head tremors in 1 h
Prostration in 2 h, normal
3 h after exposure
Carpenter et al., 19?6b
Slight loss of coordination Carpenter et al., 1976b
No-effect-level
LC50
10) mortality
100$ mortality
LC,
50
Carpenter et al., 1976b
Carpenter et al., 1976b
Cameron et al., 1938
Cameron et al., 1938
Svirbely et al., 1943
-------
TABLE 12-1 (cont.)
Route
Species
Dose
Effect
Reference
inhalation mice
inhalation mice
inhalation mice
inhalation cats
tVJ
inhalation guinea pigs
inhalation rabbits
inhalation dogs
inhalation mice
inhalation mice
inhalation dogs
n = 2
6,942 ppm for 6 h
(99.5$ purity)
6,631* ppm
9,288 ppm
7,800 ppm for 6 h
("toluene concentrate")
1,000 ppm for 1 h
5,500 ppm
850 ppm for 1 h
8,600 ppm, 15,000 ppm
("toluene concentrate")
5,000 ppm "toluene
concentrate"
760 ppm "toluene con-
centrate" 6 h/d x 2 d
rested for,Id, exposed
again for 3d
LC,
50
LC50
Lethal dose
Progressive signs: slight
loss of coordination,
mydriasis, and slight hyper-
sensitivity to light within
20 min
Prostration - 80 min
Anesthesia - 2 h
One death during 1<4 d
observation period
2/3 dead within a few days
Lethal within 10 min
Increased respiration rate,
decreased respiration
volume
50$ reduction respiratory
rate
No-effect-level on
respiratory rate
Weight loss of 1.1 kg in
1 dog, otherwise normal
Bonnet et al., 1979
Faustov, 1958
Faustov, 1958
Carpenter et al., 1976b
Smyth and Smyth, 1928
Carpenter et al., 19M
Von Oettingen et al.,
19l2b
Carpenter et al., 19?6b
Carpenter et al., 1976b
Carpenter et al., 1976b
-------
TABLE 12-1 (cont.)
Route
inhalation
oral
oral
oral
Species
dogs
n = 2
rats
Wistar rats
adult
Sprague-Dawley rats
Dose
1,500 ppm "toluene con-
centrate" 6 h/d x 3 d
7.53 g/kg (6.73 to 8. 43)
7.0 g/kg
5.58 g/kg
Effect
Slight lacrimation and head
tremors
LD50
LD50
LD*n
Reference
Carpenter et al., 19760
Smyth et al. , I969a
Wolf et al. , 1956
Wit hey and Hall, 1975
ro
oral
i.p.
i.p.
i.p.
i.p.
i.p.
(150 to 200 g)
rats
14 d old, both sexes
young adults
older adults
rats and mice
rats
rats
rats (both sexes)
mice (male)
(5.3 to 5.9 g/kg)
3.0 mil/kg (2.6 g/kg)
6.4 ml/kg (5.5 g/kg)
7.4 mi/kg (6.4 g/kg)
2.0 mi/kg (1.7 g/kg)
0.75 mA/kg (0.7 g/kg)
1.75 to 2.0 m«,/kg
(1.5 g/kg to 1.7 g/kg)
800 mg/kg at 26°C
530 mg/kg at 8°C
255 mg/kg at 36 °C
1.15 g/kg in olive oil
(1.04 to 1.31 g/kg)
(graded doses between
0.79 and 1.65 g/kg)
5*
Lethal dose
Apathy
Death from respiratory
failure
Approximate lethal dose
LD50
Observed for 24 h
Cause of death:
respiratory failure
Kiraura et al., 1971
Cameron et al., 1938
Batchelor, 1927
Batohelor, 1927
Keplinger et al., 1959
Koga and Ohmiya, 1978
i.p.
mice (female)
1.64 g/kg
LD,
'50
Ikeda and Ohtsuji, 1971
-------
TABLE 12-1 (cont.)
Route
i.p.
i.p.
s.c.
i.v.
dermal
(single
application)
dermal ,
abdomen
Species
mice
guinea pigs
rats and mice
rabbits
rabbits
rabbits
Dose
1 g/kg
2.0 mi pure solvent
(1.7 g)
5 to 10 mi/kg
(1.3 to 8.2 g/kg)
0.15 mfc/kg (.13 g/kg)
0.20 raft/kg (.17 g/kg)
11.1 rafc/kg
uncovered application
Effect
Lethal dose
6/10 dead after 2 h
All dead after 6 h
Lethal dose
13$ mortality
100$ mortality
LD50
Slight irritation
Reference
Tsuzi, 1956
Wahlberg, 1976
Cameron et al.
Braier, 1973
Smyth et al. ,
Smyth et al. ,
, 1938
1969a
1969a
dermal
rabbits
dermal
guinea pigs
10 to 20 applications of Perceptible erythema, Wolf et al., 1956
undiluted toluene to thin layer of devitalized
rabbit ear and bandaged tissue which exfoliated
No effect on gross appearance,
behavior, or weight
to shaved abdomen
1 mfc for 16 h
Karyopyknosis, karyolysis,
perinuclear edema,
spongiosis,
junctional separation,
cellular infiltration in
dermis,
no liver and kidney damage
Kronevi et al., 1979
-------
TABLE 12-1 (oont.)
Route
Species
Dose
Effect
Reference
dermal
ro
guinea pigs
2.0 mil, covered
Completely absorbed by 5th
to 7th d
No mortality up to 1 wk
Weight less than controls
for wk 1 to 3i no difference
at wk 1
Wahlberg, 1976
corneal
corneal
corneal
rabbits
rabbits
rabbits
0
0
2
.005 mfc
.005 mi
drops
Moderately severe injury
Moderately severe injury
Perceptible irritation of
con June tival membranes
No corneal injury
Smyth et al.,
Carpenter and
Wolf et al.,
1969a
Smyth,
1956
1946
h = hour; min = minute; d = day; wk = week; i.p. = intraperitoneal; s.c. = subcutaneous;
i.v. = intravenous; n = number; ns = not specified
-------
TABLE 12-2
Subchronic Effects of Toluene
Species
Route
Dose
Effect
Reference
Rat
Rat
Inhalation
Inhalation
ro
i
Rat
Rat
Rat
Inhalation
Inhalation
Inhalation
1600 ppm
18 to 20 h/d
1600 ppm
18 to 20 h/d x 3
1250 ppm
18 to 20 h/d
620 ppm, 1100 ppm
18 to 20 h/d
1000 ppm solvent mix-
ture (50 to 60$
benzene, 30 to 35$
toluene, b% xylene)
7 h/d x 5 d x 28 wk
Initial effect of instability
and incoordination, conjunc-
tivitis, lacrimation, and
sniffles; then narcosis
Mild twitching; drop in body
temperature; death. Histology:
severe cloudy swelling of
kidneys, no effect on liver,
•heart, or testes
Slight instability and
incoordination; mucous
membrane irritation
No-effect-level on symptoms;
hyperplasia of bone marrow
No effect on body weight;
lymphopenia followed by leuco-
cytosis and lymphocytosis; tran-
sient changes in blood picture
before or after each daily
exposure; splenic hemosiderosis
greater than that found after
inhalation of benzene only:
slight to moderate reduction
2-1/2 wk after exposure. Nar-
rowing of peri-follicular collars
of cells in sleen, no fat in
livers and kidney; iron-negative
pigment in kidneys of few animals.
Batchelor, 1927
Batchelor, 1927
Batchelor, 1927
Batchelor, 1927
Svirbely et al.f
-------
TABLE 12-2 (cont.)
Species
Route
Dose
Effect
Reference
Rat
Inhalation
2140, 180, 980 ppm
"toluene concentrate"
6 h/d x 5 d/wk x 65 d
Rat
Inhalation
r\>
oo
Rat
Inhalation
ppm
4 h/d x 30 d
200 ppm , 600 ppm
7 h/d x 5 d x 6 wk
No effect on red blood cell
count white blood cell count,
hematoorit, hemoglobin, total
and differential white count,
blood urea nitrogen, SCOT,
SGPT, alkaline phosphatase,
or body weight.
Increased levels of SCOT,
SGPT, 3-lipoproteins
decreased levels of gluta-
thione, catalase, peroxi-
dase, total cholesterol
No narcosis; body weight
normal; no significant
change in WBC count, RBC
count,or hemoglobin during
weekly sampling; increase in
percentage of segmented cells;
histological changes: slight
pulmonary irritation; few
casts in straight collecting
tubules in rats at 600 ppm;
no change in liver, spleen,
heart, and bone marrow
Carpenter et al., 1976b
Khinkova, 1974
Von Oettingen et al., 1942b
-------
TABLE 12-2 (cont.)
Species
Rat
Route
Inhalation
Dose
2500 ppm ,
5000 ppm
Effect
Transient decrease
in body
Reference
von Oettingen et
al., 19l2b
7 h/
-------
TABLE 12-2 (cont.)
Species
Route
Dose
Effect
Reference
Dogs
n=2
experimental,
1 control
Inhalation
Dogs
Inhalation
ro
o
Dogs
Mice
n=4-6 animals
Inhalation
Inhalation
Mice
Mice
Inhalation
Inhalation
2000 ppm 8 h/d x
6 d/wk x 1 mo, and
then 2660 ppm 8 h/d,
6 d/wk x 2 oo
200, 400, 600 ppm
3 8 h exposures
for 1 wk, then 5 x 7 h
for 1 wk and finally
850 ppm for 1 hr
Death on days 179 and 180; slight
nasal and ocular irritation; motor
incoordination and paralysis of
extremities during terminal phase;
congestion in lungs, hemorrhagic
liver, reduced lymphoid follicles
and hemosiderosis in spleen;
hyperemio renal glomeruli; albumin
in urine
No effect on circulation, spinal
pressure; increase of respiratory
rate, small increase of minute
volume, decrease of respiratory
volume
tOO ppm; 7 h/d x 5 d Moderate temporary lymphocytosis
7 consecutive cycles
daily, 5 d/wk x 8 wk:
each cycle, 10 min. to
12,000 ppm followed
by 20 min. solvent-
free interval
1(000 ppm 99.9} pure
toluene for 3 h
4000 ppm 99.9$ pure
toluene for 3 h/d x
1, 3, or 5 d
Depression of body weight gain; Bruckner and Peterson, 1981a
no effect on LDH; decreased BUN
levels; SCOT levels increased
(not significantly) depression
of kidney, brain and lung weights;
Histology: no effect on brain,
lung, liver, heart, or kidneys;
no sign of lipid vaculoation in
liver.
No effect on LDH activity
significant increase of
SCOT 24 h post exposure only
SCOT levels increased after 1
and 3 days of treatment; no
effect 21 h after 5 d
Bruckner and Peterson, 198lb
Bruckner and Peterson, 198lb
-------
TABLE 12-2 (cont.)
Species
Route
Dose
Effect
Reference
Mice
Inhalation
UOOO ppm 99.9$ pure
toluene for 3 h/d x
5 d wk x 8 wk
Mice
Inhalation
1, 10, 100, 1000 ppra
6 h/d x 20 d
Depression of body weight gain Bruckner and Peterson, 198lb
during first 7 wk; increased
liver-to-body weight ratio after
1 wk exposure, no effect at 1, 2,
or 8 wk; no increase in kidney,
brain, and lung; SCOT activity
increased after U wk of exposure,
and 2 wk post-exposure, but not
after 2 wk of exposure, or 8 wk;
no change in BUN. Histology: no
effect on heart, lung, kidney,
brain and liver
No effect on body weight; 1 and Horiguchi and Inoue, 1977
10 ppm caused increase of RBC
count on 10th day; recovery on
day 20; 100 ppra, 1000 ppm -
decrease of RBC count; all doses -
increase (10 to 70$) of WBC count
on day 10; recovery for all
doses except 1000 ppm; 10 ppm to
1000 ppm - decrease of thrombo-
cytes; histology: 100 ppm -
slight decrease in density
of bone marrow cells and in
megakaryocytes and red cell
elements; 1000 ppm - slight
hypoplasia of red cell elements;
slight to moderate disturbance
in maturity of neutrophils and
thrombocytes, moderate increase
of reticulocytes; no change in
brain, lung, liver, spleen,
or kidney.
-------
TABLE 12-2 (cont.)
Species
Guinea
pig
Route
Inhalation
Dose
1250
ppra 4
h/d x
Effect
Prostration,
marked liver
Reference
Smyth and
Smyth,
1928
Inhalation
ro
CFY rats
(both sexes)
CFY rats
(males)
CFY rats
(males)
6 d/wk (18 exposures)
1000 ppm 4 h/d x
6 d/wk (35 exposures)
265 ppm 6 h/d x
5 d/wk x 1, 3 or
6 mo
929 ppm 8 h/d x
5 d/wk x 1 wk,
6 wk, 6 mo
398, 796, 1592 ppm
8 h/d x 5 d/wk x
14 wk
and renal degeneration,
marked pulmonary inflammation
No symptoms; slight toxic
degeneration in liver and
kidney
Bromsulphthalein retention
decreased; Cytochrome P-450
increased independent of
period of exposure; SCOT
and SGPT activity unaffected
Cytochrome P-150 increased
independent of exposure
period; no effect on SGOT
or SGPT; aniline hydroxylase
and aminopyrine N-demethylase
activity; increased cytochrome
b concentrations increased.
Histological effects:
dilation of cisternae of
rough endoplasmic reticulum;
increase of autophagous
bodies which was dose and
time dependent; retarded
growth of females but not
males; glycogen content
decreased
Cytochrome P-450 increased
with dose
Ungvary et al., 1980
-------
TABLE 12-2 (cont.)
Species
Rats
Route
Subcutaneous
Dose
1 cc/kg x 21
d
Effect
Slight induration at
injec-
Reference
Batchelor,
1927
Guinea pig
Subcutaneous
0.25 cc/d x 30 to 70 d
Rabbit
Subcutaneous
1 cc/kg x 6 d
cc/kg
tion site; 5 to 14$ loss of
body weight; transient slight
drop in RBC and WBC counts;
hyperplasia of bone marrow;
moderate hyperplasia of
malpighian corpuscle in spleen;
marked pigmentation of spleen;
focal necrosis in liver, slight
cloudy swelling in kidney; no
effect on heart, testes, or lungs
Local necrosis at injec-
tion site; survival period:
30 to 70 days; polypnea and
convulsions during last
days of survival; hemorrhagic,
hyperemic, and sometimes
degenerative changes in
lungs, kidneys, secondary
adrenals, liver, and spleen
Transient slight granulo-
penia followed by granulo-
cytosis; no change in bone
marrow
More marked effect on
granulocytes; all rabbits
dead by end of second day;
no effect on bone marrow
Sessa, 1948
Braier, 1973
-------
TABLE 12-2 (cont.)
Species
Rats
Route
Oral
Dose
118 mg/kg/d,
Effect
None; parameters observed:
Reference
Wolf et al., 1956
3511 mg/kg/d, body and organ weights,
590 mg/kg/d x 138 d adrenals, pancreas, femoral
bone marrow, lungs, heart,
liver, kidney, spleen,
testes, bone marrow, BUN,
blood counts
h = hour; d = day; wk = week; SCOT = serum glutamic oxalacetic transaminase; SGPT = serum
glutamic pyruvio transaminase; WBC = white blood cell; RBC = red blood cell; UDP = uridine 5'-phosphate;
BUN = blood urea nitrogen; mo = month.
rv>
i
-------
reported in this study. Inhalation of a thinner containing less toluene (=33?)
and only 0.01$ benzene elicited less toxic symptoms at a similar range of doses
in rats in a companion study by the same laboratory (Carpenter et al., 1976a).
In a study by Smyth et al. (1969), inhalation of 4000 ppm technical grade
toluene for 4 hours produced 1 death in 6 rats. In an early study, Batchelor
(1927) noted that inhalation of 1600 ppm of toluene for 18 to 20 hours daily pro-
duced initial effects of instability and incoordination, conjunctivitis, and
lacrimation, then narcosis and mild twitching. A drop in body temperature in
rats, followed by death occurred after 3 days of exposure. At necropsy, a severe
cloudy swelling of the kidneys was found. In this study, there were no effects
on liver, heart, or testes, although hyperplasia of the bone marrow was noted,
suggesting possible contamination of the solvent with benzene.
In the study of Cameron et al. (1938), a concentration of 24,400 ppm of
toluene produced a mortality of 60$ and 10$ in rats and mice, respectively, after
1.5 hours of exposure. In another group of rats and mice exposed to 1/2 the
concentration but for a longer period, 6.5 hours, the mortality was 50$ and 100$,
respectively. These two species are probably equally sensitive. Other studies
of mice include that of Svirbely et al. (1943), in which the LC^ in Swiss mice
was determined to be a concentration of 5320 ppm for 7 hours, and that of Bonnet
et al. (1979), in which an LC^0 of 6942 ppm for 6 hours of exposure was noted.
In the study of Carpenter et al. (1976b), 4 cats survived exposure to
inhalation of 7800 ppm "toluene concentrate" for 6 hours. During exposure, they
showed progressive signs of toxicity, including slight loss of coordination,
mydriasis, and slight hypersensitivity to light within 20 minutes, prostration
within 80 minutes, and light anesthesia within 2 hours. All survived the
exposure, and only 1 cat died during the 14 day observation period.
12-15
-------
Inhalation of 4000 ppm toluene (purified by distillation) for 4 hours daily
was lethal within a few days to 2 of 3 guinea pigs. The other animal was severely
prostrated. Under the same regimen, animals exposed to less than 1/3 of this
concentration (1250 ppm) for 6 days a week survived 3 weeks of exposure,
although they were severely affected. At 1000 ppm, guinea pigs were not affected
even after 35 exposures, although there were slight toxic degenerative changes
in the liver and kidney (Smyth and Smyth, 1928).
Carpenter et al. (1944) reported that inhalation of* a concentration of
about 55,000 ppm was lethal to 6 rabbits in about 40 minutes (range of 24 to
62 minutes).
Von Oettingen et al. (19425) observed that inhalation of 850 ppm toluene
containing 0.01J benzene for 1 hour by 6 dogs produced an increase of respiratory
rate and a decrease of respiratory volume. Exposure to 1500 ppm of "toluene
concentrate" for 6 hours daily for 3 days produced only slight lacrimation and
head tremors in dogs. Reduction of the concentration to 1000 ppm did not allevi-
ate the head tremors (Carpenter et al., 1976b).
Bruckner and Peterson (1981) found an age-dependent sensitivity in rats and
mice. Mice, 4 weeks of age, were found to be more susceptible to exposure of
2600 ppm toluene vapor for 3 hours than 8 and 12 week old animals.
12.1.1.2. ACUTE ORAL TOXICITY — An LD5Q of 7.53 g/kg and 7.0 g/kg body
weight for a single oral dose in rats has been reported by Smyth et al. (1969a)
and Wolf et al. (1956), respectively. Withey and Hall (1975) found 5.58 g/kg to
be the LD50 in male Sprague-Dawley rats. Immature 14 day old Sprague-Dawley rats
were more sensitive than young or mature adult male rats of the same strain to
the acute effects of toluene (analytical grade) in the studies of Kimura et al.
(1971). These investigators determined an oral LD,-0 of 3-0 mfc/kg body weight,
12-16
-------
6.4 mi/kg bpdy weight, and 7.4 mi/kg body weight for each group, respectively.
This age-dependent sensitivity was also noted by exposure to inhalation (see
Section 12.1.1.1.). Cameron et al. (1938), however, reported that very young
rats were more resistant to toluene than adult animals of the Wistar strain.
ft.' lit
Thirty-three percent of a group of 12 3 day old rats survived 5.25 hours of
exposure to air saturated with toluene, in contrast to 100J mortality in the same
period in a group of adult rats.
Based on the results of their studies on the oral toxicity of toluene in
animals of different age groups, Kimura et al. (1971) suggested a maximum per-
missible limit for a single oral dose of 0.002 mil/kg body weight. This was
obtained by taking 1/1000 of the dose giving the first observable gross signs of
drug action on the CNS.
12.1.1.3. ACUTE EFFECTS FROM INTRAPERITONEAL INJECTION — Mortality is
produced by a single intraperitoneal injection of toluene in the range of 0.8 to
1.7 g/kg in rats and mice. In a series of doses of toluene graduated between
0.79 and 1.65 g/kg and diluted in olive oil, Koga and Ohmiya (1978) determined an
LD_Q of 1.15 g/kg body weight in male mice. Respiratory failure was the main
cause of death in these animals. An LD5Q of 1.64 g/kg was reported in female
mice by Ikeda and Ohtsuji (1971). Whether the disparity is due to interlabora-
tory differences or whether a sexual difference in sensitivity exists has not
been tested. In rats 0.75 cc/kg produced apathy, while 1.75 to 2.0 cc/kg pro-
duced death from respiratory failure (Batchelor, 1927); 2.0 cc/kg was a lethal
dose in rats, mice (Cameron et al., 1938), and guinea pigs (Wahlberg, 1976).
Savolainen (1978) observed that after an intraperitoneal injection of
radiolabeled toluene, the concentration of the label in the CNS was highest in
the cerebrum. The content of label in the CNS was undetectable by 24 hours after
12-17
-------
injection, which may be a simulation of acute toluene intoxication where clinical
signs of toxicity are lost within 21 hours.
A temperature-dependent sensitivity t.o the solvent was observed in adult
rats of both sexes by Keplinger et al. (1959). At 26 °C, the lethal dose was
800 mg/kg, while at S°C and 36 °C, lethal doses were 530 mg/kg and 225 mg/kg,
respectively. The toxicity of toluene is greater in hot and cold environments.
Whether increased susceptibility to the solvent is caused by the stress of
altered environmental temperature or by altered physiological processes, e.g.,
absorption, diffusion, distribution, or metabolic rate, is unknown.
12.1.1.4. ACUTE EFFECTS FROM SUBCUTANEOUS INJECTION — Ranges of 1.25 to
2.0 cc/kg and 5 to 10 cc/kg have been found to produce mortality in rats and
mice, respectively, when Injected subcutaneously (Batchelor, 1927; Cameron
et al., 1938). Braier (1973) reported that 4 cc toluene/kg injected into
rabbits produced marked transient granulopenia within 24 hours and marked granu-
locytosis and ensuing death in all animals by the end of the second day. A slight
area of induration was seen at the injection site.
12.1.1.5. ACUTE EFFECTS FROM INTRAVENOUS INJECTION — Intravenous injec-
tion of 0.2 cc toluene/kg produced 100? mortality in rabbits (Braier, 1973)«
12.1.1.6. ACUTE AND SUBACUTE EFFECTS OF PERCUTANEOUS APPLICATION —
Repeated application of undiluted solvent to the rabbit ear or shaved skin of the
abdomen produced slight to moderate irritation (Wolf et al., 1956; Smyth et al.,
I969a) and increased capillary permeability locally (Delaunay et al., 1950).
Continuous cutaneous contact in the guinea pig resulted in slowed weight gain,
karyopyknosis, karyolysis, spongiosis, and cellular infiltration in the dermis
12-18
-------
within 16 hours (Kronevi et al., 1979; Wahlberg, 1976). Application to the
abdominal skin of the rat produced hemoglobinuria (Schutz, 1960). Slight irrita-
tion of conjunctival membranes, but no corneal injury (Wolf et al., 1956) or
moderately severe injury (Carpenter and Smyth, 19^6; Smyth et al., 1969a), fol-
lowed direct application to the eye.
12.1.2. Subchronic and Chronic Exposure to Toluene. Subchronic and chronic
exposures to toluene in animals reveal little toxic effect with the exception of
the study of Fabre et al. (1955) in 2 dogs subjected to high concentrations.
Svirbely et al., C\9W) found that repeated inhalations of 1000 ppm of a solvent
mixture containing 30 to 35$ toluene, 50 to 60$ benzene, and a small amount of
xylene for 28 weeks (7 hours/day, 5 days/week) had no effect on body weight in
rats or dogs. There was no significant increase of liver volume, and no fat was
found in the liver or kidneys; however, narrowing of perifollicular collars was
observed in the spleen (Table 12-2). Splenic heraosiderosis was greater than that
found after exposure to benzene (Svirbely et al., 1911).
Neither continuous exposure to 107 ppm toluene for 90 days nor repeated
exposure to 1085 ppm for 6 weeks (8 hours/day, 5 days/week) affected the liver,
kidney, lungs, spleen, or heart in 30 rats, 30 guinea pigs, 1 dogs, or 6 monkeys.
In addition, there were no effects of treatment seen in the brain or the spinal
cord of dogs or monkeys. No significant change was observed in any of the
hematologic parameters (hemoglobin, hematoerit, or leucocyte count). All
animals except 2 of 30 treated rats survived exposure, and all gained body weight
with the exception of the monkeys (Jenkins et al., 1970).
Similarly, repeated inhalation of 210, 480, or 980 ppm of "toluene concen-
trate" for 13 weeks (6 hours/day, 5 days/week) produced no treatment-related
organ damage in rats or dogs. SAP, SGPT, SCOT, and blood urea nitrogen (BUN)
12-19
-------
activities were normal. Prior treatment with toluene did not render the animals
either more susceptible or more resistent to a subsequent challenge dose of
12,000 ppm (Carpenter et al., 1976b).
Fabre et al. (1955) exposed 2 dogs for 8 hours daily, 6 days a week, to
inhalation of 7.5 mg/i (2000 ppm) pure toluene for 4 months and then to 10 mg/Jl
(2660 ppm) for 2 months. Slight nasal and ocular irritation occurred at the
lower concentration. Motor incoordination preceding paralysis of the extremi-
ties occurred in the terminal phase. Death occurred on days 179 and 180. There
was no effect on gain in body weight, on the bone marrow, adrenal glands,
thyroid, or pituitary gland. Congestion in the lungs, hemorrhagic liver, a
decrease of lymphoid follicles, and hemosiderosis in the spleen were observed.
Glomeruli of the kidney were hyperemic, and albumen was found in the urine.
An unreviewed 26 week inhalation study in rats performed by Bio/dynamics
for the American Petroleum Institute (1980) has been made available recently.
Groups of 15 Sprague-Dawley rats of each sex were exposed 6 hours per day, 5 days
per week for 26 weeks, to cumulative concentrations of 0, 100, and 1481 ppm.
Initially, the high dose group was exposed to 2000 ppm, but the dose was lowered
to 1500 ppm after 7 exposures because CNS depression was apparent. A battery of
blood and clinical chemistry tests (BUN, SGPT, alkaline phosphatase, glucose),
urinalysis, and neurohistological examination of tissue was performed.
The only treatment related sign was increased incidence of dry roles and
staining of the ano-genital fur in the high level treatment group. Blood,
glucose, and glutamic pyruvic transaminase levels were within normal limits,
although there was a dose-related decrease of blood glucose level in the female
rats and a dose-related increase in serum glutamic pyruvic transaminase levels in
female rats. Body weight of high-dose male rats were significantly higher than
control rats, but this was not considered a toxic effect.
12-20
-------
There were no solvent-related neurohistopathological changes found.
Neither were there any significant changes in hematology or in the urine.
In a recent chronic 24 month study (CUT, 1980), Fischer 344 rats of both
sexes were exposed to 30, 100, or 300 ppm 99-98? pure toluene for 6 hours/day,
5 days/week. A battery of clinical chemistry tests (BUN, SAP, SGPT), hematologic
studies, and urinalyses (specific gravity, blood, ketones, protein, and pH)
(Table 12-3) revealed normal levels in the treated animals except for two hemato-
logic parameters in the female. Females exposed to 100 or 300 ppm showed signi-
ficantly reduced hematocrit levels, while the mean corpuscular hemoglobin con-
centration was significantly increased in females exposed to 300 ppm. Body
weights in males of the treatment groups were significantly higher than body
weights of controls from approximately week 48 until termination of the study,
while body weights of females in the treatment group were higher than body
weights of controls from week 70 until the final 4 weeks of the study when the
effect disappeared (Table 12-4). No dose-response relationship was noted.
Mortality in the treatment groups did not differ from controls (14.6$). Although
a variety of proliferative, degenerative, and inflammatory lesions were observed
in various organs, the lesions occurred with equal frequency in all control and
treatment groups, and the authors concluded that no tissue changes could be
attributed to toluene inhalation. Neoplasms were observed frequently in the
lungs and liver, as well as in the endocrine organs, lymphoreticular system,
mammary gland, integument, testis, and uterus. Chronic progressive nephropathy
was present in the urinary system (CUT, 1980).
Although this study was comprehensive and is the only chronic study of
toluene in laboratory animals, it is inadequate because there are several defi-
ciencies. The high spontaneous incidence (16$) of mononuclear cell leukemia in
aging Fischer 344 rats reported by Coleman and coworkers (1977) suggests that
12-21
-------
TABLE 12-3
21 Month Chronic Exposure of Fischer 311 Rats Exposed 6 Hours/Day, 5 Days/Week, to Toluene by Inhalation
ro
A,
ro
Group
Control
30 ppo
100 ppm
300 ppm
Control
30 ppm
100 ppm
300 ppm
Control
30 ppm
100 ppm
300 ppm
Control
30 ppm
100 ppm
300 ppm
Number of
Animals
89
89
89
90
89
89
89
90
90
90
90
. 90
90
90
90
90
do3
6
9
6
6
7
8
8
7
1
4
3
1
1
5
5
1
WBC
/cu mm)
.03
.96»
.51
.53
.51
.66
.13
.50
.01
.59
.91
.21
.93
.10
.71
.87
RBC
(10°/cu
18 Months
8.757
8.766
8.700
8.891
21 Months
9.866
8.736
9.925
9.107
18 Months
8.022
7.956
7.915
8.010
21 Months
8.397
8.271
8.076
8.090
HB HCT
mm) (g/DL) (%)
of Exposure
16.56
16.61
16.17
16.80
of Exposure
18.91
16.58
18.17
18.33
of Exposure
15.67
15.77
15.75
15.78
of Exposure
16.16
15.89
15.91
15.86
(Males)
13.10
12.12
11.93
12.31
(Males)
51.78
16.51
51.61
17.35
(Females)
11.70
11.25
10.83
11.20
(Females)
11.99
13.06
12.17*
12.02**
MCV
(Cu. Mic.)
50
19
19
18
51
52
50
50
53
52
52
52
51
53
53
53
.1
.6
.5
.8**
.2
.5
.7
.9
.0
.8
.7
.1
.7
.3
.9
.1
MCH
(uug)
18
18
18
18
19
19
18
19
19
19
19
19
19
19
19
19
.87
.90
.91
.85
.21
.05
.67
.11
.19
.77
.85*
.63
.50
.11
.68
.52
MCHC
<*)
38.01
38.82
38; 93
39.30**
37.87
36.33
38.81
39.33
37.26
37.90*
38.21*
37.98
36.10
36.12
37.08
37.16*
"Source: CUT, 1980
•Statistically significant difference from control (P <0.05)
•"Statistically significant difference from control (P <0.01)
WBC = white blood cell count; RCB = red blood cell count; HB = hemoglobin concentration; DL = 100 milliliters;
HCT = hematocrit; MCV = mean corpuscular volume; Mic. = micron; MCH = mean corpuscular hemoglobin; MCHC =
mean corpuscular hemoglobin concentration.
-------
TABLE 12-4
24 Month Chronic Exposure of Fischer 344 Rats Exposed
6 Hours/Day, 5 Days/Week, to Toluene by Inhalation
Group
Number
Animals
Mean Body Weight in Grams
Weeks of Exposure
0 26 52 78 100
Total
104 Weight
Change
Males
Control
30 ppm
100 ppm
300 ppm
89
89
89
90
141
141
142
340
349»
351»»
341
384 426
396" 445"
404" 447"
403" 446"
430
456"
454"
451"
430
454"
452"
445
286
314"
312"
304«»
Females
Control
30 ppm
100 ppm
300 ppm
90
90
90
90
109
109
109
109
203
191"
194
195"
213
211
211
211
214
246"
248"
248"
260
272"
272"
271"
265
273*
275
272
156
164
166
163
Source: CUT, 1980
•Statistically significant difference from control (P <0.05)
"Statistically significant difference from control (P <0.01)
12-23
-------
this strain is inappropriate for the study of a chemical that might be myelo-
toxic. A high testicular interstitial cell tumor incidence (66.29 reported by
Coleman et al., 1977 and 859 bileral reported by Mason et al., 1971) removes this
organ from any assessment of carcinogenic!ty. The low mortality of rats in this
study (14.6$) differs from the mortality rate (up to 259) associated with main-
taining these animals under barrier conditions (NCI, 1979a,b). If these animals
were not raised under barrier conditions (which is not stated), then still higher
mortality rates could be expected in this age group of Fischer 344 rats. No
quality assurance of the study was extant after 6 months into the chronic study
(CUT public review of toluene study, May 12, 1981).
Furthermore, a maximum tolerated dose was not reached in either the 90 day
test where no effects were noted at the highest dose (1000 ppm) used, nor the 2
year study where the highest dose tested was 300 ppm (Powers, 1979).
In the only subchronic oral study, female rats fed up to 590 mg toluene/kg
by intubation for periods of up to 6 months did not show ill effects as deter-
mined by gross appearance, growth, periodic blood counts, analysis for blood urea
nitrogen, final body and organ weights, bone marrow counts, or histopathological
examination of adrenals, pancreas, lungs, heart, liver, kidney, spleen, and
testis (Wolf et al., 1956).
12.2. EFFECTS ON LIVER, KIDNEY, AND LUNGS
Toxic effects in the kidney, and possibly in the liver and lungs after
higher doses, have been reported.
12.2.1.1. LIVER — No histological damage was observed after subchronic and
chronic inhalation of 1000 ppm of a solvent mixture containing 30 to 359 toluene
for 28 weeks, 980 ppm of "toluene concentrate" for 13 weeks, 1085 ppm of toluene
12-24
-------
for 6 weeks, and 300 ppm of 99.98$ pure toluene for 24 months in a variety of
species in studies described in Section 12.1.2. (Svirbely et al., 1944;
Carpenter et al., 1976b; Jenkins et al., 1970; CUT, 1980). Furthermore, no
liver damage was detected in female rats after subchronic daily oral doses of
590 mg/kg for 6 months (Wolf et al., 1956).
Two preliminary reports (abstracts) from the laboratory of Bruckner and
Peterson noted no effect on hepatorenal function. In a regimen mimicking solvent
"sniffing", male rats and mice were exposed to 12,000 ppm toluene for 7 ten
minute periods (with 20 minute solvent-free periods intervening), 5 days/week
for 8 weeks. No organ pathology was found. Lactic dehydrogenase, SGPT
activities, BUN content, and liver triglyceride content were normal (Bruckner
and Peterson, 1978). In another study, inhalation of 4000 ppm toluene
(3 hours/day, 5 times weekly) for up to 8 weeks failed to reveal toluene induced
hepatorenal injury by a battery of toxicological tests (SOOT activity, BUN
levels, urinary glucose and protein concentration, and urinary cell count) and
upon histopathological examination of the liver, kidney, and lung (Bruckner and
Peterson, 1976).
In a study in which reagent grade toluene that was dissolved in corn oil was
injected intraperitoneally in doses of 150, 300, 600, or 1200 mg/kg into adult
male guinea pigs, there was no change in serum ornithine carbamyl transferase
activity at any dose level in blood collected 24 hours later. Histological
examination revealed no liver abnormalities or lipid accumulation with the
exception of the highest dose, where there was evidence of lipid accumulation
(Divincenzo and Krasavage, 1974).
Two hours after male rats (weighing 150 to 300 g) were administered
2600 umol/100 g body weight of toluene in mineral oil by gavage, there was no
evidence of injury to the microsomal function of the liver. There was no effect
on protein synthesis, cell sap RNA, glucose 6-phosphatase, oxidative
12-25
-------
demethylase, nicotinamide adenine dinucleotide phosphate (NADPH) neotetrazolimn
reductase, or lipid conjugated diene content of microsomes (Reynolds, 1972).
Inhalation of 300 ppm toluene (6 hours/day, 5 days/week) for 15 weeks slightly
increased cytochrome P-U50 content in the liver, appreciably enhanced ethoxycou-
marin o-deethylase, and at the end of exposure, increased UDP glucuronyltrans-
ferase activity. The content of toluene in perirenal fat tended to decrease
during continued exposure, while the presence of toluene in the brain was
detected throughout exposure. The diminuation of toluene content in perirenal
fat at the same time that drug metabolizing enzymes increased suggests an adapta-
tion to continued presence of the solvent (Elovaara et al., 1979)*
Continuous cutaneous contact with a dose of 2.0 mil toluene, which was com-
pletely absorbed within 5 to 7 days, produced no change in liver morphology
(Wahlberg, 1976).
Although the studies just cited indicate the absence of toluene-induced
toxicity, there are others which suggest a slight toxic effect. In a study by
von Oettingen et al. (19*»2b), inhalation of concentrations of 600 to 5000 ppm
toluene containing 0.01% benzene for 5 weeks (7 hours/day, 5 days/week) in rats
caused an enlargement of the liver (increase of weight and volume) in a dose-
dependent manner 16 hours after the last exposure. Histologically, there was a
progressive decrease of density of the cytoplasm in the liver cells as the
concentration of toluene increased. These observations were not seen in rats
sacrificed two weeks after the last exposure. No evidence of hyperemia was seen
in the liver. Matsumoto et al. (1971) reported an increase in liver weight and
liver weight to body weight ratio in rats exposed 9 hours/day, 6 days/week for
43 weeks to 2000 ppm toluene vapor. This was not noted at lower doses (100 ppm
or 200 ppm).
12-26
-------
In the study of Fabre et al. (1955), 2 dogs exposed for 1 months (8 hours/
day, 6 days/week) to inhalation of 7.5 mg/2, (2000 ppm) pure toluene and, subse-
quently, to 10 mg/2, (2660 ppm) for 2 months had hemorrhagic livers.
Tahti et al. (1977) observed that inhalation of 1000 ppm toluene 8 hours/
day, for 1 week increased SCOT and SGPT activity and induced metabolic acidosis
in rats.
Although early reports from this laboratory revealed no effect on SCOT
activity or BUN levels in mice and rats, a recent paper (Bruckner and Peterson,
198lb) noted an increase in SCOT activity in mice and rats during intermittent
exposure to 12,000 ppm toluene (Section 12.3.). Increase in LDH activity was
seen in rats and decrease in BUN levels was seen in mice. No histological
changes were observed, but an increase of organ weight to body weight was found.
Histological changes in the liver were found when male CFY rats were
injected intraperitoneally with 0.05 or 0.1 mJl/100 g body weight of analytical
grade toluene for up to 4 weeks. There was a dose-dependent increase in the
number of mitochondria per unit of cytoplasmic area in the liver. Total area,
nuclear density, and nucleus/cytoplasmic ratio increased at the higher dosage.
Dose-dependent decreases in nuclear volume were seen after intraperitoneal or
subcutaneous injection, with subcutaneous injection being less effective than
intraperitoneal injection. The authors suggested that the considerable accumu-
lation of mitochondria was related to increased metabolism of the liver and that
oxidative detoxification of the solvent might involve mitochondrial enzymes as
well as hepatic microsomal enzymes (Ungvary et al., 1976). In an earlier paper,
Ungvary et al. (1975) found that intraperitoneal or subcutaneous administration
of toluene produced degenerative changes, i.e., separation of ribosomes and
vacuolar dilation of the rough endoplasmic reticulum. In these studies, the
higher concentrations of toluene also decreased glycogen content. Following
12-27
-------
discontinuation of exposure, the hepatic changes indicating increased load on
detoxification processes (increased succinate dehydrogenase (SDH) activity,
increase of mitochondria and smooth endoplasmic reticulura, decreased glycogen
content) as well as degeneration (dilation of endoplasmic reticulum, accumu-
lation of autophagous vacuoles) rapidly regressed, indicating that the toxic and
liver loading effects of toluene are reversible. The regenerative property of
the liver after hepatectomy was not significantly affected by exposure to toluene
(Hudak et al., 1976).
In a more recent study by Ungvary et al. (1980), male CFY rats were exposed
to inhalation of 265 ppm (6 hours daily), 929 ppm or 1592 ppm (8 hours daily)
analytical grade toluene and female rats were exposed to the lowest dose only (5
times a week up to 6 months). Growth was inhibited in males at the higher.
concentrations and in females at the low dose. No abnormal histological changes
were found in the liver. Liver weight was increased by treatment. Signs of
adaptive compensation that were observed include proliferation of smooth endo-
plasmic reticulum, increased cytochrome PU50 and cytochrome be activity,
increased aniline hydroxylase activity and aminopyrine M-demethylase activity.
These changes, which were dose-dependent and reversible, showed little or no
dependence on length of exposure. There was no effect on SCOT or SGPT activity.
The authors concluded from their latest studies that subchronic exposure to
toluene vapors has no specific hepatotoxic effect. The results of toluene
inhalation corroborated earlier histological findings by the intraperitoneal or
subcutaneous route, with the exception that necrotic areas were not found after
inhalation. Whether or not this reflects the different route of exposure or the
higher concentration of toluene administered intraperitoneally has not been
ascertained.
12-28
-------
12.2.2. Kidney. No histological effects of renal toxicity were seen in sub-
chronic inhalation studies (Table 12-2) in mice exposed to 1000 ppm for 20 days
(Horiguchi and Inoue, 1977), in rats, guinea pigs, dogs, or monkeys exposed to
1085 ppm for 6 weeks (Jenkins et al., 1970), in rats and mice exposed to UOOO ppm
vapors for 8 weeks (Bruckner and Peterson, 198lb), or in chronic inhalation
studies in rats exposed to 300 ppm for 2M months (CUT, 1980). Toluene did not
elicit an observable effect in renal histology after subchronic oral dosing of
590 mg/kg for 138 days in rats (Wolf et al., 1956).
Pathological renal changes, however, have been observed in some studies.
von Oettingen et al. (19l2b) found increasing numbers of casts in the collecting
tubules of rat kidneys during inhalation of concentrations ranging from 600 ppm
to 5000 ppm for 5 weeks (7 hours daily, 5 days/week). A few casts in the kidney
were seen after the third week of exposure at 600 ppm and earlier in the higher
doses. Appreciable fat in the convoluted tubules and hyaline casts in the
collecting tubules of the kidney were observed in dogs after inhalation of 200 to
600 ppm for approximately 20 daily 8 hour exposures, then inhalation of MOO ppm
for 7 hours/day, 5 days/week for 1 week, and finally to 850 ppm for 1 hour. In
the studies of Matsumoto et al. (1971), exposure of rats to inhalation of
2000 ppm for 8 hours/day, 6 days/week for M3 weeks produced hyaline droplets in
renal tubules. There was an increase of kidney weight and an increase of the
ratio of kidney weight to body weight.
After inhalation of 7.5 mg/2, toluene 8 hours/day, 6 days/week, for U months
followed by exposure to 10 mg/!. during the remaining 2 months, hyperemic renal
glomeruli and albuminuria were observed at autopsy in dogs by Fabre et al.
(1955). Inhalation by guinea pigs of 1000 ppm (of distilled pure toluene)
H hours/day, 6 days/week, for a total of 35 exposures produced slight toxic
degeneration in the kidney. Eighteen exposures at a higher dose of 1250 ppm
12-29
-------
produced more marked degeneration (Smyth and Smyth, 1928). Degeneration of
convoluted tubular epithelium in guinea pigs exposed by the subcutaneous route
was reported in an abstract of a paper by Sessa (1948).
12.2.3. Lungs. No histological damage of the lungs was seen after inhalation of
1000 ppm toluene vapors for 20 days in mice (Horiguchi and Inoue, 1977), inhala-
tion of 1085 ppm for 6 weeks in rats, guinea pigs, dogs, or monkeys (Jenkins
et al., 1970), inhalation of 4000 ppm for 8 weeks in rats and mice (Bruckner and
Peterson, 198lb), 300 ppm for 24 months in rats (CUT, 1980), or ingestion of
590 mg/kg for 138 days in rats (Wolf et al., 1956).
Irritative effects on the respiratory tract, however, have also been
reported (Browning, 1965; Gerarde, 1959; Fabre et al., 1955; von Oettingen
et al., 1942b).
Marked pulmonary inflammation was seen in guinea pigs after exposure to
inhalation of 1250 ppm of distilled pure toluene 4 hours daily, 6 days/week, for
18 exposures (Smyth and Smyth, 1928).
Hemorrhagic, hyperemic, and sometimes degenerative changes in the lungs
have been observed in guinea pigs after a subcutaneous injection of 0.25 cc of
toluene daily for 30 to 70 days as reported in an abstract (Sessa, 1948). Con-
gestion in the lungs of dogs which had undergone repeated exposure to concen-
trations of 200 to 600 ppm toluene and to a final exposure by inhalation of
850 ppm for 1 hour, and pulmonary lesions in rats after 1 week of inhalation of
2500 ppm (7 hours/day, 5 days/week) were reported by von Oettingen et al.,
(I942b).
Congestion in the lungs was noted by Fabre et al. (1955) in dogs and in
rabbits at the higher doses.
12-30
-------
12.3. BEHAVIORAL TOXICITY AND CENTRAL NERVOUS SYSTEM EFFECTS
Excessive depression of the CNS has been linked with acute exposure to high
levels of toluene. A concentration of 20,000 ppm toluene was lethal to rats
after 30 to 50 minutes of exposure, with death attributed to depression of the
CNS (Kojima and Kobayashi, 1975, cited in NRC, 1980). Inhalation of 12,000 ppm
of "toluene concentrate" containing 0.06$ benzene was lethal to rats following
tremors which appeared within 5 minutes of exposure and prostration which
occurred within 15 minutes of exposure (Carpenter et al., 1976b).
A dose-related effect on instability, incoordination, and narcosis was
\found in rats exposed 18 to 20 hours daily to toluene concentrations of 1600 ppm
and 1250 ppm. No symptoms were seen at 1100 ppm (Batchelor, 1927). Carpenter
et al. (1976b) reported that rats were unaffected by exposure to inhalation of
1700 ppm of a "toluene concentrate" for U hours and suffered only slight incoor-
dination at 3300 ppm. Dogs were unaffected by exposure to vapors of 760 ppm for
6 hours, but exhibited head tremors at 1500 ppm. After inhalation of 7800 ppm
"toluene concentrate" for 6 hours, cats exhibited loss of coordination followed
by prostration and, finally, light anesthesia within 2 hours. All survived
exposure.
Bruckner and Peterson (198lb) observed that the onset of narcosis and the
depth of CNS depression was dose-dependent in mice exposed to inhalation of
12,000 ppm, 5200 ppm, and 2600 ppm toluene. Recovery was rapid. After exposure
to 12,000 ppm for 20 minutes, mean performance levels scored prior to exposure
were restored within approximately one-half hour in *» week old rats.
Within 10 seconds after 1 intravenous injection of 0.07 cc toluene per kg
body weight in 1 dog, generalized rigidity with hyperextension of the back was
noted in a study made by Baker and Tichy (1953). Recovery occurred within
12 minutes. When a series of 10 doses of 0.07 cc toluene/kg was given intra-
12-31
-------
venously every 3 to 5 days to another dog, the effect was rigidity in the animal
and twitching of the extremities. Recovery occurred in 5 to 10 minutes. At
necropsy, cortical and cerebellar atrophy was found. Marked shrinkage and hyper-
chromaticity of many cortical neurons, patchy myelin pallor, and fragmentation,
especially in perivascular areas, were found. Multiple fresh petechiae,
especially in the white matter, was seen. There was a decrease and degeneration
of Purkinje cells in the cerebellum (Baker and Tichy, 1953).
12.3.1. Effect of Solvent-Sniffing Abuse. In the section on effects on humans
(Section 10.1.), inhalation of readily available thinners by young adults has
been described as a prevalent practice which typically affects the CNS. Inhala-
tion of solvent mixtures containing toluene in the laboratory rat have demon-
strated similar effects. Inhalation of a mixture of solvents containing 25%
methylene chloride, 5% methanol, 43J heptane, and 23% toluene for 10 minutes (60
to 226 ing/2.) caused a decrease in grooming, the appearance of ataxia, abnormal
scratching, hind limb flaccid paralysis, and, finally, unconsciousness in male
Fischer rats. Cumulative effects were noted with 4 intermittent 10 minute expo-
sure periods with 15 minutes between exposures. When the interval between each
exposure was increased to 40 minutes, recovery was almost complete (Pryor
et al., 1978).
Subchronic exposure to a thinner containing toluene impaired acquisition of
a complex behavior. Rats inhaled 50,000 ppm of a readily available commercial
paint thinner composed of 42? toluene, 25% methanol, 10/t methyl iso-butyl ketone,
and minor amounts of other solvents for 4, 8, or 16 weeks (twice-daily for 10
minute periods, 5 days a week) and then were observed for acquisition of temporal
discrimination in a differential reinforcement of low rate schedule (DHL 20). In
this test, the animal is rewarded for a bar press separated from the last
12-32
-------
response by 20 seconds. These results suggested that persistent inhalation of
thinner vapors impaired temporal discrimination when the animals were tested
within a relatively short time after the period of inhalation. However,
responses in rats that had a period of rest after exposure did not differ from
controls (Colotla and Bautista, 1979).
Studies in laboratory animals have shown that toluene contributes to the
symptoms of thinner toxicity. In the studies of Peterson and Bruckner (1978),
impairment of cognitive function and muscular coordination were used to monitor
CNS depression and narcosis. Behavioral performance (visual placing, grip
strength, wire maneuver, tail pinch, and righting reflex) in mice exposed to
3980 ppm (15 mg/i) toluene for 3 hours decreased over time of exposure, which was
inversely correlated with toluene concentration in brain tissue. Concentration
of toluene in the brain increased exponentially with the length of exposure and
similarly decreased after termination of exposure, as did levels of toluene in
liver and blood (Figure 12-1). A single 10 minute exposure to a higher concen-
tration (10,615 ppm) followed the pattern elicited by the lower concentration
for a longer period. Recovery of behavioral performances occurred as solvent
concentration in the brain decreased after exposure. Bruckner and Peterson
(198la) noted that ataxia, immobility in the absence of stimulation, hypnosis
with difficult arousal and unconsciousness were apparent in mice at concentra-
tions in blood of 40 to 75 ug/g, 75 to 125 ug/g, 125 to 150 ug/g and >150 ug/g,
respectively, as measured by the air bleb method.
A study was made by Peterson and Bruckner (1978) in mice to mimic the
conditions typical of human solvent-sniffing abuses. During intermittent expo-
sure to 10,615 ppm (5 minutes of exposure followed by 10 minutes without toluene
or 10 minutes of exposure followed by 20 minutes without toluene) for approxi-
mately 3 hours or 11,9^2 ppm (10 minutes of exposure followed by 20 or 30 minutes
12-33
-------
3
I
r~
M
8
CO
TISSUE LEVELS
800 -i
ui
I
w 400H
z
2 200H
1
4
0123123
HOURS OF EXPOSURE HOURS POSTEXPOSURE
100 -i
50-
e
£
NORMALIZED TISSUE LEVELS
r
2
BRAIN
LIVER
BLOOD
i
3
0 1
HOURS OF EXPOSURE
1
i
2
r
3
i
4
HOURS POSTEXPOSURE
600-,
400-
\u
3 200-
BRAIN CONCENTRATION VERSUS
CHANGE IN PERFORMANCE SCORE
BRAIN
> •* APERFORMANCE
m 5
I-3
1
0123
HOURS OF EXPOSURE
1234
HOURS POSTEXPOSURE
— a.
0
Figure 12-1 Toluene Levels in Tissue and Behavioral Performance (Mice were con-
tinuously exposed for 3 hours to an intoxicating concentration of
toluene (15 mg per liter of air). Groups of animals were analyzed for
air bleb concentration, reflex performance, and tissue levels after
15, 30, 60, 120, and 180 minutes of exposure and 1, 2, and 1 hours
postexposure. Figure 12-1A shows toluene levels in liver, brain, and
blood. Figure 12-1B shows toluene normalized to the highest mean
level in each tissue. Figure 12-1C compares brain levels of toluene
with change in performance of the animals. Lines represent means.
N = 7 mice on all but M hours postexposure, in which case, N = 6.)
(Peterson and Bruckner, 1978)
12-34
-------
without toluene) for approximately 3 hours, reflex performance became progres-
sively lower throughout the experimental period for the regimens allowing
20 minutes or less toluene-free intervals. A 30 minute toluene-free interval
between exposures permitted almost unimpaired performance, indicating complete
recovery between exposures (Peterson and Bruckner, 1978).
In a later acute study, Bruckner and Peterson (198la) exposed mice and rats
to seven consecutive cycles. Each cycle consisted of 10 minute inhalation
exposure to 12,000 ppm toluene followed by a 20 minute solvent-free recovery
period. Unconditioned performance and reflexes of the animals were tested prior
to and following exposure. The mice showed almost complete recovery during the
course of treatment, while performance scores of rats exhibited a progressive
decline. The authors speculate that the rapidity of recovery in mice might be
attributed to the higher circulatory, metabolic, and respiratory rates of mice;
the increasing CMS depression seen in rats over a 3 hour period of intermittent
inhalation might result from a progressive accumulation of the chemical. Sub-
stantial residual quantities in the brain one hour post exposure had been noted
by the same authors in an earlier paper (Bruckner and Peterson, 1981 a).
In a subchronic study, groups of 6 mice or U rats with comparable numbers of
controls were subjected to 7 consecutive cycles (as described in the preceding
paragraph) on a daily basis, 5 times a week for 8 weeks. Depression of body
weight gain was seen in both rats and mice during 8 weeks of intermittent toluene
exposure. An increase in SCOT levels was noted in rats and mice, but the
increase in mice was not statistically significant. An increase in LDH was seen
only in rats exposed to toluene at all sampling intervals. BUN levels in rats
were unaffected by treatment, whereas BUN levels in mice were consistently lower
during the period of exposure. Recovery occurred 2 weeks after exposure. There
were no effects on brain, lung, liver, heart, or kidney histology, although a
12-35
-------
depression in gain of organ weights (kidney, brain, lung) was noted in treated
mice and rats (Bruckner and Peterson, 198ta).
12.3.2. Effects on Simple and Complex Behavioral Performance. After a single
exposure to 800 ppm toluene for 1 hours, unconditioned reflexes and simple
behavior (corneal, grip, and righting reflexes, locomotor activity, and coor-
dination) began to fail (Krivanek and Mullin, 1978). In these studies, male rats
were exposed to concentrations of 0, 800, 1600, 3200, and 6100 ppm and tested at
0.5, 1, 2, and U hours during exposure and 18 hours after exposure (Table 12-5).
Concentrations of toluene as low as 1 ppm administered 6 hours/day
depressed wheel turning performance (a spontaneous activity) after 10 days of
exposure in adult male mice (Horiguchi and Inoue, 1977). No effect on body
weight was seen at any of the dosages used (1, 10, 100, and 1000 ppm) during the
20 daily exposures. However, there were alterations in blood elements in animals
exposed to 10, 100, and 1000 ppm, which are noted in Section 12.5.
An exposure as low as 1 ppm of toluene suppressed wheel-turning activity,
whereas exposure to 100 ppm benzene approximated the depression caused by expo-
sure to 10 ppm toluene; therefore, the narcotic action of toluene appears to be
greater than benzene (Horiguchi and Inoue, 1977).
The positive findings at 1 ppm reported by Horiguchi and Inoue (1977) and
the change of motor nerve chronaxies in rats exposed continuously to 4 ppm
toluene for 85 days (Gusev, 1967; cited by NRC) have been questioned in the MRC
(1980) review as being at variance with negative effects observed in other
experiments at much higher levels. For example, Ikeda and Miyake (1978) did not
find any effect on spontaneous activity in their studies of repeated exposure to
4000 ppm toluene in rats. However, the behavioral tests of the latter authors
were carried out U days after final exposure. Rapid recovery of behavior after
12-36
-------
TABLE 12-5
Behavioral Effects of Toluene
Species
Ulstar rats
Sprague-Dawley
rats
Rats (male)
Rats
Rats (aale)
Rats (male)
ro
l
u>
"** Rats (male)
Rats
Nice (male)
Route
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
I. p.
Dose
574. 1148. 2296, and
4595 ppa
150 ppa for 0.5, 1, 2 or
4 h
550 to 800 ppn for
4 h/d x 2 wk
4000 ppa 2 h/d x 60 d
3000 ppa for 4 h
(no effect at 1000 ppa)
3200 ppm for 4 h
1600 ppa for 4 h
800 ppa for 4 h
4 to 5 al In 40 to 50 t of air
for 1/2 h/d x 7.6 d
0.96 g/kg
effect
Deficit in isultlple
response schedule
Initial stlaulatlon
followed by depression In
aultlple response schedule
No effect on avoidance
response
Multiple response schedule
No effect on CRF or FR30
Deficit In DHL 12 seo
schedule
Deficit In conditioned
avoidance response
Deficit conditioned
avoidance response
No-effect-level
Deficit In unconditioned
reflexes and simple
behavior
Induced forced turning
Loss of righting reflex in
Reference
Colotla and Bautlata,
1979
Geller et al., 1979
Battlg and Grand jean, 196')
Ikedn and Hiyake, 1978
Shlgeta et al., 1978
Krlvanek and Hullln, 1978
Krlvanek and Hullln, 1978
Ishlkaua and Sohaldt, 1973
Koga and Ohaiya, 1978
Mice
Mice
Mice (nale)
Mice
Inhalation
Inhalation
Inhalation
Inhalation
3980 ppm for 3 h
10,615 ppa for 10 aln
4,000 ppa for 3 h/d x
5 d/wk for 8 wk
1, 10, 100, 1,000 ppa for
6 h/d x 10 d
2650 ppa
5/7 In 20.6 + 1.6 aln
Interval froa loss of
righting reflex to re-
covery 35.0 » 8.2
14.3$ lethality In 24 h
Deficit In visual placing,
grip strength, wire maneuver
tall pinch, righting reflex
Deficit on an accelerating,
rotating bar
Deficit In wheel-turning
Causes aloe to fall on side
Peterson and Bruckner,
1978
Bruckner and Peterson,
1976
Horlguchl and Inoue, 1977
Faustov, 1958
h = hour; d = day; wk = week; l.p. = intraperltoneal; aln = alnute; seo * second.
-------
exposure (Shigeta et al., 1978; Peterson and Bruckner, 1978; and Ishikawa and
Schmidt, 1973) nay explain the disparate results just cited.
A single exposure to 3000 ppm toluene for 4 hours disrupted established
timing of bar pressing in a conditioned avoidance response test in adult male
Wistar rats (Shigeta et al., 1978). Concentrations of 0 and 1000 ppm toluene did
not affect this operant behavior. At 3000 ppm, increased response and shortening
of the inter-response-interval were noted, but no change in shock counts was
seen. Behavioral recovery occurred one hour after exposure. Krivanek and Mullin
(1978) reported a decrease in conditioned avoidance reflexes after inhalation by
male rats of 3200 ppm toluene for 4 hours, but they reported no effect at dose
levels of 1600 or 800 ppm.
In another study of operant behavior, Colotla and Bautista (1979) used;rats
that had been trained to .reinforced bar pressing in a multiple schedule com-
prising fixed ratio (FR) 10 and differential reinforcement of low rates (DRL)
20 second components with 60 second time out between reinforcement periods. Five
trained adult Wistar rats were exposed to concentrations of 574, 1148, 2296, and
4595 ppm toluene. Test sessions were 36 minutes long. Control sessions inter-
vened between solvent exposure sessions to assess recovery. A decrease in rate
of response of FR responding and an increase of frequency rate of the DRL
component were observed with all doses in a dose-dependent manner. No residual
effects were observed. An effect on behavioral rate was shown.
A lower concentration, 150 ppm toluene, for periods of 0.5, 1, 2, or 4 hours
affected performance on a multiple fixed ratio-fixed interval schedule of rein-
forcement in 3 male Holtzman, Sprague-Dawley rats. An initial enhancement of FR
and FI rates occurred during shorter exposure periods, followed by a decrease in
rates during longer exposure periods (Cellar et al., 1979); however, only a small
number of animals was used, and the response was not uniform. Battig and
12-38
-------
Grandjean (1964) found no. effect on acquisition or consolidation of an avoidance
response after inhalation of toluene varying from 550 to 800 ppm, 4 hours/day for
2 weeks, by 6 adult male rats. Continued exposure at similar levels for another
week effected a somewhat slower extinction of the avoidance response.
Repeated exposure of rats to inhalation of 4000 ppm toluene, 2 hours daily
for 60 days, did not affect spontaneous locomotor activity, emotionality, or
learning on 2 operant schedules: memory in a continuous reinforcement schedule
(CRF) where every bar press was rewarded by food and extinction of a fixed ratio
(PR 30) schedule performance where every 30th response is reinforced. This
exposure impaired learning on a third operant schedule, acquisition of a dif-
ferential reinforcement of a low rate of responding (DHL 12 seconds) schedule
that required the rat to allow at least 12 seconds between responses to receive a
reward. Impaired performance was present 80 days after final exposure. Exposure
, to toluene appears to more seriously affect higher levels of cognition. Histo-
logical examination of the brain did not reveal any changes (Ikeda and Miyake,
1978).
Inhalation of 4000 ppm toluene by mice for 3 hours/day, 5 times weekly for
up to 8 weeks, caused a steady deterioration of performance on an accelerating,
rotating bar during the initial hour of each session of exposure. Solvent levels
in blood and liver increased during each exposure session and decreased quickly
after exposure (Bruckner and Peterson, 1976).
Circling (forced turning) was produced within a mean of 7.6 days in 90 day
old male Sprague-Dawley rats (n=10) by repeated toluene inhalation (4 to 5 m& in
40 to 50 i of air) for 1/2 hour per day. After 15, 21, or 34 days of recovery,
the rats were reexposed daily to toluene. When only 15 days of recovery had
elapsed, the number of exposures required to elicit forced turning was signifi-
cantly less than the number required to acquire the behavior originally. This
12-39
-------
effect was not seen when a longer period of recovery had elapsed. Thus, toluene
has a residual effect. Furthermore, the effect is reversible. This turning was
not associated with any histological lesions in the brain (Ishikawa and Schmidt,
1973).
12.3.3. Effect on Electrical Activity of the Brain and Sleep. The .effect of
toluene on electrical, as well as behavioral, parameters in the brain was studied
by Contreras et al. (1979). Twenty cats were exposed for up to 40 days (10
minute periods, 7 days/week) to 25•5 to 204.7 mg/i/min (approximately 7,000 to
52,000 ppm) toluene administered through a tracheal cannula in increments of
25.5 mg/i/min with 10 minute recovery intervals between exposures. During the
first seconds of acute intoxication at 12,000 ppm, the behavior consisted of
restlessness, polypnea, coughing, sneezing, and vegetative responses consisting
of salivation, mydriasis, and lacrimation. Ataxia appeared two minutes later,
ending with postural collapse. Changes of electrical activity at this point were
found in the anterior lobe of the cerebellum, the amygdala, and the visual
cortex. There was no behavioral response to light, sound, or pain stimuli
(Table 12-6).
Threshold dose for restlessness was approximately 7,000 ppm. No behavioral
response to external stimuli occurred at approximately 39,000 ppm. Recovery
from ataxia occurred 12 minutes after removal from exposure. With repeated
exposure, at a concentration of 102.3 mg/i/minutes, hypersynchronous rhythms
spread from the amygdala to the reticular formation, visual cortex, and cere-
bellum, and electrical activity appeared in the gyrus cinguli, which coincided
with a display of hallucinatory behavior. These EEC and behavioral signs are
similar to complex partial seizures in man (Contreras et al., 1979).
12-40
-------
TABLE 12-6
Central Nervous System Effects of Toluene
Species
Route
Dose
Effect
Reference
i
Cats
Rats
Inhalation
Inhalation
Rats (male) Inhalation
Rats and mice Inhalation
Rats (male) Inhalation
Sprague-Dawley
n = 6
ca. 7,000 to 52,000 ppm
10 min/d x 10 d
1000, 2000, or UOOO ppm
for U h
2000 ppm toluene for
8 h/d x 1 wk
265 ppm
500 ppm 6 h/d x 3 d
Killed 16 to 18 h after
exposure
1000 ppm 6 h/d x 5 d
decapitated U h after
exposures
Restlessness
Autanomic nervous system
stimulation, ataxia,
collapse
EEC changes
Seizures
EEC changes
Increased excitability
Changed sleep cycle
Increased pulse rate
Decreased threshold for
Bemegride-induced
convulsions
Threshold affecting CNS
Increase of catecholamines
in lateral palisade
zone of median eminence
Increase of catecholamines
in subependymal layer of
median eminence
Increase of FSH
Contreras et al., 1979
Takeuchi and Hisanaga,
1977
Takeuchi and Suzuki,
1975
Faustov, 1958
Andersson et al., 1980
min = minute; d = day; h = hour; wk = week; EEC = electroencephalogram; FSH = follicle-stimulating hormone; CNS = central
nervous system.
-------
Takeuchi and Hisanaga (1977) found that 1000, 2000, or 4000 ppm toluene
administered for 4 hours to groups of 4 or 5 male Wistar rats elicited changes in
the sleep cycle, altered cortical and hippocampal EEC rhythms, and increased
pulse rates. All phases of sleep were disturbed at a concentration of 2000 and
4000 ppm, while 1000 ppm deterred entry of sleep into the slow-wave phase, but
facilitated entry into the paradoxical phase.
A similar observation was made by Fodor et al. (1973), where an increased
percentage of REM during sleep was found in female albino rats during exposure to
1000 ppm. A concentration of 1000 ppm decreased cortical and hippocampal com-
ponents of the EEC (Takeuchi and Hisanaga, 1977). Exposure to 2000 ppm toluene
increased cortical fast components and hippocampal components, whereas exposure
to 4000 ppm increased the hippocampal fast component as well. At 4000 ppm,
excitability measured by rearing reactions (standing on hind legs) increased
during the first hour of exposure, but this phase was followed by a depression
and the rats were unable to stand or walk. Excitability increased again after
exposure. At 2000 ppm, only increased excitability was observed. At 1000 ppm,
excitability was not increased significantly. Myoclonic seizures were seen in
both 2000 and 4000 ppm treated groups, with greater frequency at the higher
concentration.
Convulsion threshold after intraperitoneal injection of Bemegride was
decreased significantly by preexposure to 2000 ppm toluene for 8 hours/day in
6 Sprague-Dawley male rats. The change was noted after one week of exposure.
The convulsion threshold continued to decrease for six weeks of exposure. After
eight weeks of exposure, the difference from the controls was not significant,
although the convulsion threshold remained lower. The data suggest that toluene
renders the CNS more susceptible to induction of a convulsion state. Body
12-42
-------
weights of these rats were lower than those of controls during the exposure
period, although differences were not significant (Takeuchi and Suzuki, 1975).
12.3.M. Effect on Neuromodulators. Andersson et al. (1980) reported an increase
of dopamine and noradrenaline in the median eminence after inhalation of 500 ppm
and 1000 ppm toluene, respectively, by male rats. The higher levels also pro-
duced increases of noradrenaline turnover within the median eminence and the
anterior periventr'icular and paraventricular hypothalamic nuclei. A significant
increase of plasma levels of follicle-stimulating hormone (FSH) and a non-
significant elevation of prolactin and corticosterone were also noted.
12.3*5. Minimal Effect Levels. Although most studies, acute as well as chronic,
indicate minor effects of toluene at concentrations under 1000 ppm and most
reviews (NRC, 1980; EPA, 1980; NIOSH, 1973) have emphasized the negligible
effects on the CNS at this level, several recent studies indicate that lower
level exposures may not be innocuous. Horiguchi and Inoue (1977) found a decre-
ment in performance during a simple task; Gusev (1967) found lengthened motor
nerve chronaxies at 1 ppm, Colotla and Bautista (1979) noted a decrement in
operant behavior at concentrations of 571 ppm; and Anderson et al. (1980)
reported histochemical changes in the brain at 500 ppm. In all of these studies,
sensitive parameters of CNS activity were measured. Higher concentrations
tended to affect more complex tasks. Furthermore, the studies of Andersson
et al. (1980) indicate that 500 ppm affects an area of the brain which regulates
many vegetative, as well as reproductive, functions. These findings indicate
that effects of toluene on the CNS at levels below 1000 ppm cannot be totally
ignored.
12-13
-------
12.4. EFFECTS ON OTHER ORGANS
12.4.1. Blood-Forming Organs. Myelotoxicity is an effect that has been attri-
buted to toluene. Prior to the early 1940*3 it was believed that toluene had the
same effect as benzene; however, in most of the earlier studies toluene was
contaminated with benzene. Since then, there have been studies indicating a lack
of myelotoxicity and several which indicate a positive effect (Table 12-7).
One of the first studies using toluene free of benzene which demonstrated
that it had no injurious effect on blood-forming organs was that of von Oettingen
et al. (1942b) in rats and dogs. Exposure of rats to 200 to 5000 ppm toluene
contaminated with less than 0.01} benzene for 5 to 6 weeks (7 hours/day, 5 days/
week) did not affect blood-forming organs, as indicated by the absence of anemia
and changes in the bone marrow and spleen. Exposure to the higher concentrations
of 2500 and 5000 ppm did produce a daily temporary shift in the blood picture,
characterized by a decrease of lymphocytes and total white blood count with a
moderate increase of segmented cells (Table 12-8). Exposure of dogs to inhala-
tion of 400 ppm toluene on 5 consecutive days for 7 hours daily produced no
appreciable changes in the blood picture, with the exception of a temporary
lymphocytosis at the end of exposure (von Oettingen et al., 1942b). Exposure of
dogs to inhalation of higher concentrations of toluene containing less than 0.12
benzene (7.5 mg/i for 8 hours daily, 6 days weekly during 4 months and then
10 mg/S, for the 2 remaining months) had no effect on the bone marrow (Fabre
et al., 1955).
Male Wistar rats administered a daily subcutaneous dose of 1.0 cc/kg body
weight for 14 days had a normal leucocyte count, thymus and spleen weight,
femoral marrow nucleated cell count, and femoral marrow nucleic acid content
(Gerarde, 1956).
12-44
-------
TABLE 12-7
Myeloto icity Effects of Toluene
Species
Route
Dose
Effect
Reference
Rats
n=20/group
Inhalation
Rats n=15
Guinea pigs
n=15
Dogs n=15
Monkeys n=3
Rats n=90
male + female
Inhalation
Inhalation
Rats
Dogs
Inhalation
200, 600, 2500,
5000 ppm 7 h/d x 5 d
x 5 to 6 wk
107 ppm continuous
exposure for 90 d
or 1085 ppm 8 h/d,
5 d/wk, for 6 wk
30, 100, 300 ppm
6 h/d x 5 d/wk x 24 mo
240, 480, 980 ppm
6 h/d x 5 d/wk
x 65 d
At highest doses: a
temporary decrease of
lymphocytes and total
white blood cell count;
no anemia; no effect on
bone marrow or spleen
No significant change in
leukocyte count, hemo-
globin, or hematocrit
No effect on any hemato-
logical parameter except
2 parameters in females:
at 100 or 300 ppm hemato-
crit was reduced, at
300 ppm mean corpuscular
hemoglobin concentration
was higher; no histo-
pathology on any organ
including spleen and bone
marrow
No effect on red blood
cell count, white blood
cell count, hematocrit,
hemoglobin, total and
differential white count,
SAP, SGPT, SCOT, or BUN;
no effect on bone marrow.
Von Oettingen et al., 1942b
Jenkins et al., 1970
CUT, 1980
Carpenter et al., 1976b
-------
TABLE 12-7 (cont.)
Species
Route
Dose
Effect
Reference
to
Dogs
Dogs
Rats
Rats
Mice
Inhalation
Inhalation
Subcutaneous
Oral
Inhalation
Donryu strain Inhalation
rats n=6/group
100 ppm 7 h/d x 5 d
7.5 mg/4, 8 h/d x
6 d/wk x 1 mo, and
then 10 mg/8,, 8 h/d
x 6 d/wk x 2 mo
1 cc/kg body weight
x 14 d
118, 351, 590 mg/kg/d
x 138 d
1, 10, 100, 1000 ppm
6 h/d x 20 d
200, 1000, 2000 ppm
99.9H pure toluene
8 h/day for 32 wks
No change in blood picture;
temporary lymphocytosis
No effect on bone marrow
Normal leukocyte count,
spleen, and bone marrow
Normal bone marrow,
spleen, bone marrow
counts, blood count
Leukocytosis at all dose
levels; 100, 1000 ppm:
depressed red cell count;
10 to 1000 ppm: decreased
thrombocyte count;
1000 ppm: trend toward
hypoplasia in bone marrow
Significant retarded weight
gain at 2 higher doses during
initial 1 wks; no significant
difference in hemoglobin
hematocrit and total plasma
protein; no significant in-
crease of RBC; significant
increase of leucocytes at
highest dose at first week
of exposure followed by
recovery; eosinophile counts
decreased rapidly in the
first 2 to 1 weeks and then
recovered; increase of
Mommsen's toxic granules.
Von Oettingen et al.,, l:9.t.2b;
Fabre et al., 1955
Gerarde, 1960
Wolf et al., 1956
Horiguohi and Inoue, 1977
Takeuchi, 1969
-------
TABLE 12-7 (cont.)
Species
Route
Dose
Effect
Reference
Rat
Rat
Rat
Inhalation
Subcutaneous
Dermal
120 mg/m3
1 h/d x 1
mo
1 g/kg/d x 12 d
10 g/kg body weight/d
Leukocytosis and chromo-
some damage in bone marrow
11.5$ chromosome damaged
cells vs. 3.9$ in controls
Impaired leukopoiesis
Dpbrokhotov and
Enikeev, 1977
(cited in EPA, 1980)
Lyaphalo, 1973
Yushkevich and Malysheva,
1975
to
i
n = number; h = hour; d = day; wk = week; mo = month; SAP = serum alkaline phosphatase;
SGPT = serum glutamic pyruvic transaminase; SCOT = serum glutamic oxalacetic transaminase; BUN = blood urea
nitrogen.
-------
TABLE 12-4
Weekly 31ood Picture of Normal Rats and Rats Exposed So 600 and
2500 ppm of Toluene 7 Hours/Day, 5 Days/Week, for 5 Weeks
NORMAL
Weeks
Preexpoaure period:
First
Exposure period:
First
Second
Third
Fourth
Fifth
2 Weeks After
Exposure
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Wolf et al. (1956) could find no effect on femoral bone marrow, spleen, bone
marrow counts, or hematological parameters in female Wistar rats orally dosed
with concentrations of 94.4J pure toluene up to 590 mg/kg/day for 24 weeks.
Exposure of Fischer 344 rats for 24 months (6 hours/day, 5 days/week) to 30,
100, or 300 ppm 99.98$ pure toluene did not have any hematological effects (see
Table 12-3). There were no changes in the bone marrow or spleen (CUT, 1980).
Speck and Moeschlin (1968) noted that subcutaneous injection of 300 or
700 mg/kg pure toluene administered daily to rabbits for 6 and 9 weeks,
respectively, had no myelotoxic effects. There were no changes in DNA-synthesis
of bone marrow cells as measured by incorporation of H-methylthyraidine or in
peripheral blood elements (leucocytes, thrombocytes, reticulocytes, or erythro-
cytes).
In a study made by Braier (1973), subcutaneous injection of 862 mg/kg body
weight daily for 6 days produced a moderate depression of granulocytes during the
first 2 days of treatment. This was followed by a sharp rise in granulocytes by
the end of 6 days, a rise which was twice that of the pretreatment level. No
significant change was noted in the bone marrow. In contrast, subcutaneous
injection of benzene at the same dosage elicited a progressive decrease in
granulocyte count throughout the period of treatment.
CO
The effects of toluene and benzene on the incorporation of "^Fe in erythro-
cytes were studied by Andrews et al. (1977). While benzene inhibited the incor-
poration of "Fe, toluene did not.
The studies suggesting a myelotoxic effect include Horiguchi and Inoue
(1977) who exposed groups of 6 male mice to toluene vapor at concentrations of 1,
10, 100, and 1000 ppm for 6 hours daily over a period of 20 days and found that
•the 2 highest doses decreased red cell count. Concentrations of 10 ppm and above
decreased thrombocyte count. All groups showed an increase in white cell count
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midway in the study, followed by recovery except in the 100 ppm group. Slight
hypoplasia of the bone marrow was noted at the highest dose.
Takeuchi (1969) observed a transient increase in leucocytes in 6 Donryu
strain rats exposed to 2000 ppm 99.9% pure toluene containing less than 0.2 ppm
benzene in the course of 8 hour daily exposures for 32 weeks, as well as a
transient decrease of eosinophile counts upon exposure to 200, 1000, or 2000 ppm
toluene under the same regimen (see Table 12-7). After 32 weeks of toluene
exposure, all groups including an unexposed control group were subjected to 39 3
hour daily exposures to benzene prior to histopathological examination after
sacrifice. The adrenal weight to body weight ratio was depressed significantly
in all groups which had been exposed to toluene. Histologically, the zona
glomerulosa of the adrenal cortex of toluene-exposed rats was thicker, while the
zona fasciculata and zona reticularis were reduced. The authors suggested that
toluene affected the hypothalamo-pituitary-adrenal system. While that
hypothesis is tenable, since the rats exposed to toluene differed from unexposed
controls, all groups exposed and unexposed to toluene were also exposed to
benzene, therefore, this conclusion can only be regarded as tentative. : An
abstract of a later paper (Takeuchi et al., 1972), which was not available for
review, noted that exposure of male rats to toluene for 8 hours daily for 4 weeks
increased adrenal weight and eosinophil counts and decreased corticosteroid
concentration after 1 week.
Topical application of 10 g/kg toluene to rats 4 hours daily for 4 months
had no effect on maturation of erythroblasts in the bone marrow, but an increase
of plasmic and lymphoid reticular cells in the marrow indicated an impairment of
leucopoiesis. A lower dosage of one g/kg toluene daily had no effect (Yushkevich
and Malysheva, 1975).
Leucocytosis and chromosomal damage in the bone marrow (Section 14.2.3.3.)
was noted in rats that had been exposed via inhalation to 112 ppm of toluene,
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4 hours daily, for 4 months (Section 14.2.4.1.). Recovery from leucocytosis
occurred one month after termination of exposure, but the chromosomal damage was
unchanged. On the other hand, inhalation of a combination of toluene and benzene
produced chromosomal aberrations, which were approximately equal to the sum of
aberrations induced by single administration of the solvents. Whereas benzene
caused leukocytopenia, the mixture caused leukocytosis (Dobrokhotov and Enikeev,
1975).
In the studies of Matsumoto et al., (1971) exposure of Donryu male rats to
inhalation of 2000 ppm toluene vapor 8 hours/day, 6 days/week for 43 weeks
decreased the ratios of thymus weight to body weight and spleen weight to body
weight.
Although the evidence tends to weigh more heavily toward the absence of a
myelotoxic effect from toluene exposure in animals, the suggestion made in NRC
(1980) that the positive findings may indicate subtle unrecognized hematopoietic
responses is sound. For example, the effect of toluene on hematocrit and mean
corpuscular hemoglobin concentration in female Fischer rats and not in male rats
is of interest in view of the observation of Hirokawa (1955), where there appears
to be a higher susceptibility of the female rabbit to benzene. In that study,
the pattern of decrease of erythrocytes, hemoglobin content, white blood cells,
increase of mean corpuscular volume, and decrease of mean corpuscular hemoglobin
concentration in the female was simulated in the estradiol propionate treated
orchidectomized male.
There was no increase of erythrocyte fragility seen in 6 rats that inhaled
20,000 ppm "toluene concentrate" for 45 minutes (Carpenter et al., 1976b). A
slight increase in coagulation time was noted in rabbit blood by Fabre et al.
(1955) and in rats by von Oettigen et al. (1942b).
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12.4.2. Cardiovascular Effects. Several animal studies have shown that massive
doses cause a number of electrocardiographic changes. In addition, a sensitiza-
tion of the heart to low oxygen levels was observed.
Inhalation of glue fumes containing toluene for 1 minute significantly
slowed sinoatrial heart rate of 8 ICR mice and slightly lengthened the P-R
interval. Subjecting the animals to 5 minutes of asphyxia after inhalation of
the glue fumes produced a 2:1 atrioventricular block in all animals within an
average of 42 seconds of asphyxia. In contrast, after 24 5 minute periods of
asphyxia, the sinoatrial heart rate rose, the P-R internal did not lengthen, and
atrioventicular (AV) block did not occur in 12 mice (Taylor and Harris, 1970).
In acute inhalation of toluene, atrial fibrillation, bradiarrhythmia, and
asystole, along with respiratory paralysis occurred. Injection subcutaneously
of 2 doses of 0.1 mil/100 g body weight daily for 6 weeks elicited repolarization
disorders, atrial fibrillation, and in some of the rats, ventricular extra-
systoles (Moravai et al., 1976).
Intravenous injection of 0.01 mgm/kgm epinephrine into dogs following
inhalation of toluene vapors elicited ventricular fibrillation (Chenoweth,
1946). This observation is of interest, because the "sudden death" syndrome
following "glue sniffing" in humans might possibly be explained by an increased
.secretion of epinephrine which could cause fibrillation of the heart as a result
of the combined effect of the two compounds.
Intravenous injection of 0.05 mg/100 g body weight of toluene into rats
reduced arterial blood pressure; however, injection of the same dosage by the
intraperitoneal or subcutaneous route had no effect on blood pressure (Moravai
et al., 1976). No effect on blood pressure was seen in the chronic inhalation
studies of von Oettingen et al. (1942b), where dogs were exposed to inhalation of
200 to 600 ppm toluene several times weekly for several months. In this study,
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there was no, effect observed on blood pressure, heart rate, venous pressure,
spinal pressure, respiratory rate, minute volume, or respiratory volume.
12.M.3- Gonadal Effects. Matsumoto et al. (1971) found that exposure of Donyru
strain male rats to inhalation of 100 or 200 ppm toluene vapor 8 hours/day,
6 days/week for 1 year produced, no change in erythrocyte and leucocyte counts,
and no change in serum total protein or cholinesterase activity. However, at the
higher dose, degeneration of germinal cells of the testes was found in U of 12
animals while normal germinal epithelium was found in controls. Testicular
weight was lower than controls at both dose levels. There was a trend toward a
decrease of testicular to body weight ratio.
12.5. SUMMARY
The most pronounced effect of toluene in animal studies is on the CNS.
Acute exposure to high levels of toluene has been linked with depression of the
CNS. A level of approximately 1000 ppm toluene vapor appears to have little or
no effect on gross observations of this parameter. While a dose related response
of instability, incoordination and mild narcosis was observed in rats exposed
daily to toluene vapor at concentrations of 1250 and 1600 ppm, no effect was
noted at 1100 ppm (Batchelor, T927). Inhalation of 1000 ppm toluene vapor for
M hours did not increase rearing reactions (standing on hind legs) in rats
(Takeuchi and Hisanaga, 1977). Operant behavior (conditioned avoidance
response) was unaffected at 1000 ppm of vapor in the studies of Shigeta et al.
(1978) and at 800 ppm in the studies of Krivanck and Mullin (1978). Inhalation
of 1000 ppm for 6 hours/day, 5 days/week for 13 weeks did not produce observable
behavioral effects in rats in the pilot study for the chronic CUT report (CUT,
1980). Smyth and Smyth (1928) noted that daily inhalation of 1250 ppm for
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4 hours each day for 18 days produced narcosis in guinea pigs, while no effect
was noted at 1000 ppm during a longer period of exposure. Fabre et al. (1955)
noted that exposure to 2000 ppm toluene for 8 hours daily, 6 days weekly, for
4 months produced only slight nasal and ocular irritation after a transient
initial hyperactivity in one of two dogs. No behavioral effects were found in
. ?•.
rats and dogs after inhalation of 980 ppm "toluene concentrate" (150 ppm
toluene) for 6 hours daily for 13 weeks.
However, use of more sensitive methods of detection have revealed an effect
in simple behavioral parameters and the CNS at lower levels. EEC changes were
seen in rats after inhalation of 1000 ppm (Fodor et al., 1973; Takeuchi and
Hisanaga, 1977). A deficit was noted in unconditioned reflexes and simple
behavior at 800 ppm for 4 hours in rats (Krivanek and Mullin, 1978), in multiple
response schedule at 574 ppm in rats (Colotla and Bautista, 1979), and in wheel*
turning in rats at 1 ppm (Horiguchi and Inoue, 1977). Neuromodulator 'content in
the hypothalamus was affected at 500 ppm (Anderson et al., 1980).
Early studies suggested a myelotoxic effect by toluene. However, several
studies done since the early 1940's using toluene of greater purity have indi-
cated an absence of injurious effect on blood-forming organs by toluene in rats
and dogs (von Oettingen et al., 1942; Gerarde, 1959; Wolfe et al.; 1956; Fabre
et al., 1955; Jenkins et al., 1970; Carpenter et al., 1976b; CUT, 1980). None-
theless, there is no unanimity on this point. Leukocytosis, impaired leukopoie-
sis, and chromosomal damage in the bone marrow have been observed in some studies
(Horiguchi and Inoue, 1977; Dobrokhotov and Enikiev, 1977; Lyapkalo, 1973;
Yushkevich and Malysheva, 1975).
Inhalation of concentrations up to 1085 ppm toluene for 6 weeks or 300 ppm
for 24 months, and ingestion of 590 mg toluene/kg body weight for 6 months pro-
duced no liver, damage (Svirbely et al., 1944; Carpenter et al., 1976b; Jenkins
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et al., 1970; CUT, 1980; Wolf et al.f 1956). Exceptions were the studies of
von Oettingeri et al. (1942b), where inhalation of 600 ppm toluene caused
increases of weight and volume in the liver of rats; the studies of Fabre et al.
(1955) in dogs where hemorrhagic livers were found; and Ungvary et al. (1976),
where 0.05 or 0.1 mi/100 g toluene injected intraperitoneally produced histo-
logical changes in the liver.
However, in a more recent study by Ungvary et al. (1980), male CFY rats were
exposed to daily inhalation of 265 ppm or 929 ppm analytical grade toluene and
female rats were exposed to lower doses only five times a week up to 6 months. No
abnormal histological changes were found in the liver, although growth was inhi-
bited at the higher concentration in males and at the lower dose in females.
Subchronic exposure to inhalation of toluene had no specific hepatoxic effect,
although signs of adaptive compensation were observed.
Renal changes consisting of casts in collecting tubules of rats were
observed in the studies of von Oettingen et al. (1942b) after exposure to inhala-
tion of 600 ppm. Hyperemic renal glomeruli and albuminuria were seen in 2 dogs
after inhalation of toluene vapors at concentrations of 2000 ppm followed by
2660 ppm for 4 and 2 months, respectively (Fabre et al., 1955). Slight renal
degeneration was observed in guinea pigs (Smyth and Smyth, 1928; Sessa, 1948).
No renal damage was found after repeated inhalation of 1085 ppm toluene for
6 weeks in rats, guinea pigs, dogs, or monkeys, up to 300 ppm for 24 months in
rats or ingestion of 590 mg toluene/kg body weight for 6 months in rats (Jenkins
V)
et al., 1970; CUT, 1980; Wolf et al., 1956).
Irritative effects were noted in the respiratory tract in dogs, guinea pigs,
and rats (Browning, 1965; Gerarde, 1960; Fabre et al., 1955; von Oettingen
et al., 1942b; Smyth and Smyth, 1928; Sessa, 1948). Sensitization of the heart
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after inhalation of toluene was observed in mice, rats, and dogs (Taylor and
Harris, 1970;'Morvai et al., 1976; Chenoweth, 1946).
The acute oral toxicity (LD5Q) of toluene is in the range of 6.0 to 7.5 g/kg
in rats (Kimura et al., 1971; Smyth et al., 1976b; Withey and Hall, 1975; Wolf
et al., 1956). Exposure to toluene by the dermal route revealed an LD,-Q of
14.1 ing/kg in the rabbit (Smyth et al., 1969). Slight to moderate irritation of
the rabbit and guinea pig skin was observed after acute and subacute application
of toluene (Kronevi et al., 1979; Wolf et al., 1956), while application to the
rabbit cornea caused slight to moderate irritation (Wolf et al., 1956; Smyth
et al., 1969; Carpenter and Smyth, 1946).
The LC5Q for mice is in the range of 5500 to 7000 ppm of vapor for an
exposure period of 6 to 7 hours (Svirbely et al., 1943; Bonnet et al., 1979). An
LCcQ.of 8800 ppm of "toluene concentrate" for 4 hours (4,038 ppm toluene) was
observed in rats (Carpenter et al., 1976b). In guinea pigs, exposure to inhala-
tion of 4000 ppm for 4 hours caused death in 2 of 3 animals (Smyth and Smyth,
1928).
Subchronic treatment of rats (von Oettingen et al., 19425) and rats, guinea
pigs, dogs, and monkeys (Jenkins et al., 1970; Smyth and Smyth, 1928) reveal that
inhalation of 200 and 1085 ppm, respectively, do not have a deleterious effect on
hematology and organ pathology, with the exception of the study of Horiguchi and
Inoue (1977) in mice which showed changes in blood elements at levels as low as
10 ppm. Toluene levels of 590 mg/kg/day administered orally for 6 months were
tolerated by rats with no adverse effects (Wolf et al., 1956).
The only chronic study was the study performed for CUT (1980) in rats
exposed for 24 months to inhalation of toluene at levels up to 300 ppm. No
effect on hematology, clinical chemistry, body weight or histopathology was
noted except for two hematologic parameters in females. Females exposed to 100
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or 300 ppm showed reduced hematocrit levels and mean corpuscular hemoglobin
concentration was increased at 300 ppm concentration of toluene.
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