United Slates .
EnviionmenMl PioU'ciioij
Ayenr.y
Office of Hi.-alih •ind
Environmental Assassin en I
Wasluniiion DC ^0460
EPA 600 8-82-008I-"
August 1983
Final Report
FINAL
RliPORT
PB84-100056
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NOTICl:
This document has been reviewed in ncconiuiK c wi.;h
U.S.. Lnv i ronme.ntai I'rot.cction Agency polic;,' ;iniJ
approvi'J i'or publication. '-lent i <>n of t r;nK: runncs
or commercial products Jui'S not riHiSt i. tut '-• en Ju r ••;(_•-
nont or- recoiniiieiiuia t. ion for'use.
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EPA-600/8-82-008F
August 1983
Pinal Report
Document for Toluene
FINAL
RLTORT
US ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Office of Health .-ind Environmental Assessment
Environmental Criteria and Assessment Office
Research Tnangie Park. NC 27711
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PREFACE
This document has been prepared by the Environmental Criteria and Assess-
ment OfTice of the U.S. Environmental Protection Agency (EPA). The document was
originally developed to support U.S. EPA decision-making regarding possible
regulation of toluene as a hazardous air pollutant. The scope of the document
has since been expanded to address multimedia aspects and thus enables the
document to serve as a "source document" for other U.S. EPA programs requiring
comprehensive information concerning the health effects of toluene.
The Health Assessment Document for Toluene was reviewed and critiqued by the
Environmental Health Committee of the U.S. EPA Science Advisory Board in August
1982. This committee provides advice on scientific matters to the Administrator
of the U.S. Environmental Protection Agency.
In the development of the assessment document, the scientific literature
has been critically evaluated and the conclusions presented in such a manner that
the toxicity of toluene and related characteristics are qualitatively identi-
fied. Observed effect levels and ether measures of dose-response relationships
are discussed, where appropriate, in order that the nature of the adverse health
responses are placed in perspective with observed environmental levels.
ii
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ABSTRACT
Toluene is the most prevalent hydrocarbon in the atmosphere. Levels
generally range from 0.11-57 ppb. Levels in water generally are below 10 ppb.
Gasoline usage and automobile exhaust represent the largest atmospheric source.
Ov4r 3 million metric tons of toluene are produced annually in the United States.
^"ailable evidence associated with effects upon humans and experimental
animals indicates that the health effect of primary concern is dysfunction of the
central nervous system (CNS). However, observed effects are associated with
exposure levels greatly in excess of those levels in the environment. Dysfunc-
tion of the CNS may occur during short-term (£8 hours) exposure tn 100-300 ppm.
Toluene has not demonstrated any overt signs of kidney or liver damage upon
animal experimentation. It was non-carcinogenic in rats exposed to 300 ppm for
24 months. However, the full extent of toluene's carcinogenic potential is
currently being evaluated, at higher exposure levels, in a lifetime bioassay of
rodents in the National Toxicology Program. Toluene is classified as
provisionally non-mutagenic, and its teratogenic potential has not been fully
explored.
The results of the available evidence indicate that exposure to environ-
mental levels of toluene is unlikely to constitute a significant hazard to the
general population.
ill
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TABLE OF CONTENTS
LIST OF TABLES xi
LIST OF FIGURES xv
AUTHORS, CONTRIBUTORS, AND REVIEWERS xvi
SCIENCE-ADVISORY BOARD ENVIRONMENTAL HEALTH COMMITTEE xix
1. EXECUTIVE SUMMARY 1-1
1.1. ENVIRONMENTAL SOURCES, FATE, AND LEVELS 1-1
1.2. EFFECTS ON HUMANS ' 1-3
1.3. ANIMAL STUDIES 1-5
1.4. ABsohPTioN, iJi.-yr.-uBijTiON, METABOLISM, ELIMINATION,
AND RELATED PHAiiMACOKI.NETICS 1-6
1.5. CARCINOGENICITY, MUTAGENICITY, AND TERATOGENIC1TY 1-6
1.6. EFFECTS ON ECOSYSTEMS 1-7
1.7. HEALTH EFFECTS SUMMARY 1-8
1.8. RESEARCH NEEDS 1-9
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 F'R&PFRTIES 3-1
3.4.1. Description 3-1
3.4.1*. Other Physical Properties 3-1
3-^.3- Sigr.if icance of Physical Properties with
Rucpect to Environmental Behavior 3-2
.3.5. CHEMICAL HhOPEff] ii,S 3-3
3.6. REFERENCES 3-5
14, PRODUCTION', USE, AND RELEASES TO THE ENVIRONMENT i)-i
4.1. MANIiTACTChlNG PRDCEHS TECHNOLOGY 4-1.
U. 1. I. y^tfoleum Refining Processes '(-1
A. I, 1.1. CATALYTIC REFORMING 4-1
H.i.1.2. PYHOLYTIC CRACKING 4-1
4.1.2. By-Product of Styrene Production 4-3
4.1.J}. By-Product of Coke-Oven Operation 4-3
4.2. PROD'jCEK." 4-3
4.3. USERS 4-10
4.4. ENVIRONMENTAL RELEASE 4-13
iv
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TABLE OF CONTENTS (cont.)
I.U.I. Emission from Production Sources 4-13
4.4.2. Emission from Toluene Usage 4-18
4.4.3. Emission from Inadvertent Sources 4-23
4.4.4, Non-anthropogenic Sources 4-23
4.4.5. Sum of Emissions from All Sources 4-26
4.5. USE OF TOLUENE IN CONSUMER PRODUCTS 4-25
4.6. REFERENCES 4-29
5. ABATEMENT PRACTICES IN INDUSTRY 5-1
5.1. ABATEMENT PRACTICES FOR INADVERTENT SOURCES 5-1
5.2. ABATEMENT PRACTICES FOR SOLVENT USAGE 5-2
5.3. ABATEMENT FOR COKE OVEN EMISSIONS 5-2
5.4. ABATEMENT FOR EMISSIONS FROM MANUFACTURING SITES 5-2
5.5. ABATEMENT PRACTICES FOR RAW AND FINISHED WATERS 5-3
5.6. ECONOMIC BENEFITS OF CONTROLLING TOLUENE EMISSIONS 5-3
5.7- REFERENCES 5-3
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
6.2. AQUATIC MEDIA 6-5
6.2.1. Fate 6-5
6.2.2. Transport 6-6
6.3. SOIL 6-7
6.3.1. Fate 6-7
6.3.2. Transport 6-6
6.3-2.1. SOIL TO AIR 6-8
6.4. ENVIRONMENTAL PERSISTENCE 6-8
6.4.1. Biodegradation and Biotransformation 6-8
6.4.1.1. MIXED CULTURES 6-8
6.4.1.2. PURE CULTURES 6-10
6.5. REFERENCES 6-13
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TABLE OF CONTENTS (cont.)
Page
7. ENVIRONMENTAL AND OCCUPATIONAL CONCENTRATIONS 7-1
7.1. ENVIRONMENTAL LEVELS 7-1
7.1.1. Air 7-1
7.1.2. Aqueous Media 7-9
7-1.2.1. SURFACE WATERS 7-9
7-1.2.2. INDUSTRIAL WASTEWATERS 7-11
7. 1.2.3. PUBLICLY-OWED TREATMENT WORKS (POTW) 7-11
7.1.2.1. UNDERGROUND WATER 7-11
7.1-2.5. DRINKING WATER 7-11
7.1.2.6. RAINWATER 7-15
7.1.3- Sediment 7-15
7.1.1. Edible Aquatic Organisms 7-15
7.1.5. Solia Wastes and Leachates 7-15
7.2. OCCUPATIONAL CONCENTRATIONS 7-15
7.3. CIGARETTE SMOKE 7-20
7.1. REFERENCES 7-20
8. ANALYTICAL METHODOLOGY . 8-1
8.1. AIR 8-1
8.1.1. Ambient Air 8-1
8.1.1.1. SAMPLING 8-1
8.1.1.2. ANALYSIS 8-2
8.1.1.3. PREFERRED METHOD 8-3
8.1.1.1. DETECTION LIMITS 8-1
8.1.2. Occupational Air 8-1
6.1.2.1. SAMPLING 8-1
8.1.2.2. ANALYSIS 8-5
8.1.2.3. PREFERRED METHOD 8-6
8.1.2.1. DETECTION LIMIT 6-7
8.1.3. Forensic Air 8-7
8.1.1. Gaseous Products from Pyrolysis of Organic Wastes 8-7
8.2. WATER 8-7
8.2.1. Sampling 8-7
8.2.2. Analysis 8-8
8.2.2.1. PURGE AND TRAP 8-8
8.2.2.2. HKADSPACE ANALYSIS 8-9
8.2.2,3. SORPTION ON SOLID SORBENTS 8-10
vi
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TABLE OF CONTENTS (cent.)
Page
8.3. SOILS AND SEDIMENTS , 8-10
8.3.1. Sampling 8-10
8.3.2. Analysis 8-11
8.U. CRUDE OIL AND ORGANIC SOLVENTS 8-11
8.5. BIOLOGICAL SAMPLES 8-12
8.5.1. Blood 8-12
8.5.2. Urine 8-12
8.5.3. Mother's Milk 8-13
8.6. FOODS 8-13
8.7. CIGARETTE SMOKE 8-13
8.8. REFERENCES 8-14
9. EXPOSED POPULATIONS 9-1
9.1. REFERENCES 9-3
10. ESTIMATE OF HUMAN EXPOSURE 10-1
10.1. EXPOSURE VIA INHALATION 10-2
10.2. INGESTION EXPOSURE BASED ON MONITORING DATA 10-9
10.2.1. Exposure from Drinking Water 10-9
10.2.2. Exposure from Edible Aquatic Organisms 10-9
10.3. OCCUPATIONAL EXPOSURE 10-9
10.4. CIGARETTE SMOKERS 10-10
10.5. LIMITATIONS OF EXPOSURE ESTIMATE BASED ON MONITORING DATA 10-10
10.6. COMPARISON BETWEEN EXPOSURE DATA BASED ON THEORETICAL AND
EXPERIMENTAL VALUES 10-11
10.7. REFERENCES 10-12
11. EFFECTS ON HUMANS 11-1
11.1. EFFECTS ON THE NERVOUS SYSTEM 11-1
11.1.1. Central Nervous System 11-1
11.1.1.1. ACUTE EFFECTS 11-1
11.1.1.2. SUBCHHONIC AND CHRONIC EFFECTS 11-9
11.1.2. Peripheral Nervous System 11-16
11.2. EFFECTS ON THE BLOOD AND HEMATOPOIETIC TISSUE 11-22
11.2.1. Bone Marrow 11-22
11.2.2. Blood Coagulation 11-29
11.2.3. Phagocytic Activity of Leukocytes 11-30
11.2.4. Immunocompetencs 11-30
vii
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TABLE OF CONTENTS (cont.)
11.3. EFFECTS ON- THE LIVER 11-30
11.1. EFFECTS ON THE KIDNEYS 11-31
11.5. EFFECTS ON THE HEART 11-38
11.6. EFFECTS ON MENSTRUATION 11-39
11.7. EFFECTS ON THE RESPIRATORY TRACT AND THE EYES 11-10
11.7-1. Effects of Exposure 11-140
11.8. EFFECTS ON THE SKIN 11-12
11.9. SUMMARY 11-12
11.10. REFERENCES 11-16
12. ANIMAL TOXICOLOGY 12-1
12.1. SPECIES SENSITIVITY 12-1
12.1.1. Acute Exposure to Toluene 12-1
12.1.1.1. ACUTE INHALATION 12-1
12.1.1.2. ACUTE ORAL TOXICITY 12-17
12.1.1.3. ACUTE EFFECTS FROM INTRAPERITONEAL
INJECTION 12-17
12.1.1.1. ACUTE EFFECTS FROM SUBCUTANEOUS INACTION 12-18
12.1.1.5. ACUTE EFFECTS FROM INTRAVENOUS INJECTION 12-18
12.1.1.6. ACUTE AND SUBACUTE EFFECTS OF PERCUTANEOUS
APPLICATION 12-13
12.1.2. Subchronic and Chronic Exposure to Toluene 12-18
12.2. EFFECTS ON LIVER, KIDNEY, AND LUNGS 12-22
12.2.1. Liver 12-21
12.2.2. Kidney 12-27
12.2.3- .Lungs 12-27
12.3. BEHAVIORAL TOXICITY AND CENTRAL NEHVOUS SYSTEM EFFECTS 12-28
12.3.1. Effect of Solvent-Sniffing Abuse 12-29
12.3-2. Effects on Simple and Complex Behavioral Performance 12-32
12.3.3. Effect on Electrical Activity of the Brain and Sleep 12-38
12.3.1. Effect on Neuromcdulators 12-11
12.3-5. Minimal Effect Levels 12-11
12.1. EFFECTS ON OTHER ORGANS 12-12
12.1.1. Blood-Forming Organs 12-12
12.1.2. Cardiovascular Effects 12-16
12.1.3. Gonadal Effects 12-16
12.5. SUMMARY 12-1?
12.6. REFERENCES 12-50
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TAELE OF CONTENTS (cont.)
Page
13. PHARMACOKINETIC CONSIDERATIONS IN HUMANS AND IN ANIMALS 13-1
13-1. ROUTES OF EXPOSURE AND ABSORPTION 13-1
13.2. DISTRIBUTION 13-9
13-3. METABOLISM 13-14
13.4. EXCRETION 13-19
13.5. SUMMARY 13-28
13.6. REFERENCES 13-30
14. CARCINOOENICITY, MUTAGENICITY, AND TERATOGENICITY 14-1
14.1. CARCINOGENICITY 14-1
14.2. MUTAGENICITY 14-2
14.2.1. Growth Inhibition Tests in Bacteria 14-2
14.2.2. Tests for Gene Mutatjons 14-4
14.2.2.1. ASSAYS USING BACTERIA AND YEAST 14-4
14.2.2.2, TK MUTATION IN L5178Y MOUSE
LYMPHOMA CELLS 14-6
14.2.3. Tests for Chromosomal Mutations 14-6
14.2,3.1. MICRONUCLEUS TEST IN MICE 14-6
14.2.3-2. MOUSE DOMINANT LETHAL ASSAY 14-6
14.2.3-3. CHROMOSOME ABERRATION STUDIES 14-7
14.2.3-4. SISTER CHROMATID EXCHANGE 14-14
14.3. TERATOGENICITY 14-16
14.3.1. Animal Studies 14-16
14.4. SUMMARY 14-25
14.5. REFERENCES 14-26
15. SYNERGISMS AND ANTAGONISMS AT THE PHYSIOLOGICAL LEVEL 15-1
15.1. BENZENE AND TOLUENE 15-1
15.2. XYLENES AND TOLUENE 15-2
15.3. TOLUENE AND OTHER SOLVENTS 15-3
15.4. REFERENCES 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
16.1.2.1. ALGAE 16-1
16.1.2.1.1. Closed System Studies 16-1
16.1.2.2.2. Open Studies 16-4
ix
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I
TABLE OF CONTENTS (cont.)
Page
16.1.2.2. EFFECTS ON HIGHER PLANTS 16-4
16.2. BIOCONCENTRATION, BIOACCUMULATION, AND BIOMAGNIFICATION
POTENTIAL 16-7
16.3. EFFECTS ON MICROORGANISMS 16-14
16.4. REFERENCES 16-17
17. EFFECTS ON AQUATIC SPECIES 17-1
17-1. GUIDELINES FOR EVALUATION 17-1
17.2. EFFECTS OF ACCIDENTAL SPILLS 17-2
17.3- LABORATORY STUDIES OF TOXICITY 17-3
17.3.1. Lethal Effects 17-3
17.3.1.1. FRESHWATER FISH 17-3
17.3.1.2. MARINE FISH 17-13
17.3-1-3. FRESHWATER INVERTEBRATES 17-15
17.3-1.4. MARINE INVERTEBRATES 17-15
17.3.2. Sublethal Effects 17-18
17.3-2.1. FISH 17-18
17.3.2.2. INVERTEBRATES 17-22
17.4. REFERENCES 17-25
18. HEALTH EFFECTS SUMMARY 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 18-2
18.2. INHALATION EXPOSURES 18-3
18.2.1. Effects of Single Exposures 18-3
18.2.2. Effects of Intermittent Exposures Over
Prolonged Periods 18-6
18.3. ORAL EXPOSURES 18-9
18.4. DERMAL EXPOSURES 18-9
18.5- RESPONSES OF SPECIAL CONCERN 18-10
18.5.1. Carcinogenicity 18-10
18.5.2. Mutagenicity 18-10
18.5.3. Teratogenicity 18-11
18.6. REFERENCES 18-13
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LIST OF TABLES
Number Page
4^1 U.S. Production of Isolated Toluene in 1978 4-2
4-2 Isolated and 'cion-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
4-5 Producers of Isolated Toluene from Styrene By-Product 4-9
4-6 Producers of Isolated Toluene from Coke-Oven Crude
Light Oils ^-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- '.3
4-9 Producers of Toluene Diisocyanat.e (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 Tc*-al Yearly Release of Toluene into Different Media 4-29
4-20 Consumer Product Formulations Containing Toluene 4.31
xi
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LIST OF TABLES (cont.)
Number
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
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 Plr\nts 7-19
9-1 Population Distribution and Inhalation Exposure Levels
of Toluene from Different: Sources 9-2
10-1 Concentration of Toluene (mg/nr) at Different
Distances (m) From A Sources Emitting 200 Million
kg/Year Toluene 10-5
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 11-6
11-3 Mean Concentrations of Organic Solvents in the Breathing
Zone of 40 Car Painters 11-15
xii
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LIST OF TABLES (cont.)
Number
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 cf Paint Used by Painters 11-29
11-10 Hematologic Examination of 8C9 Rotogravure Workers 11-33
11-11 Renal Function Investigations of Glue Sniffers 11-42
11-12 Toluene Induced Metabolic Acidosis 11-44
11-13 Frequency of Lens Changes and Distribution by Exposure
Time in 69 Age-Matched Pairs of Car Painters and
Railway Engineers 11-50
12-1 Acute Effects of Toluene 12-2
12-2 Subchronic Effects of Toluene 12-7
12-3 24 Month Chronic Exposures 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 Toluene 12-36
12-6 Central Nervous System Effects of Toluene 12-40
12-7 Myelotoxicity Effects of Toluene 12-44
12-8 Weekly Blood Picture of Normal Rats and Rats Exposed to
600 and 2500 pptn of Toluene 7 Hours/Day, 5 Days/Week,
for 5 Weeks 12-47
xiii
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LIST UK TABLES (cent.)
Number
13-1 Uptake of Toluene in Thin and Obese Her. During Exposure
to a Toluene Concentration of 375 rag/m^ (100 ppm) 13-6
13-2-s Partition Coefficients for Toluene at 37'C 13-12
13-3 Toluene Concentration in Workplace Air and Peripheral
Venous Blood of Exposed Workers 13-34
14-1 Epidermal Tumor Yield in 20 Week Two-Stage Experiments 14-4
14-2 Miorobial Mutagenicity Assays 14-6
14-3 Rat Brine Marrow Ceil Aberrations Following Intraperitoneal
Injection of Toluene 14-11
14-4 Frequency of Unstable and Stable Chrososoa« Changes and
Chromosome Counts in Subjects Exposed to Benzene or
' Toluene or Both U-13
14-5 Effect of Occupational Toluene Exposure and Smoking on
Chromosomal Aberrations and Sister Chrotcatid
Exchanges 14-14
14-6 Chromosome Aberrations in Rotoprinting Factory Workers 14-16
14-7 Teratcgenicity Evaluation of Toluene in CFY Rats and
CFL.P Mice , 14-20
14-8 Teratogenic Effects of Exposure to Toluene, Benzene, and
a Combination of Toluenp and Bsrzene in CFY Rats 14-23
14-9 Teratogenioity and Reproductive Performance Evaluation
in Rats Exposed to Toluene 14-25
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 Toiuens to Fish and Aquatic
Invertebrates 17-5
xiv
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LIST OF FIGURES
Number Page
6-1 Proposed Reaction Pathways of Toluene Under
Atmospheric Conditions 6-4
6-2 Microbial Metabolism of Toluene • 6-15
12-1 Toluene Levels in Tissue and Behavioral Performance 12-33
13-1 Metabolism of Toluene in Humans and Animals 13-18
16-1 Phytoplankton Growth in Vrrious Concentrations of Toluene 16-4
16-2 Growth of Chi orella vulgaris in Medium Containing Toluene 16-6
xv
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AUTHORS, CCOTRIBUTORS, AND REVIEWERS
This health assessment document for toluene was prepared -by the Syracuse
Research Corporation under contract with U.S. EPA Environmental Criteria and
Assessment Office (Mark Greenberg, Project Manager).
The following scientific staff members of the Syracuse Research Corporation
(Syracuse, New York) are listed, by chapter, as principal and contributing
authors .
Chapter 1: Executive Summary
Chapter 2: Introduction
Chapter 3: Physical and Chemjcal Properties
Author: Dipak K. Basu
Chapter M: Production, Use, and Releases to the Environment
Author: Dipak K. Basu
Chapte" 5: Abatement Practices in Industry
Author: Dlpak K. Basu
Chapter 6: Environmental Fate, Transport and Persistence
Prinicipal Author: Dipak K. Basu
rer.trit*;tor: Arthur Roser.bcrg
Chapter 7: Environmental and Occupational Concentrations
Author: Dipak K.. Basu
Chapter 8: Analytical Methodology
Author: Dipak K. Basu
Chapter 9: Exposea Populations
Author: Dipak K. Basu
Chapter 10: Estimate of Human Exposure
Author: Dipak K. Basu
Chapter 11: Effects on Humans
Author: Stephen J. Bosch
Chapter 12: Animal Toxicology
.Principal Author: Ethel Ryan
Contributor: Stephen J. Bosch
Chapter 13: Phannacokinetic Considerations in Hucans and In Animals
Author: Joan T. Colman
xv i
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Chapter 1U: Carcinogenic!ty, Mutagenicity, and Teratogenicity
Author: Stephen J. Bosch
Chapter 15: Synergisms and Antagoni3iD3 at the Physiological Level
Author: Ethel Ryan
Chapter 16: Ecosystem Considerations
Author: Knowlton Foote
Chapter 17: Effects on Aquatic Species
Author: Richard H. Sugatt
Chapter 18: Health Effects Summary
Prinicipal Author: Patrick Durkin
Contributor: Stephen J. Bosch
The following individuals reviewed portions of the document during its
preparation and provided valuable comments. Individuals are listed in alpha-
betical order.
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, Office of Program Management and Evaluation, U.S. EPA,
Washington, DC.
Josephine Brecher, Criteria and Standards Division, Office of Water Regulations
and Standards, U.S. EPA, Washington, DC.
George Cushraac, Department of Transportation, Washington, DC.
Arnold Edelman, Office of Toxics Integration, U.S. EPA, Washington, DC.
Dr. Penelope Fenner-Crisp, Criteria and Standards Division, Office of Drinking
Water, U.S. EPA, Washington, DC.
Dr. John Fowle, Reproductive Effects Assessment Group, Office of Health and
Envirotnental Assessment, U.S. EPA, Washinton, DC.
David Friedman, Office of Solid Waste, U.S. EPA, Washington, DC.
Frank Gostoraski, Office of Water Regulations and Standards, U.S. EPA,
Washington, DC.
Alan Jennings, Office of Program Management and Evaluation, U.S. EPA,
Washington, DC.
xvii
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Frank Kirvan, Office of Air Quality Planning and Standards, U.S. EPA, Durham, NC.
Stephen Kroner, Monitoring and Data Support Division, Office of Water Regula-
tions and Standards, U.S. EPA, Washington, DC.
Dr. Donna Kuroda, Reproductive Effects Assessment Group, Office of Health and
Environmental Assessment, U.S. EPA, Washington, DC.
Wanda LeSleu-Biswas, Office of Solid Wast", U.S. EPA, Washington, DC.
Craig McCormack, Office of Toxic Substances, U.S. EPA, Washington, DC.
Dr. Thomas McLaughlin, Exposure Assessment Group, Office of Health and Environ-
mental Assessment, U.S. EPA, Washington, DC.
Audrey McBath, Industrial Enviro;nnental Research Laboratory, Cincinnati, OH.
Dr. Lakshrr,: Misl'jra, Consumer Products Safety Commission, Bethesda, MD.
Dr. Debdas Mukerjee, Enviror/aentai Criteria and Assessment Office, U.S. EPA,
Cincinnati, OH
Dr. Dharm Singh., Carcinogen Assessment Group, Office of Health and Environmental
Assessment, U.S. EPA, Washington, DC.
Michael Slinak, Monitoring and Data Support Division, Office of Water Regula-
tions and Standard.**, U.S. EPA, Washington, DC.
Dr. Douglas L. Smith, National Institute for Occupational Safety and Health,
Cincinnati, OK.
Wade Talbot, Office of Health Research, U.S. EPA, Washington, DC.
xviii
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SCIENCE ADVISORY BOARD
ENVIRONMENTAL HEALTH COMITTEE
The substance of this document was independently peer-reviewed in public
session by the Environmental Health Committee, Environmental Protection
Science Advisory Board.
Chairman ; Environmental Health
Dr. Roger 0. McCleilan, Director of Inhalation Toxicity Research" Institute,
Lovelace Bioraedical and Environmental Research Institute, Albuquerque, New
Mexico 87H5
Acting Director, Scier.ee Adv. sory Board
Dr- Terry F. Yosie, Science Advisory Board, U.S. EPA, Wasnington, DC 20*160
Metspers
Dr- Herman E. Collier, Jr., President, Moravian College, Bethlehem,
Pennsylvania 18018
Dr. Morton Corn, Professor and Director, Division of Environmental Health
Engineering, School of Hygiene and Public Health, The Johns Hopkins Univer-
sity, 615 N. Wolfe Street, Baltimore, Maryland 21205
Dr. John Doull, Professor of Pharmacology arid Toxicology, University of
Kansas Medical Center, Kansas City. Kansas 66207
Dr. Edward F. Ferrand, Assistant Commissioner for Science and Technology,
New York City Department of Environmental Protection, 51 Astor Place, New
York, New York 10003
Dr. Herschel E. Griffin, Associate Director and Professor of Epidemiology,
Graduate School of Public Health, San Diego State University, San Diego,
California 92182
xix
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Dr. Jack D. Hackney, Chief, Environmental Health Laboratories, Professor of
Medicine, Rancho Los Amigos Hospital Campus of the University of Southern
California, 7601 Imperial Highway, Downey, California 902^2
\
Dr. D. Warner North, Principal, Decision Focus, Inc., 5 Palo Alto Square,
Palo Alto, CaJ ifornis
Dr. William J. Schull, Director and Professor of Population Genetics,
Center for Denographic and Population Genetics, School of Public Health,
University of Texas Health Science Center at Houston, Houston, Texas 77030
Dr. Michael J. Syssons, Professor, Department of Bi ostatistics, School of
Public Health, University of North Carolina, Chapel Hill, North Carolina
2771 ',
Dr. Sidney Weinhouse, Professor of Biochemistry, Senior Member, Pels
Research Institute, Temple University School of Medicine, Philadelphia,
Pennsylvania 191 <*0
Consultant
Dr. Bernard Weiss, Division of Toxicology, University of Rochester of
Medicine, Rochester, New York
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1. KXF.CUTIVE SUMMARY
1.1. ENVIRONMENTAL SOURCES, FATE. AND LEVELS '
Toluene, a homolo? of t^en'/ene that contains a single methyl groop, is a
clear, colorless liquid at rcxim temperature. The molecular formula of toluene is
C_H and -the molecular weight i.4 Q2.13. The structural formula is given below.
Other physical properties of toluene include a melting point of -95°C, a
boiling point of 110.6°C, a flash poin", of i4.44°C, a vapor pressure of 28.7 torr
at 25°C, and a density of 0.8669 g/mZ at 20°C. Toluene is slightly soluble ir.
both fresh and salt water (535 mg/2 and 379 mg/S., respectively) at a temperature
of 25°C. The physical properties of toluene 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, psrticularly under atmospheric smog conditions. In
aqueous media under the conditioas of water chlorination, toluene may be chlor-
inated 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 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. In addition to air, toluene has been detected in drinking
water and in the flesh of edible fish. Dermal exposure to toluene occurs
pritaarily in the workplace. The estimated quantities of toluene taken in by the
general public from each source are between a trace and 9** mg/week by inhalation
(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
1-1
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modelingand those obtained from calculations using monitoring data. It should be
noted that the exposure scenario discussed above does not account for inhalation
and dermal exposure to toluene from gasoline during vehicular filling
operations, or frotu. solvents or other toluene-containing consumer products. No
quantitative estimate of either the number of people exposed or the extent of
exposure can be provided for these sources, although consumer usage could
contribute significantly to total exposure.
The total amount of «-.oluene produced in the United States in 19?8 was
3595 million k<3- The majority (96.5?) 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 115 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. Toluene is also used as 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.
The preferred method for the monitoring of toluene in ambient air consists
of sorbent collection, tnermal elution, and GC-FID determination. For a 25 I
sample, the detection limit is <0. 1 ppb (0.38 ug/nH). Purge and ~,rap with GC-
photoionization detection is the most widely used method for the analysis of
toluene in aqueous samples. With a 5 m£ sample, the method has a detection limit
of 0.1 ppb (0. 1 ug/2,).
Toluene is the most prevalent aromatic hydrocarbon in the atmosphere, with
average measured levels ranging from O.'M to 59 ppb (=0.53 to 200 ng/rn^).
Toluene has also been detected in surface waters and in treated wastewater
effluents at levels generally below 10 ppb (10 \ig/H). A concentration of toluene
as high as 19 ppb (72 ug/2.) has been detected in a drinking water supply. In a
study of toluene levels in the tissue of edible aquatic organisms, 95$ of the
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samples contained less than 1 ppm (1 mg/kg) 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 0.27 ppb (1.0 ng/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
140 era of sand. Because 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
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 results of these studies indicate
that although people exposed occupationally may be at risk, exposure to ambient
levels of toluene is not likely to constitute a significant hazard to the general
population.
The health effect of primary concern is dysfunction of the central nervous
system (CMS). Acute experimental and occupational exposures to toluene in the
range of 200 to 1500 ppm (=750 to 5600 mg/nr) have elicited dose-related CNS
alterations such as fatigue, confusion, and incoordination, as well as
impairments in reaction time and perceptual speed. Following initial CHS
excitatory effects (e.g., exhilaration, lightheadedness), progressive
development of narcosis has characterized acute exposures to excessive
concentrations of toluene (i.e., levels approaching the air saturation
concentration of approximately 30,000 ppm ( = 113,000 mg/m )). Repeated
1-3
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occupational exposures to toluene' over a period of years at levels of 200 to
400 ppm (=750 to 1500 pg/m3) have resulted in some evidence of neurologic
effects, and chronic exposure to mixtures of solvent vapors containing
predominantly toluene at levels of 30 to 100 ppm (=100 to 100 mg/m3) have
resulted in impaired performance on tests for intellectual and psychomctor
ability and muscular function. 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 myelotoxic 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
toluene have not resulted in any definite effects on heart rate or blood pres-
sure.
Liver enlargement was reported in an early study of painters exposed to 100-
1100 ppm (=400 to 4100 mg/m ) 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 function. 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 (=400 to 4100 mg/m ) toluene for
2 weeks to 5 years and 60 to 100 ppm (=200 to 400 mg/m3) 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.
Subjective complaints of dysmenorrhea have been reported by women exposed
for over 3 years t.o 60 to 100 ppm (=200 to 400 mg/m ) 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, xylene, and other unspecified solvents. The limited available data do
not, however, specifically associate occupational exposure to toluene with
menstrual effects. Information on the possible reproductive effects of toluene
in males is not available.
Single short-term exposures to moderate levels of toluene have, on occa-
sion, been reported to cause transitory eye and respiratory tract irritation, but
1-4
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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 animals is on the CNS. Acute
exposure via inhalation to high levels of toluene has been associated with
depression of activity. Levels below 1000 ppm (=3800 mg/m^) have little or no
effect on gross manifestations of behavior, although more sensitive methods of
assay (i.e., detection of changes in cognition •arid brain neuromodulator levels)
have indicated effects at lower levels.
Early studies with animals suggested thdt toluene induced myelotoxicity,
but most studies that used toluene that contained.negligible amounts of benzene
have not produced injury on blood-forming organs.
Inhalation of concentrations of up to 1085 ppm (=^100 mg/m ) toluene for
6 weeks or 300 ppm (=1100 mg/m^) for 24 months, or ingestion of 590 mg
toluene/kg body weight/day for 6 months produced no evidence of liver damage;
however, several studies noted an increased liver weight or slight histological
changes suggestive of possible liver damage at higher levels of vapor exposure
(=2000 ppm (=7500 mg/m ) in rats), or in animals treated by the intraperitoneal
route (=0.i) g/kg).
Renal injury was noted in rats, dogs, and guinea pigs after subchronic
inhalation of toluene vapors at levels in excess of 600 ppm (=2300 mg/nr) in
three studies, but other subchronic exposures in which rats, dogs, guinea pigs,
and monkeys inhaled (concentrations up to 1085 ppm (=U100 mg/mjj) or ingested
(590 mg toluene/kg body weight/day) toluene did not produce **enal damage.
Although no effect was observed on the lungs of rats, guinea pigs, dogs, or
monkeys after intermittent exposure to 1085 ppm (=4100 mg/m ) toluene vapor for
6 weeks, in rats after inhalation of up to 300 ppm ( = 1100 mg/m ) toluene for
2U months, or in rats after ingestion of 590 mg toluene/kg body weight/day for
6 months, other studies have noted irritation effects in the respiratory tract in
dogs, guinea pigs, and rats. Ser.sitization of the heart in mice, rats, and dogs
has been associated with inhalation of toluene.
The acute oral toxicity (LDr ) of toluene in rats is in the range of 6.0 to
7.5 g/kg, which indicates only slight toxicity in this species. Inhalation LC<-Q
values have been reported in the range of 500 to 700 ppm (=1900 to 2600 mg/nr)
for mice and 4000 ppm ( = 15,000 mg/m ) for rats. Acute dermal toxicity appears to
1-5
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be tjuite low (rabbit LD,-0 of 12.2 g/kg), but slight to moderate irritation has
been noted in rabbit and guinea pig skin and in rabbit corneas after application
to the skin and eye, respectively.
1.14. ABSORPTION, DISTRIBUTION, METABOLISM, ELIMINATION, AND RELATED
PHARMACUK1NETICS
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 concentration0 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 hippurlc 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
dose or whether the chemical was administered orally or by inhalation. Much of
tne 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. CARCINOGENICITY, MUTAGEN1CITY, AND TERATOGENICITY
Inhalation exposure to toluene at concentrations of up to 300 ppm
(=1100 mg/m ) for 24 months did not produce an increased incidence of
neoplastic, proliferative, inflammatory, or degenerative lesions in various
organs of rats relative to unexposed controls. It should be noted, however, that
the 300 ppm (=1100 mg/m ) exposure did not represent a maximum tolerated dose. A
bioassay of commercial toluene in rats and mice exposed via inhalation is
currently being conducted by the National Toxicology Program Carcinogenesis
Testing Program. Other studies indicate that toluene is not carcinogenic when
applied topically to the shaved skin of laboratory animals and that it does not
1-6
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promote the development of skin tumors following initiation with 7,12-dimethyl-
benz[a]anthracene.
Toluene has been shown to be non-mutagenic in a battery of microbial,
nanmalian cell, and whole organism test systems, but assays for sister-chromatid
exchange (SCE) and cytogenetic effects nave provided conflicting results.
Increased frequencies of SCEs and/or chromosome aberrations were found in some,
but not all, studies of lymphocytes from workers who were chronically exposed to
toluene, and SCEs-and/or aberrations were not induced in Chinese hamster ovary
cell.3 or human lymphocytes exposed to toluene in culture. Russian studies have
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 intraperitorieal injection of
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.
1.6. EFFECTS ON ECOSYSTEMS
The ecological effects of toluene have been investigated using aquatic and
terrestrial microorganisms, aquatic invertebrates, fish, and higher plants.
Toluen-e 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 TOO mg/H, Toluene is acutely toxic to aquatic
invertebrates and fish at concentrations ranging between 3 and 1180 mg/i. The
lowest concentration shown to cause sublethal effects in aquatic animals was
2.5 mg/JL. Chronic toxicity data are available for two species of fish; marine
sheepshead minnows were affected at toluene concentrations of 7.7 mg/8, but not at
3.2 mg/i, and fathead minnows were affected at 6 rag/it but not at ^ mg/8,. Chronic
effects occurred at concentrations that were about 2 to 18 times lower than the
acute LCj-Q for these si.'cies, 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 surface waters (0.1 to 1.0 mg/X.) and sediments
(0.1 to 1.0mg/kg). 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 from 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 impact of
toluene spills or chronic low-level pollution on ecosystems is unknown. Adverse
effects may occur but probably are limited by rapid rates of loss of toluene
through evaporation and biodegradation.
1.7. HEALTH EFFECTS SUMMARY
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 numan
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
huaans of single short-tenn exposures to toluene can be estimated as:
10,000 to 30,000 ppm : Onset of narcosis within a few
(=38,000 to 113,000 mg/m ) minutes. Longer exposures may
be lethal.
>'i,000 ppm : Would probably cause rapid
(=15,000 mg/m ) impairment of reaction time and
coordination. Exposures of one
hour or longer might lead to
narcosis and possibly death.
1,500 ppm : Probably not lethal for exposure
(=5600 mg/nr) periods of up to eight hours.
300 to 800 ppm : Gross signs of incoordination
(=1100 to 3000 mg/m ) may be expected during
exposure periods up to
eight hours.
400 ppm : Lacrimation and irritation
(=1500 mg/m ) to the eyes and throat.
100 to 300 ppm : Detectable signs of incoordination
(=400 to 1100 mg/m ) may be expected during exposure
periods up to eight hours.
1-8
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200 ppm : Mild throat and eye irritation.
(=750 mg/m3)
50 to 100 ppm : Subjective complaints
(=200 to 400 mg/m3) (fatigue or headache)
but probably no
observable impairment
of reaction time or
coordination.
>37 ppm : Probably perceptible to most
(=150 mg/m-0 humans.
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
exposures failed to define precisely levels or durations of exposure, involved
relatively 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 mpre 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.
1.8. RESEARCH NEEDS
Although the available data from human and animal toxicologic studies
indicate that ambient exposure to toluene does not currently present a human
health hazard, it is apparent that further investigation is needed in several
areas. Some of the most important areas In which incomplete information is
available, and that should be considered in foitnulating research needs, are
represented below. This list of research needs, however, is not structured in
terms of relative priorities among the various areas of investigation noted
below.
1. Monitoring data. Up-to-date monitoring data pertaining to atmos-
pheric levels around point sources involving solvent use, ambient
air levels in rural and remote areas, and drinking water levels are
needed to more accurately evaluate human exposure to toluene.
1-9
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2. Consumer exposure. General population exposure to toluene from
gasoline usage/spillage during vehicular filling operations, from
use of paint and varnish thi nners/removers, arid from the use of
other toluene-containing consumer products rtamina unevaluated,
although exposure from these sources could substantially cont-
ribute to total exposure. Data are needed on the magnitude, fre-
quency, duration, and extent of exposureCs) from these sources to
properly assess general population toluene exposure.
3. Neurobehavioral toxicity. It is evident that the CNS is most
sensitive to the effects of toluene. Although the effects of acute
' high level toluene exposure are fairly well do direr) ted, there is a
paucity of data regarding the behavioral aned to be detenr' ,ed to
properly evaluate potential risk fr-e ambient exposure.
!*. Carcinogenic! ty. Although it is improbable that toluene is a
strong carcinogen, the possibility that it is a weak one cannot be
excluded on the basis of the information that Is presently
available. The results of the ongoing NTD carcinogenesis bio-
assays cf toluene should help resolve the issue, and mitigate
concern for the apparent deficiencies cf the CUT (198C) bioassay.
5. Mutagenicity. Toluene has been shown to be non-rautagenic in a
variety of microbial and raamialiar; systems, but the results of
cytogenetic assays (sister-chromatid exchange and chromosome
aberration) are conflicting. Additional testing is needed to
resolve the possibility that toluene may be a weak clastogen or
mutagen.
6. Teratoeenicity. Toluene has been reported to be teratogenic to
mice fallowing oral exposure 'Nawrot and Staples, 1979), but not
to mice or rats following inhalation exposure (Huddle and Ungvary,
1978; Litton BJonetics, Inc., 1978b; Tatrai et al., 1980). The
uncertainty over the teratogenicity of toluerte should serve as a
stimulus for further research, including evaluation of the
association between teratogenic effects ap.d chronic lew level
exposure to toluene.
7, Reproductive effects. Th^ reports of dysraenorrhea in female
vrorkers (Matsushita et al., 1975), degeneration of germinal
epithelium in the testes of male rats (Matsushita et al., 1971),
and increased follicle-stimulating hormone (FSH) levels in rats
(Andersson et al., 1980) that have been associated with toluene
exposure suggest that the reproductive effects of this compound
should also be considered in formulating research needs. .Again,
this should include evaluation of effects associated with chronic
low level exposures to toluene.
8. Respiratory Defense Mechanism. Various gaseous air pollutants,
(e.g., nitrogen oxides and ozone) have boen demonstrated to affect
respiratory tract defense mechanisms, resulting in increased
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susceptibility to respiratory infectic/i in some mammalian species
(e.g., rat, mome) studied. Complex dose-response relationships
have been demonstrated, wnereby specific patterns of duration and
frequency of exposure, as well as the concentration of the
particular gaseous air pollutant, appear to be important factors.
To date, little or no information has been published in regard to
the evaluation of potential.effects of volatile organic substances
such as toluene on respiratory defense mechanisms. It is
recommended that such studies be conducted in the near future.
1-11
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2. INTRODUCTION
EPA's Office of Research and Development has prepared this health assess-
ment to serve as a "source document" for Agency use. The scope of this docu-
ment addresses toluene in relation to the total environment. It is expected
that this document will serve the information needs of many government agencies
and private groups that may be involved in decisionmaking activities related
to toluene.
In the development of the assessment document, existing scientific litera-
ture has been surveyed in detail. Key studies have been evaluated and summary
and conclusions have been prepared so that the chemical's toxicitv and related
characteristics are qualitatively identified.
The present document represents an up-to-date evaluation of the available
'toluene data base. The document assesses all major sources of toluene in the
environment, general ambient concentrations representing potential human
exposure levels, and health effects demonstrated to be associated with expo-
sure of man or lower organisms. More detailed, updated evaluations regarding
sources, emissions, ambient air concentrations, and public exposure levels
will be carried out in the future should EPA decide to undertake specific
regulatory action(s) for toluene.
The information found in this document is integrated into a format designed
as the basis for performing risk assessments. Where appropriate, the authors
of the document have attempted to identify gaps in current, knowledge that
limit risk evaluation capabilities.
2-1
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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
toluene are described below.
3.1. SYNONYMS AND TRADE NAMES
Methacide
Methylbenzene
Methyl benzol
Phenylraethane
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
CH.
Molecular Formula: ^,. Hg
Molecular Weight: 92.13
3.4. 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 (Windholz,
1976) .
3.4.2. Other Physical Properties.
Melting Point (Weast, 1977): -°5°C
Boiling Point (Weast, 1977): 110.6°C
Density (g/m2., 20°C) (Weast, 1977): 0.8669
Specific Gravity (15.6/15.6°C) (Cier, 1969): 0.8623
Vapor Pressure (25°C) (Weast, 1977): 28.7 torr
Vapor Density (air 1) (Weast, 1977): 3.20
•
3-1
-------
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):
28.7 torr
3.20
1.09
534.8 mg/i
379.3 Bg/i
1.17 to 7.10
40°F
552°C
2.69
4.68 ppm
2. 14 ppm
28.53 dynes/cm
0.6 cp
1.49693
1 ppm =_ 3.77 mg/m3
1 mg/nr = 0.265 ppm
3.4.3 Significance of Physical Properties with Respect to Environmental
Behavior. The .volatility of toluene, as indicated by its relatively high vapor
pressure, indicates that a substantial fraction of environmental toluene is
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
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
3-2
-------
cal properties such as flammable limits and flash point is 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 aide
group (-CH-,) or on the benzene ring. These substitutions occur exclusively at
the ortho (2) and para
positions marked in the following figure:
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, 1982).
Thermal
or
Catalytic
CH,
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.
Hydrogenation of toluene takes place readily to produce methylcyclphexane
(Cier, 1969).
n
+ H_
catalyst
o
3-3
-------
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).
Oxidation of toluene under catalytic conditions yields benzoic acid as a
principal product (Cier, 1969).
n
catalyst
Chlorinati-on of toluene under actinic light conditions yields methyl sub-
stitution products (Cier, -1969) .
hv
HC1,
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 o- and £-chlorotoluene (Cier, 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, Azeptropes 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
Materials (Cier, 1969). 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. 'J? purity, respectively
(USITC, 1979). 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 (USITC, 1979).
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 necespary 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. REFERENCES
BRADSHER, C.K. (1982). Toluene. In: McGraw-Hill Encyclopedia of Science and
Technology, 5th ed. Vol. 13., McGraw-Hill Book Co., NY. p. 759-760.
3-5
-------
BROWN, S.L., CHAN, F.Y., JONES, J.L., LIU, D.H., MCCALEB, K.E., MILL, T., KAPIOS,
K.N., and SCHENDEL, D.E. (1975). Research Program on Hazard Priority Ranking of
Manufactured Chemicals, Phase II—Final Report, chemicals 1i-20. Prepared by
Stanford Research Institute, Menlo Park, CA. National Science Foundation,
Washington, D.C. Available from: National Technical Information Service,
Springfield, VA (NTIS PB 263 161).
CIER, H.E. (1969). Toluene. In: Kirk-Othmer Encyclopedia of Chemical
Technology, 2nd ed. Standen, A.. Editor. New York: John Wiley and Sons, Inc.,
Vol. 20, p. 528.
GAIT, A.J. (1967). Heavy Organic Chemicals. Oxford, England: Pergamon Press,
Ltd., 249 pp.
SUTTON, C. and J.A. CALDER, 1975. Solubility of Alkylbenzenes in Distilled Water
and Seawater at 25°C. J. Chem. Eng. Data, 20: 320-322.
TUTE, M.S. 1971. Principles and Practice of Hansch Analysis: a guide to
Structure-activity Correlations for the Medical Chemist. Adv. Drug Res.,
5: 1-77.
U.S. EPA. 1980. Ambient Water Quality Criteria for Toluene, Office of Water
Regulations and Standards, Criteria and Standards Division. U.S. EPA,
Washington, DC. Available ,from NTIS, Order No. PB 81-117855, Springfield, VA.
USITC (UNITED STATES INTERNATIONAL TRADE COMMISSION). (1979). Synthetic
Organic Chemicals: United States Production and Sales, 1973, USITC Publication
1001, USITC, Washington, DC. 20^36.
WALKER, P.- 1976. Air Pollution Assessment of Toluene. Report prepared by Mitre
Corporation. Prepared for U.S. Environmental Protection Agency. Available
through NTIS Order No. PB 256735, Springfie.IJ, VA.
3-6
-------
WEAST, R.C., Ed. (1977). CRC Handbook of Chemistry and Physics, 58th ed.
Cleveland, OH: Chem.ical Rubber Co.
WINDHOLZ, M., Ed. (1976). The Merck Index: An Encyclopedia of Chemicals and
Drugs, 9th ed. Rahway, NJ: Merck and Co., Inc.
3-7
-------
4. PRODUCTION, USE, AND RELEASES TO THE ENVIRONMENT
14.1. 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.
4.1.1. Petroleum Refining Processes. Low levels of toluene are present in crude
p^roleu-. Toluene is produced from petroleum by two processes: (1) catalytic
reforming and (2) pyrolytic cracking.
4.1.1.1, 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 (fable 4-1).
Catalytic reforming involves the catalytic dehydrogenation of selected
petroleum fractions that are rich in naphthenic hydrocarbons to yield a mixture
of aromatics and paraffins. The proportions of aromatics and paraffins in the
reformate depend upon the feedstock used and the severity of the reforming
operation (Cier, 1969). At present, reforming operations are geared primarily to
producing a benzene-toluene-xylene (BTX) reformate from which the individual
aromatics are recovered (.Cier, 1969). Toluene is isolated from the reformate by
distillation, followed by washing with sulfuric acid and redistillation. Only a
small fraction of catalytic refcrmate, however, is utilized for isolating
toluene. The unseparated toluene in catalytic refornate is used for gasoline
blending.
4.1.1.2. PfROLYTIC CRACKING — The second largest quantity of toluene comes
from pyrolytic cracking. Of the total isolated toluene produced in the United
States in 1978, approximately 9J (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
conditions (Mara et al., 1979). The by-product, pyrolysis gasoline, contains a
high percentage of aromatics. Toluene can be isolated from pyrolysis gasoline by
-------
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: Little, 1981
This value does not include toluene obtained from tar distillers.
4-2
-------
distillation, removal of any olefins and diolefins, and redistillation. Not all
pyrolysis gasoline produced in the United States is used 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 unsuitable 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 hydrode-
alkylation process (Mara et al., 1979). In 1978, approximately 135 million kg of
isolated toluene, which was about 4J 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-
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
gasoline as a benzene-toluene-xvlenp (BTX) "ixtur". TV.c Luuai 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 styrt.r"? 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
isolated 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 17.6$ over 1978 (USITC, 1979). The production of toluene
from petroleum refiners has been reported to have decreased by 4.3J during the
4-3
-------
TABLE 4-2
Isolated and Non-Isolated Toluene Available
in the United States in 1978a
Source
Catalytic reforming
Pyrolytic cracking
Styrene by-product
Coke oven by-product
Imports
Exports
SUBTOTAL
TOTAL
Isolated
3,110
324
135
26
192
-364
3,^23
Quantity
(10fc kg)
Non-Isolated as BTX
27,000
197
NA
96
NR
27,293
30,716
Source: Little, 1981
NA = not applicable, NR = not reported
*-«»
-------
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 - Penuelaa, PR
Crown - Pasadena, TX
Exxon - Baytown, 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
b
20
194
92
49
148
72
280
33
c
33
335
56
197
Isolated Toluene Produced
(105 kg)
310
110
84
67
26
8U
33
26
3b
» 266
31
277
NA
13
130
62
33
100
49
189
22
NA
22
226
38
133
1-5
-------
Table 4-3. (cont.)
V
Company and Location
Sunoco - Corpus Christ!, TX
Marcus Hook, PA
Toledo, OH
Tulsan, OK
Termeco - Chalmt-tta, LA
Texaco - Port Arthur, TX
Wesr-ville, NJ
Union Oil - Lemont , IL
Union Pacific ~ Corpus Christi, TX
TOTAL
Toluene
Capacity
(10b kg)
138
151
2U7
66
115
92
T32
56
99
M613
Isolated Toluene Produced
(106 kg)
93
102
166
*Ul
78
62
89
38
67
3108
Source: Little, 1981
1980 capacity for this producer was 85 million kg.
I960 capacity for this producer was 72 million kg.
NA = not applicable.
-------
TABLE
Producers of Isolated Toluene frora Pyrolyaia Gasoline'"1
Toluene
Capacity Isolated Toluene Produced
Company and Location (105 kg) (10° kg)
Arco - Chanelview, TX 105 76
Commonwealth - Penuelas, PR ^9 36
Dow - Freeport, TX 13 9.1)
Gulf - Cedar Bayou, TX 66 IS
Mobil - Beaumont, TX 16 15
Monsanto - Chocolate Bayou, TX 132 96
Union Carbide - Taft, LA 66 48
TOTAL UH7 328,4
aSource: Little, 1981
K-7
-------
TABLE 14-5
Producers of Isolated Toluene froa .Styrene By-Product3
Company and Location
American Hoechst - Baton Rouge, LA
Arco - Beaver Valley, Ih
Cos-Mar - Carville, LA
Dow - Freeport , TX
Midland, MI
El P-A3Q Natural Gas - Odessa, TX
Gulf - Donalasville, LA
Monsanto - Texas City. TX
Standard Oil (Indiana1) -
'I'exas "ity, TX
SJHOCO - Corpus Christi , TX
U.S. Steel - Houston, TX
TOTAL
Styrene
Capacity
(105 kg')
uoo
100
590
660
UO
68
270
630
380
36
54
3)400
Isolated Toluene Produced
(10" kg)
16
U
24
26
5.
2.
11
27
15
1.
2.
134.
5
1
14
2
8
Source: Little, 1981
U-8
-------
TABLE U-6
\ Producers of Isolated Toluene from Coke-Oven Crude Light Oils3
Plant
Annco Middletown, OH
Ashland Oil Catlettsburg, KY
N. Tonawanda, NY
Bethlehem Steel Bethlehem, PA
Sparrows Pt., MD
CF and I Pueblo, CO
Interlake Toledo, OH
Jones and Laughlin Aliquippa, PA
Lone Star Lone Star, PA
Republic Steel Youngster, OK
Cleveland, CH
U.S. Steel Clairton, PA
Geneva, UT
aSource: Little, 198l
-------
same period (USITC, 1979). This resulted in a net decrease of 't.2S in the
overall isolated toluene production in 1979 as compared to 1978 (Table li-1)
(USITC, 1979).
U.3. USERS
As mentioned in Section li.2., most of the toluene produced as BTX mixture is
never isolated but remains in various refinery streams for use in gasoline.
Isolated toluene, on the other hand, is used for different purposes; the
consumption of isolated toluene in different usage is shown in Table ^-7. The
fluctuating, but largest, single use of isolated toluene is in the production of
benzene through the hydrodpalky]ation (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.
producers of benzene through the KDA process, their capacity, and the amount
produced are shown in Table .-8.
The second largest use of isolated toluene is back-blending into gasoline
for increasing the octane ratings. Approximately 1^65 million kg of isolated
toluene, representing 35.1? of 1978 consumption, was used for gasoline back-
bler.ding.
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
solvents 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 toe 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
isolated toluene (Mara et al., 1979). A small amount of isolated toluene
(6.6 million kg, <1J of total) is used for the manufacture of p_-cresol (Little,
1981). The latter compound is used primarily for the manufacture of the-
pesticide 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.
lJ-10
-------
TABLE I*-7
Consumption of Isolated and Non-Isolated Toluene in Different Usages'
Usage
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
Benzoic acid
Benzyl chloride
Vinyl toluene
Miscellaneous others
Net export
TOTAL
Amount Used /year
(10° kg)
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
aSource: Little, 1981
-------
TABLE H-8
Consumers of Toluene for the Manufacture of Benzene by HDA Process3
Company and Location
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 - Guayama, PR
Quintana-Howell - Corpus Christi, TX
Shell - Odessa, TX
Sunoco - Corpus Christi, TX
Toledo, OH
Tulsa, OK
TOTAL
Toluene Used Benzene Production Capacity
(1(T kg) (10b kg)
59
103
9V
156
298
59
65
122
52
103
103
191
18
52
163
39
1674
77
130
120
200
380
77
84
160
67
130
130
250
23
67
210
50
2155
aSource: Anderson et al., 1980
1-12
-------
The identification 9f 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 tolueqe 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.
4.4. ENVIRONMEOTAL RELEASE
The three primary sources of toluene release or emission to the environment
are production, usage, and inadvertent sources. In addition to these anthro-
pogenic sources, some toluene is released into the environment from natural
sources.
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 usad for venting gases. Storage emissions
.originate from losses during loading and handling of the product used for
manufacturing processes and storage of the final product. Fugitive emissions are
those that have their origin in plant equipment leaks. The air emission factors
used to estimate the total omission 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 4-11, 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 4-12 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 (Little, 1981).
4-13
-------
TABLE 4-9
Producers of Toluene Diisocyanate (TDI) in 19?8a
Company and Location
Allied Chemical - Moundsville, WV
BASF Wyandotte - Geismar, LA
Dow Chemical - Freeport, TX
Du Pont - Deepwater, KJ
Mobay Chemical - Baytown, TX
New Martinsville, WV
Olin - Astabula, OH
Lake Charles, LA
Rubicon Chemical - Geismar, I A
Union Carbide - S. Charleston, WV
TOTAL
TDI Capacity
(10° kg)
36
45
15
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
4-14
-------
Other Toluene
Company and Location
Arco - Houston, TX
Sunoco - Marcus Hook, PA
TOTAL
Kalaraa - Kalama, WA
Monsanto - St. Louis, MO
Velsical - Beaumont, TX
Chattanooga, TN
Pfizer - Terre Haute, IN
Tenneco - Gar field, NJ
TOTAL
Monsanto - Bridgeport, NJ
Sauget , IL
Stauffer - Edison, NJ
UOP - E. Rutherford, NJ
TOTAL
Dow - Midland, MI
TABLE 1-10
Chemical Intermediate Users in
Production
Capacity
(10° kg)
Xvlene Producer's
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
1978a
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
1-15
-------
TABLE 4-1
Toluene Air Emission Factors from Production Sources
Emission Factor
(kg lost/kg produced)
Source
Process
Storage
Fugitive
Total
Catalytic reforming 0.00002
Pyrolytic cracking 0.00015
Styrene by-product 0.00001
Coke oven by-product 0.00050
0.00006
0.00060
0.00060
0.00060
0.00002
0.00015
0.00015
0.00015
0.0001
0.0009
0.00076
0.00125
Source: Kara et al., 1979
1-16
-------
TABLE 14^12
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 3,110
- Non-isolated 27,000
Pyrolytic cracking - Isolated 324
- Non-isolated 197
Styrene by-product 135
Coke oven by-product - Isolated 26
- Non-isolated 96
TOTAL
0.0001
0.0009
0.00076
0.00125
3,011
469
103
153
3,736
-------
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 (Little, 1981):
Direct discharge: 33$
Publ?cly 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
containing toluene is actually discharged to the environment.
The average volume of effluents produced from coke-oven operation (Little,
1981), the toluene concentration in these effluents (Little, 198D, and the
emission factors in these effluents are given in Table 4-13.
For a total coke production of 44 x 10^ kg in 1978 (Little, 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 (Little, 1981). Therefore, the
distribution of total released toluene in untreated wastewater can be estimated
as given in Table 4-14.
4.14.2. 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 fc-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
emission 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.
4-18
-------
TABLE U-13
a
Toluene Emission Factors in Wastewater from Coke Oven Operation
Effluent
Liters of Effluent
Produced/kg Coke
Toluene
Con/i
(mg/J.)
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
2.21 x 10
-6
1.72 x 10
x 10
-6
-6
Source: Little, 1981
-------
TABLE 11-14
Toluene Released in Different Media from Coke-Oven Wastewater3
Medium
Air
W^ter
Land
POTW
Percent of
Total Released
20
33
22
25
Amount released/yr
(103 kg)
28
^7
31
36
Toluene releases fros quenching are arbitrarily assumed to be evenly distr
buted between land and air.
-------
TABLE H-15
Toluene Emission Factors for Its Uses'
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
Eenzoic 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
O.OOOHO
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.
H-21
-------
TABLE H-16
Estimated Toluene Emission from Different Uses
Source
Benzene production
Solvent for paint and
coatings
Solvent for adhesives,
Pharmaceuticals, and
others
Toluene diisocyanate
Xylene production
Benzoic acid
Benzyl chloride
Vinyl toluene
Miscellaneous others
TOTAL
Amount Used/yr
(10b kg)
1675
263
inks ,
132
200
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 . 00 1 0
0.0010
0.0010
Total Emission/yr
(103 kg)
335
263,000
112,000
256
20
98
36
25
39
375,809
H-22
-------
It can be concluded from Table 4-16 that, among the different usages of
toluene, the maximum emission (excluding inadvertent sources) occurs from sol-
vent application (see Section 4.14.3.).
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 (Little, 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 proctjses
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
orgariics.
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.
4.4.4. Non-anthropogenic Sources.-- Substantial amounts of toluene can be
released into the environment from petroleum seepage in the oceans and on land,
and from the weathering of exposed coal strata. However, no estimate of total
environmental release of toluene from these natural sources is available. Some
vegetations can be natural sources of toluene in the environment. Toluene is
naturally produced by the tropical tolu tree. It has been identified in roasted
filberts, in peanuts and macadamia nuts^ in grape essence, and in cooked potatoes
(NRC, 1980). It is, however, unlikely that significant amounts of toluene are
released into the environment from the vegetations in the United States (NRC,
1980; Seila, 1979).
4-23
-------
TABLE 14-17
Toluene Released in Aqueous Media from Use as a Solvent in Various Industries'
Toluene Cone.
in
Wastewater
Source (|ig/Ji)
Ink formulating 1600
Textile products 14
Gum and wood chemicals 2000
Paint formulating 990
Leather tanning 78
Pharmaceuticals 515
TOTAL
Wastewater
Discharged
Percent (10° 8,/d)
Occurrence
87 0.092
i>S 2000
78 0.11
87 2.8
25 200
62 250
Amount of
Toluene
Released
(103 kg/yr)b
0.033
3.8
0.17
0.72
1.2
24
29.9
Source: Little, 1981
Based on 300 operating d/yr-
-------
TABLE 4-18
Toluene Emission from Different Inadvertent Sources'
Environmental Release
(103 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
MR
NR
NR
36
460
90
it, 200
NR
NR
NR
59
4,400
13,000
7,000
1,000
<1,000
53
8
703,306
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
247
Source: Little, 1981
NR = not reported
4-25
-------
4.4.5. 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 0.00024 (Mara et al., 1979) and
an estimated coke production of 44 x 109 leg (Little, 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
evaporative 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 1 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.
4-26
-------
TABLE 4-19
Total Yearly Release of Toluene into Different Media
Source
Production (see Tables
4-12 and 4-14)
Usage (see Tables 4-16
and 4-17)
Inadvertent (see 'lable
4-18)
'Coke production
TOTAL
Air
3,764
375,809
708,306
10,560
1,098,439
Environmental
(103 kg/yr)
Water
47
30
1,089
NA
1, 166
Release
Land
31
NA
247
NA
278
POTW
36
NA
NA
NA
36
NA = not available.
4-27
-------
TABLE 4-20
Consumer Product Formulations Containing Toluene
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 cleane. 3
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
214
may contain toluene
>80
contain 25 to 90 BTX
may contain toluene
35
30
<_60
may contain' toluene
80 to 90
140 to 60
may contain toluene
^Source: Gleason et al., 1969
4-28
-------
M.6. REFERENCES
ANDERSON, G.E,, LIU, C.S., HOLMAN, H.Y. and KILLUS, J. P. (1980). Human Exposure
to Atmospheric Concentrations of Selected Chemicals. Prepared by Systems
Applications, Inc., San Rafael, CA, under Contract No. EPA 68-02-3066. U.S.
Environmental Protection Agency, Research Triangle Park, NC.
BOLGER, M. (1981). Private communication between M. Green burg", ECAO, EPA and M.
Bolger, Toxicologist, Food and Drug Administration, Washington, DC. April 13,
1982.
CIER, H.E. (1969). Toluene. In: Kirk-Othmer Encyclopedia of Chemical
Technology, 2nd ed. Standen, A., Editor. New York: John wiley and Sons, Inc.,
Vol. 20, p. 528.
GLEASON, M.N., GOSSELIN, R.E., HODGE, H.C. and SMITH, R.P. 1969. Clinical
Toxicology of Conmercial Products: Acute Poisoning, 3rd ed. Baltimore, MD:
Williams and Wilkins, Co., pp. VI.1-132. (Cited in Slimak, 1980).
LITTLE, A.D. (1981). Exposure Assessment of Priority Pollutants: Toluene.
Draft report prepared by Arthur D. Little, Inc., Cambridge, MA, for the U.S.
Environmental Protection Agency, Research Triangle Park, NC.
MARA, S.J., SO, E,C. and SUTA, B.E. (1979). Uses, Sources, and Atmospheric
"Emissions of Alkylbenzene Derivatives, Final Report. Prepared by SRI Inter-
national, Menlo Park, CA, under Contract No. 68-02-2835. U.S. Environmental
Protection Agency, Research Triangle Park, NC.
NRC (NATIONAL RESEARCH COUNCIL). (1980). The Alkyl Benzenes. Committee on
Alkyl Benzene Derivatives, Board on Toxicology and Environment Health Hazards.
Assembly of Life Sciences, National Research Council. Washington, DC; National
Academy Press.
t-29
-------
SEILA, R.L. (1979). Non-Urban Hydrocarbon Concentrations in Ambient Air North
of Houston, Texas. EPA Report No. EPA-600/3-79-010, Environmental Sciences
Research Laboratory, Office of Research and Development, U.S. EPA, Research
Triangle Park, NC. Available through NTIS, Springfield, VA. Order No. NTIS PB
293227.
SLIMAK, M. (1930). Exposure Assessments of Priority Pollutants: Toluene.
Report (draft) prepared by Arthur D. Little, Inc., MA. Prepared for U.S.
Environmental Protection Agency. Monitoring and Data Support Division,
Washington, DC.
USITC (UNITED STATES INTERNATIONAL TRADE COMMISSION). (1979). Synthetic
Organic Chemicals: United States Production and Sales, 1978, USITC Publication
1001, USITC, Washington, DC 20^36.
1-30
-------
5. ABATEMENT PRACTICES IN INDUSTRY
The four major potential sources of toluene release to the environment, in
order of importance (Table U-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. ABATEMENT PRACTICES FOR INADVERTENT SOUBCES
The two ma lor sources of vehicular emissions of toluene in the atmosphere
are exhaust emissions and evaporative emissions from the gas tank and the
carburetor- Crankcase emissions have been eliminated essentially through the
use of positive crankcase ventilation technologies (U.S. EPA, 1980).
' The installation of catalytic converters on automobiles has resulted in a
i
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,
1980). Therefore, both the photochemical reactivity and the mass of hydrocarbons
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, 1980). Such
systems are more effective, however, for regular grade gasoline containing ?5 to
27$ aromatics than for premium grade unleaded gasoline containing H3$ aromatics
(U.S. EPA, 1980).
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
gasoline and losses during fuel transfer. The former can be reduced by educating
the public about the necessity of restricting spillage both for economic an».J
environmental reasons. The loss of gasoline during fuel transfer is already
controlled in many areas of the country by incorporating vapor recovery systems
(NRC, 1980).
5-1
-------
5.2. ABATEMENT 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 particulates are removed
from the contaminated airstream by filtration before the airstream. enters the
carbon bed (U.S. EPA, 1980).
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, I960). 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,
solvent vapors can be adsorbed in activated carbon as a method of controlling
toluene vapor emissions into the atmosphere.
5.3- ABATEMENT FOR JOKE 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 togecher and vented through a common stack. Improving the
combustion efficiency of ~he coke batteries would be a proper method of control
(U.S. EPA, 1980).
5.1. 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
catalytic incineration, chemical sorbents, vapor condensation, process and
material change, and improved maintenance (U.S. EPA, 1980). 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 (Matunar et al.,
1978).
5-2
-------
5.5. ABATEMENT PRACTICES FOR RAW AND FINISHED WATERS
No information could be found on this subject. Treating water with acti-
vated carbon, howe;er, is expected to remove toluene from drinking waters.
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 (NBC, 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 Schulze
(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
description of the cost benefits of controlling alkylbenzene 'pollution,
interested readers are referred to a recent NRC (1980) document.
5.7. REFERENCES
ADAMS, R.M., CROCKER, T.D. and THANAVIBULCHAI, N. (1980). An Economic
Assessment of Air Pollution Damages to Selected Annual Crops in Southern
California. U.S. Environmental Protection Agency, Washington, DC, 27 pp.
5-3
-------
BROOKSHIRE, D.S., D'ARGE, R.C., SCHULZE, W.D. and THAYER, M. (1979). Methods
for valuing aesthetics and health effects in the south coast air basin: An
overview. Paper presented at the 72nd Annual Meeting of the Air Pollution
Control Association, June 24-28, 1979, Cincinnati, OH, 27 pp.
MATUNAR, F.C., TRATTNER, R.B. and CHEREMISINOFF, P.N. (1978). The absorption of
organic compounds by wet scrubbing methods. Adv. Instrum. 33.1 : 307-31^.
NRC (NATIONAL RESEARCH COUNCIL). (1980). The Alkyl Benzenes. Committee on
Alkyl Benzene Derivatives, Board on Toxicology and Environment Health Hazards.
Assembly of Life Sciences, National Research Council. Washington, DC: National
Academy Press.
SANTODONATO, J., BASU, D., and HOWARD, P.H. (1978). Health Effects Associated
with Diesel Exhaust Emissions, Literature Review and Evaluation. EPA Publ. No.
EPA-600/1-78-063, Prepared for U.S. EPA, HERL., NC.
THAYER, M. and SCHULZE, W.D. (1980). An Examination of Benefits and Costs of
Achieving Ambient Standards in the South Coast Air Basin. U.S. Environmental
Protection Agency, Washington, DC.
U.S. EPA (U.S. ENVIRONMENTAL PROTECTION AGENCY). (1980). Volatile Organic
Compound (VOC) Species Data Manual, 2nd ed., Publication No. EPA-A50/4-80-015.
Office of Air, Noise, and Radiation, Office of Air Quality Planning and
Standards, Research Triangle Park, NC.
5-4
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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
6.T.I. 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 Westburg (1980). At a
point 6 km from the plar.t 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,
hydroxy (-OH), atomic oxygen (0), and peroxy (*HO_ or -R0?, whers 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 tne 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
constant for the reaction of -OH radicals with toluene of 6.1 x 10" cm^ mol"1
sec" (Perry et al., 1977), the chemical lifetime of toluene in daylight hours
has been estimated to be ^3 hours. The atmospheric residence time of toluene due
6-1
-------
TABLE 6-1
Rate Constants for Reactions of Toluene with
Reactive Species in the Atnosphere
Estimated Average Rate of
Daytime Annual Toluene
Concentration
Species ppcn
Hydroxyl „
radical 1 x 10"°
Atomic
oxygen 3 x 10~
Peroxy _^
radical 1 x 10
Ozone 3 x 10
Rate Constant, Removal, Fraction of
ppm min ppm/min Hydroxyl Rate
9.5 x 103 3.? x 10"^ 1
1.1 x 102 3.3 x 10~7 10~3
2.5 x 10~7 2,5 x 10~11 4 x 1C"8
5 x 10~7 1.5 x 10""8 5 x 10~5
Source: NRC, 1980
6-2
-------
to "OH radical reactions has been estimated to be 1.9 days by Cupitt (1980),
However, the half-life or residence time value is subject to considerable
uncertainty and may vary on a day-to-day basis by as much as an order of
magnitude depending on sola'r intensity, temperature, and local trace gas
composition of the atmosphere.
The reaction products formed from toluene under simulated atmospheric
conditions are not known with certainty. According to the study of O'Brien
et al. '(1979), the gaseous products of the reaction are o-cresol, m- and p_-
nitrotolaene, benzyl nitrate, and benzaldehyde. Of these products, o-cresol and
benzaldehyde are the major components, each composing about 8% of the total
product yield. The mechanisms by wh.Joh 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).
Other reaction products also are formed from toluene reactions under
simulated atmospheric conditions. Some of the ring fragmentation products
formed are acetylene, acetaldehyde, and acetone. The total yield of these
products is much less than 1J. 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
6-3
-------
CH,
.OH
addition
OH
•f HO,
CH,
CH,
OH
OH
NO.
CH,
CH.
OH
NO,
CH-
CH,
.OH
FIGURE 6-1
Proposed Reaction Pathways of Toluene Under Atmospheric Conditions
Source: NRC, 1980
6-H
-------
strong eye irritants tind oxidizing agents, and may induce plant damage (NRG,
I960). 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, 1973). Studies of actual and simulated oil spills in seawater indicate
that virtually all hydrocarbons smaller than C1t- 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,
1976); however, washout should be considered an insignificant removal process
for toluene from air (NRC, 1980). The probability of physical removal of toluene
from the atmosphere was also speculated to be unlikely by Cupitt (1980).
6.2. AQUATIC MEDIA
6.2;1. Fate. 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
detenu ned.
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 co tact tire. At a water temperature of 25°C and a
h
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 ether 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
hydrolysis 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
measured octanol-water partition coefficient of 2.51 (U.S. EPA, 1980) (as
opposed to the theoretical value for log BCF of 2.69 [Chiou et al., 1977]), the
6-5
-------
U.S. EPA (1930) 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 th?.t 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
calculated 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 net analyzed for toluene
because of inadequate analytical procedures. It was determined, however, that
the bioconeentration factors in starry flounder for Cj, and Cr substituted
bea-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.
Water to Air: Although there are no experimentally determined evaporation
rates ot toluene from water, there are theoretical models available for
predicting the rate of evaporation of slightly-soluble materials from aqueous
solution (Mackay and Wolkoff, 1973; Liss 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 (197*0
and the Henry's law constant for a solute as calculated by its solubility, vapor
pressure, and rnclecular 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 intramedla transfer of toluene in water can be calculated from this
half-life (t 1/2) value. If the t . and the current Telocity are assumed to be
6-6
-------
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 = -FT—, r5^ = 0.3^9 for seawater (NRC, 1980)
[toluene ]liq
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.
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
;5ystem (EXAMS), Slimak (1980) has determined that bottom sedimonts account for
ever 90$ of the total toluene discharged into surface waters under steady-state
conditions. The values for the distribution of toluene between surface water and
sudiment as determined by the.EXAMS modeling do not agree with the 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 al. (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
6-7
-------
transfer to air and water, and a portion will undergo intramwdia transfer. The
part that stays in soil may participate in chemical reactions (including photo-
chemical reactions) and biological degradation and transformation. The relative
importance of intermedia transfer and chemical and biological reactions of
toluene in soils is not known.
Investigations by Wilson et al. (1981) indicate that volatilization, bio-
degradation, and biotransfonnation 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 AIR — Laboratory experiments of Wilson et al. (1981) show
that 38 to 66$ of 0.2 to 0.9 mg/& of toluene applied to the surface of sandy soils
with 0.087? organic carbon will volatilize to air. The volatilization rate is
dependent on the nature of the soil. The volatilization rate may be signifi-
cantly lower for soils with high organic contents due to their sorption
properties (Slimak, 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 contami-
nation 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. (1981). it can be concluded that the
transport of toluene from soil to water is probably not a major transfer pathway.
These investigators showed that 2 to 13? of the applied toluene on a sandy soil
system could be eluted through a column 140 cm high. 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
"etard the aqueou? elution process due to higher sorption properties of the soils
toward toluene.
6.4. ENVIRONMENTAL PERSISTENCE
6.4.1. Biodegradation and Biotransfonnation
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
6-8
-------
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 (1961) 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. (1981) indicated that from 21 to 60? of toluene
eluted through 1*40 cm of sandy soil biodegraded. The authors stated that the
process was probably very sensitive to the soil typ-? and, therefore, may or may
not be an important removal process of toluene from a particular soil system.
More literature, however, exists on the biodegradation of toluene in
aquatic environments. In a U.S. EPA report (Slimak, 1980), 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) multicompartment Exposure Analysis
Modeling System (EXAMS). The report stated that the biodegradation of toluene
accounted for 0.31, 4.81, 0.36, 0.09, and 18.47? of the total toluene loss in
oligotrophic lakes, eutrophic lakes, clean rivers, turbid rivers, and ponds,
respectively. Using the standard dilution method and filtered wastewater
effluent as the seed to determine the biochemical oxygen der^nd (BOD), the
biodegradability (percentage 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 (TOC) 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 MO? 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 reacned 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/S, 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?
oxidation had taken place (compared to 44.7? reported by Malaney and McKinney,
6-9
-------
1966). One sludge sample, however, acclimated to benzene, oxidized greater than
30$ of the toluene after 180 hpurs. It should be noted that the high concen-
tration of toluene used in this study probably was toxic to the organisms in the
sludge.
Tabak et al-. (1981) studied the biodegradation of toluene at lower concen-
trations (5 mg/S, and 10 mg/&) with settled domestic wastewater as microbial
inoculum by the static-culture flask-screening procedure. Toluene was
completely biodegraded in 7 days at 25°C by this method. At influent concen-
tration levels of 70 \ig/i and ">12 ng/£, the removal of toluene by activated
sludge treatment at two municipal facilities was found to be at least 99?
(Patterson and Kodukala, 1981). In 31 industrial facilities, activated sludge
treatment was found to remove an average of 52? toluene at an average influent
concentration of 119 ng/&. Tne treatment of three industrial effluents in
aerated lagoons removed an average of >93? toluene initially present at an
average concentration of 143 (J.g/& (Patterson and Koaukala, 1981).
i
The degradation of toluene has also been studied in mixed cultures of
bacteria. Chambers et al. (.1963), using phenol-adapted bacteria, reported 38?
degradation of toluene after 180 minutes. It should be noted that phenol is the
metabolic degradation pathway of toluene. In another study, Dechev and Damyanova
(1977) grew sludge cultures in either phenol, xylene, or toluene as the sole
carbon source and found that phenol-adapted bacceria 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
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 .Imperfecti, 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 Wcstlake, 1979). Using an oxygen electrode to measure
oxidation, Buswell and Jurtshuk (1559) found that resting cells of an n-octane-
utilizing Corynebacterium sp. oxidized only 7% of the available toluene compared
to 100? oxidation of n-octane. Toluene did not serve as a growth substrate in
6-10
-------
this experiment. Kapraleck (1954) isolated a Pseudomonas-type bacteria from the
soil of a petroleum deposit that used toluene. Pseudomonas sp. and Achromobacter
sp. 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 hydhoxylated toluene. In contrast, Nei et al. (1973) found
little oxidation of toluene by phenol-using yeast.
The metabolic pathway for the bacterial oxidation of toluene has been
studied with soil microorganisms (Figure 6-2) and reviewed by Gibson (1971) and
Subramani-an et al. (1978). On the basis of simultaneous adaptation studies,
Kitagawa (1956) concluded that Pseudomonas aeruginosa oxidized toluene via
benzyl alcohol and benzaldehyde to' benzoic acid and ther to catechol. This
pathway was supported by the investigations of Nozaka and Kusunose (1968). A
Mycobacterium sp. also produced benzoic acid from toluene (Atkinson and Newth,
1968), as did a methanotrophic bacterium (Methylosinus trichosporium) (Higgins
et al., 1980).
An alternative pathway was proposed by Glaus and Walker (1964) using a
Pseudomonas sp. and an Achromobacter 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 Kusunose (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-methylcatechcl was found in cultures of a mutant
strain of P_. putida (strain 39/D) (Gibson £t 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) ( c^s-2,3-DH-2,3-DOH TOL) (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 "ield 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-6-0X0-2,cis-4, cis-HA) and then to acetate,
pyruvate, and acetalydehyde and to C0_ and energy (Bayly et al., 1966). The
conversion of toluene to compounds that can be used as sources of carbon and
6-11
-------
CH,
TOLUENE
• fNZYl 4LCOHOL
X
tB-J. 1-DM-I J-DOH TOL
»ENZ»LD£KroE
• ENZOICtCID
\
J-MtTHTLCATtCMOL
/
/
'
fttETHVUWUCONIC
ACID
IHUCON'C ACtO
HVDBOKVMUCONIC
ttMIALRfHVDt
J
MrTHYLNYDROSYMDCOWIC
HMIALDtMVOt
rtTALDEHVDE
ACtlATE
CO, • tutncv
FIGURE 6-2
Microbial Metabolism of Toluene
6-12
-------
I
energy suggests that toluene will be degraded rapidly by these microbiai 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,
suggesting that the plasmid-borne gene responsible for toluene degradation is
wide spread in the soil microbiai population. The plasmid can also be transposed
into other hosts, further increasing the number of toluene-degrading bacteria
(Broad 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^ a_l., 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). Broad et al. (1977) have speculated that the
ortho pathway of toluene degradation probably is chromosomally coded.
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-------
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6-18
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6-19
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6-20
-------
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6-21
-------
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, (4) 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 8.1.1.3).
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 u~ban areas not containing toluene manufacturing or gasoline refining
sites are in the same range as the sites containing these industries. It can be
concluded also from Ta-bl-e- 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 pp'o. 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 Westberg (19BO) 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
7-1
-------
I
ro
TABLE 7-1
Atmospheric Concentrations of Toluene
Concentration, ppb
Location
Urban Areas :
Azusa, CA
Azusa, CA
Baton Rouge, LA
Eatsto, NJ
Bayonne , NJ
Birmingham, AL
Burnett, TX
Camden , HJ
Deer Park, TX
Sampling
date
1967
1975
1977
1979
1969
1977
1977
1979
1974-1977
Median or
Average
14
13
0.15
0.6
11.8
2.0
30.0
6.97
67
Highest or Range
23
5.9-31
0.05-0.19
ND-3.5
NR
0.21-1). 7
NR
0.23-38
3.2-99
Reference
Altshuller et al.,
1971
Mayfsohn et al.,
1976
Pellizzari, 1979a
Bozrzelli et al.,
1980
Lonneman et al.,
1974
Pellizzari, 1979a
Oldham et al. ,
1979
Bozzelli et al.,
1980
Oldham et al.,
1979
Lonneman et al.,
1979
-------
TABLE 7-1 (cont.)
Concentration, ppb
Location
Denver , CO
Denver City, TX
Edison, NJ
El Dorado, AR
Elizabeth, NJ
El Monte, CA
El Paso, TX
Houston, TX
Irving, TX
Jacinto City, TX
Sampling
date
1973
1973-1980
1977
1976
1978
1978-1979
1975
1978
1973-1980
1977
1973-1974
Median or
Average
9
8.1
1000
350
9.7
7.5
16.0
5.7
10
9.5
18
Highest or Range
74
0.71-37
70-5500
NR
0.12-39
ND-85
2.9-51
1.0-99
0.21-53
NR
6.3-29
Reference
Russell, 1977
Singh et al.,
1980
Russell, 1977
Oldham et al. ,
1979
Pellizzari, 1977
Psllizzari, 1979a
Pellizzari, 1979a;
Bozzelli et al.r
19PO
Mayrsohn et al.,
1976
Pellizzari, 1979a
Brodzinsky and
Singh, 1982
Oldham et al.,
1979
Lonneman et al.,
1979
-------
TABLE 7-1 (cont .)
Concentration, ppb
Location
Jones State Forest, TX
La Porte, TX
Lake Charles, LA
Liberty Mound, OK
Linden, NJ
Long Beach, CA
Los Angeles, CA
Sampling
date
1978
1973
1978
1977
1969
1975
1963-1965
1966
1967
1968
1971
1973
1979
Median or
Average
1. t
5.6
0.33
0.98
15.0
6.7
59
37
30
39
50
22
1 i.7
Highest or Range
0.6-13.1
m
0.08-0.58
0.07-9.9
m
1.1-23
m
129
50
NR
m
m
1.1-53.1
Reference
Seila, 1979
Oldham et al . ,
1979
Pellizzari, 1979b
Eaton et al.,
1979
Lonneman et al.,
1971
Mayraohn et al.,
1976
Leonard et al.,
1976
Lonneman et 11 .,
1968
Altshuller et al.,
1971
Kopeznski
et al., 1972
Altshuller et al.,
1971
Leonard et al .,
1976
Singh et al . ,
1979
-------
TABLE 7-1 (cont.)
Location
Magtaa, UT
Manhattan, NY
Newark, NJ
Newbury Park, CA
Oakland, CA
Pasedena, TX
Philadelphia, PA
Phoenix, AZ
Rio Blanco County, CO
Riverside, CA
Sampling
date
1977
1969
1979
1978
1979
1973-1974
1979
1979
1978
1970-1971
Concentration, ppb
Median or
Average Highest or Range
0.33 0.23-0.43
13-5 NR
2.6 0.01-13
NR 0.7-13
3.1 0.15-16.9
25 2.4-46
4.5 2.1-5.7
8.6 0.54-38.7
1.2 0.7-2.5
NR 9-18
Reference
Pellizzari, 1979a
Lonneman et al . ,
1974
Bozzelli et al. ,
1980
Hester and
Meyer, 1979
Singh et al.,
1979
Lonneman et al^
1979
Westberg and
Svreany, 1980
Singh et al. ,
1979
Arnts and
Meeks, 1981
Stephens, 1973
-------
TABLE 7-1 (cont.)
Location
Riverside, CA
Rutherford, NJ
S. Charleston, VW
South Amboy, NJ
Sperry, OR
St. Louis, MO
Troy, NY
Tulsa, OK
Tuscaloosa, AL
Upland, CA
Vera, OK
Sampling
date
1980
1979
1977
1979
1977
1980
NR
1977
1977
1975-1977
1977
Concentration, ppb
Median or
Average Highest or Range
5. a 3.0-9.0
8.14 0.01-33
0.05 0. OH -0.07
2.2 ND-9.7
1.4 0.145-4.8
1.5 0.2-2.6
1.0 NR
1.6 0.04-13
38 24-85
9.9 0.8-38
0.81 0.26-1.8
Reference
Singh et al.,
1980
Bozzelli et al.,
1980
Pellizzari, 1979a
Bozzelli et al.,
1980
Eaton et al.,
1979
Singh et al.,
1980
Atwicker et al.,
1977
Brodzinsky and
Singh, 1982
Holzer et al.,
1977
Brodzinsky and
Singh, 1982
Eaton et al., 1979
-------
TABLE 7-1 (cont.)
-i
i
Location
Wyona, OK
Rural and Remote Areas:
Brethway-Gunderson Kill, WA
Camel's Hump, VT
Hell's Canyon, ID
Moscow Mt., ID
Point Reyes, CA
Grand Canyon , AZ
Talladega National Forest, AL
Sampling
date
1977
1971
1971
1971
1971
1971
1977
1977
Median or
Average
0.30
0.01
1.0
0.3
0.2
0.2
Trace
0.14
Concentration, ppb
Highest or Range
0.09-0.7
NR
NR
NR
NR
NR
Trace
0.2-1.3
Reference
Eaton -et al.
Robinson et
1973
Robinson -et
1973
Robinson et
1973
Robinson et
1973
Robinson et
1973
Pellizzari,
Holzer et al
, 1979
al.,
al.,
al.,
al.,
al.,
1979a
• i
Srnokey Mountain, TN
1978
0.96
0.3-2.4
1977
Arnts and Heeks,
1981
-------
TABLE 7-1 (cont.)
Location
Global:
Zurich, Switzerland
Toronto, Canada
Berlin, W. Germany
i -Stockholm, Sweden
The Hague, Nether land
Helsinki, Finland
Gatwick Airport, England
Sampling
date
NR
1971
1975-1976
NR
1974
1979
1979
Median or
Average
39
30
27
NR
18
NR
58.6
Concentration, ppb
Highest or Range
NR
188
2. if -94. 2
0-2.7
5U
15.9-37.1
1.2-809.6
Reference
Grob and Grob,
1971
Pilar and Graydon,
1973
Lahmann^et al.t
1977
Johansson, 1°78
Leonard et al.,
1976
Hasanen et al . ,
1981
Tsanl-Bazaca
et al., 1982
ND = Not Detected
NR = Not Reported
-------
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 U5 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 r.ir. 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
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 STORET system as reported by Little
(1981). Table 7-2 shows the toluene levels for major river basins in the United
States. It is evident from Table 7-2 that 33? of all the monitored surface water
contains toluene levels below a concentration of 10 ppb. The concentration of
toluene in surface water? 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
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
Utjlabeled
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 10.1-100 100.1-1000 >1000
100
100
93 4 4
81 6 66
98 2
100
67 22 11
20 77 3
44 53 3
88 13
100
100
99 1
100
100
100
100
83 14 3 IA
Source: U.S. EPA, 1980a
1A insignificant amount.
7-10
-------
7.1.2.2. INDUSTRIAL WASTEWATERS — Table 7-3 shows the levels of toluene in
industrial effluents as stored in the STORET system (Little^ 1981). It can be
concluded from Table 7-3 that 85% of the effluents showed toluene concentrations
of less than 10 ppb. Fifteen of the reporting stations showed toluene concen-
tration in excess of 100 ppb.
Wastewaters from a speciality chemicals manufacturing plant were analyzed
by Jungclaus et al. (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 to
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 manu-
facturing 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
Biro Bay, Japan, were analyzed for organic matter. It was determined that
toluene constituted 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 1-^ shows the frequency of toluene detection in industrial wastewaters
(U.S. EPA, 1980a)'.
7.1.2.3. PUBLICLY-OWNED TREATMENT WORKS (POTW) — A pilot study of two
POTWs, one handling more or,-anic 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 140 and 13 ppb, respectively. The influent sample at the other plant
had maximum and median toluene concentrations of 37 and 10 ppb, respectively.
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
7-11
-------
TABLE 7-3
Percent Distribution of U.S. Wastewaters Within
a Certain Toluene Concentration Range
Effluent
Discharged
Northeast
North Atlantic
Southeast
Tennessee River
Ohio River
i
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, 1980a
7-12
-------
Industry
TABLE 7-4
Detection Frequency of Toluene in Industrial Wastewatersc
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
Landfill
Mechanical Products
Pubicly-Owned Treatment Works
1/20
2/11
19/81
56/121
11/18
4/98
58/285
50/109
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
3/17
23/35
11/40
Source: U.S. EPA, 1980a
7-13
-------
treated industrial-domestic wastewater showed the presence cf toluene in the
concentration range of 8 to 150 ppb. The frequency of toluene detection in the
treated effluent from the same p.1 ant amounted to 36%. The toluene concentrations
in these treated effluents ranged from 1 to 10 ppb.
7.1.2.4. UNDERGROUND WATER — The Mew York State Department of Health and
the United States Geological Survey examined 39 wells in 1978 for organic contam-
ination in groundwater (Little, 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, 1980a). Eighty seven percent of the monitored data showed
less than 5 ppb (detection limit) toluene. Of the T43 monitored data, only 3
indicated the presence of toluene in the concentration range of H2 to 100 ppb.
All of chese 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 li 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
discovered to be contaminated with toluene (U.S. EPA, 1975b). Concentrations of
0.1 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.
In a survey of volatile organic compounds in water at 30 Canadian potable
water treatment facilities, Otsun et al. (1982) detected toluene in the raw water
with a frequency of 15$ and in the treated water with a frequency of 20$ during
the months of August and September. The average arid maximum concentrations of
toluene in treated Canadian water were reported to be 2 ug/Z. and 27 ug'K,
respectively. The corresponding values for the raw water were <1 (ig/S. and 15
[ig/L, respectively. The frequency of occurrence and the concentration of toluene
in water showed seasonal variation, with the summertime values found to be higher
than the wintertime values.
Nineteen volatile organic compounds, including toluene, were detected at
concentrations below 5 ppb in District of Columbia drinking water (Saunders
7-11
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et al., 1975). These investigators also found that the concentrations of the
various contaminants in tap water varied by uns-pecified amounts from Week to
week, but the chemic?.! 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, an
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
STORET (U.S. EPA, 1980a) 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.
Jungclaus et al. (1978) monitored the sediment from a river receiving
industrial effluent from a specialty chemicals manufacturing plant containing
toluene. However, these investigators could not detect the presence of toluene
i'n the river sediment.
7.1.H. Edible Aquatic Organisms. Of the 59 monitored tissue samples that were
recorded in the STORET system (U.S. EPA, 1980a), 955 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 concen-
trations 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 Miyaki, 1973). A concentration of 5 ppo
was measured in tne 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, 1980b) and in well water near a few landfill
sites (U.S. EPA, 1980c). 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
atmospheres 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.
7-15
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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
results of the monitoring showed that the concentration of toluene ranged from 0
to 277 pprr in difl'erent parts of the work areas (Forni et al., 1971). The
i
determined toluene concentrations at different parts of the plant during the
period 1957 to 1965 are shown in Table 7-5.
TABLE 7-5
luluciic Cuin.o-ii.ra1>. iGn;> J.U I/ iffei ciii. Wui iv Ai'caS
of a Rotogravure Plant in Milan, Italy3
Work Area
Center of Room
Folding Machines
Between Machine Elements
Toluene
Range
1140-239
56-277
3J6~32'4
Concentration, pptn
Annual Mean
203
203
J431
Source: Forni et al., 1971
In "96C, the atovs rotogravure plant was me1""1 to a different location and
the ventilation system of the plant was improved. Subsequent analysis for
toluene showed annual mean concentrations at 156 an'l ?65 ppm near the folding
machines and between the machine elements, respectively (Forni et al., 1971).
Tolu«ne exposure levels for other occupational groups are shown in
Table 7-6. Many of the levels given in this table either originate 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 fcr
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
Lieberraan, 1967). Toluene is used as a lacquer thinner and stain remover in the
leather finishing industry. In ruboer-coating plants, the major source of
7-16
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TABLE 7-6
Toluene Exposure Levels for Different Occupational Groups
Exposure Level
Type of Occupation
Reference
100-1100 ppma
150-1900 ppmb
3-211 ppm
30.6 ppm (mean)0
80-300 ppm
15-200 ppm (mean)
50-1500 ppm
200-400 ppm
300-430 ppm
200-100 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
Rotogv-avure printing
Rotogravure printing
Rotogravure printing
Rotogravure pringlng
Rotogravure printing
Rotogravure printing
Rotogravure printing
Rotogravure printing
Rotogravure printing
Greanburg 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
Szadkowski 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)
Concomitant exposure to butyl acetate (Section 11.2.1)
"Concomitant exposure to other organic solvents (Taolo 11-3)
Concomitant exposure to 20-50 ppm (mean gasoline in a few working places
(Section 11.1.2)
7-17
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toluene emission is the fabric-spreading machine areas. The concentration of
toluene in work areas of these industries is sijowri in Table 7-7-
TABLE 7-7
Toluene Concentrations in Work Areas of
Leather Finishing and Rubber Ccatins; Plants3
Toluene Concentration, pptc
Industry
Leather Finishing
Work Areas
Finishing Area
Washing and Topping Area
Range
19-85
29-195
Average
53
112
Rubber Coating Spreading Machines 3^-120 73
Source: Pagnotto and Liebernan, 1967
Toluene has been detected 'in other occupational atmospheres. Tor example, a
toluene concentration of 0.18 ppzn 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 °',d diesel fuel used in the submarine. Toluene
has been detected in the atmosphere of M15 and M19 antitank cines (Jenkins
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
vulcanization process in the laboratory. Toluene emission in the vulcanization
area from this experiment amounted to 1. .1 pptn. The actual field su-vey 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 7-6.
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.
7-18
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TABLE 7-S
Toluene Concentrations in Selected Work Areas of Tire Manufacturing Plants '
Work Area
Cement Mixing
Extrusion
Tire Building
Curing Prepa-ation
Inspection and Repair
Warehouse
No. of Plants
Surveyed
8
U
2
3
3
2
Area Toluene Concentration, ppa
Mean
2.9
14.0
8.0
0.6
1.9
0.28
Range
0.2-7.7
3-3-50.0
2. 5-13- H
0.1-1.1
0.6-2.7
0.01-0.76
aSource: Van Ert et al., 1980
All of the plants, with the exception of plants where the warehouse sanples
were taken, were surveyed during 1973-77. The warehouse saaples were collected
in 1977-
7-19
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7.3. CIGARETTE SMOKE
The concentration of toluene in inhaled cigarette smoke is approximately
0.1 mg/cigarette (NRC, I960; Dalhamn et al., 1968). Jermini et el. (1976)
determined the concentration of toluene in the sirtestrean smoke of cigarettes.
When 30 cigarettes were inhaled in a 30 ns 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 ffig of toluene in the sidestream smoke of each cigarette. Holzer et al.
(1976) determined the toluene concentration in a 60 m room and found an ambient
toluene concentration of <<0 ppb. When 1 cigarette was smoked in the room, the
concentration of toluene rose to *i5 ppb. This corresponds to 1.1 mg of toluene
contribution from each cigarette. It seeira from this discussion that the main-
stream smoke of 1 cigarette contributes 0. 10 Eg toluene to the smoker. The
sidestreaa saoke, on the other hand, may contain a higher amount of toluene.
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Assessment of Suspended Carcinogens in Drinking Water. Report to Congress,
Washington, DC. (Cited in Syracuse Research Corporation, i960).
7-27
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U.S. EPA (U.S. ENVIRONMENTAL PROTECTION AGENCY). (1977). National Organic
Monitoring Survey, General Review of Results and Methodology: Phases I-III.
(Cited in Syracuse Research Corporation, 1980).
U.S. EPA (U.S. ENVIRONMENTAL PROTECTION AGENCY). (1979). Fate of Priority
Pollutants in Publicly Owned Treatment Works—Pilot Study, Publication No. EPA
HV1-79-300. Performed by Feiler, Burns and Hoe Industrial Services Corp.,
Paramus, NJ.
U.S. EPA (U.S. ENVIRONMENTAL PROTECTION AGENCY). (1980a). STORET Water Quality
Information System, October. 1980.
U.S. EPA (U.S. ENVIRONMENTAL PROTECTION AGENCY). (1980b). Priority Pollutant
Frequency Listing Tabulations and Descriptive Statistics. Memo from D. Neptune,
Analytical Programs to R.B. Schaffer, Director of Effluent Guidelines Div.,
January, 1980. (Cited in Slimak, 1980).
U.S. EPA (U.S. ENVIRONMENTAL PROTECTION AGENCY). (1980c). Volatile Organic
Compound (VOC) Species Data Manual, 2nd ed., Publication Ho. EPA-U50/U-80-015.
Office of Air, Noise, and Radiation, Office of Air Quality Planning and
Standards, Research Triangle park, NC.
VAN ERT, M.D., ARP, E.W., HARRIS, R.L., SYMONS, M.J. and WILLIAMS, T.M. (1980).
Worker exposures to chemical agents in the manufacture of rubber tires: Solvent
vapor studies. Amer. Ind. Hyg. Assoc. _J. 4J_: 212-219.
VAULEMANS, H., VAN VLEM, E., JriNSSENS, H. and MASSCHELEIN, R. (1979). Exposure
to toluene and urinary hippuric acid excretion in a group of heliorotagravure
printing workers. Int. Arch. Occup. Environ. Health. ^(Z): 99-107.
WESTBERG, H. and SWEANY, P. (1980). Philadelphia Oxidant Data Enhancement
Study; Hydrocarbon Analysis. EPA Contract No. 68-02-3339, Washington State
University, Pullman, WA. (As Cited in Brodzinsky and Singh, 1982).
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WILSON, R.H. (19^3). foluene poisoning. J Amer. Med. Assoc. 123: 1106.
YAMAOKA, Y. and T. TANIMOTO. 1977. Behavior of Organic matter in polluted
coastal areas. I, Organic matter in Kraft Pulp mill effluent in Hiro Bay.
Nippon. Kagaku Kaishi, (10), 155^-1559. (Japan). Chem. Abst No, 88: 27^032.
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8, ANALYTICAL METHObOLOGY
Toluene has been analyzed in a number of media 'including the following:
(1) air; (2) waters, (3) soils and sediments, CO 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
discussed below.
8.1. AIR
In addition to the analysis of test mixtures of toluene in air for the
evaluation of methods, toluene has also been deterniined 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.
i 8.1.1.1. SAILING — Toluene can be collected from ambient air in several
different ways including grab sanpling in aluainized plastic bags Oieligan
et al., 1965), Tedlar bags (Altshuller et a.1., 1971; Lonrieman 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 do^s not provide sufficient quantity
of toluene for analytical detection and quantification. Since aabient samples
contain toluene in the parts per billion range, preconcentration steps are often
necessary.
Sample collection by cryogenic 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 tne
collection tube and may reduce or restrict the air flow through the collection
tubes. Various drying agents, such as anhydrone, anhydrous K-CCU, ascarlte, 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 fron 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 !) orders of magnitude
8-1
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higher than the total organics (Isidofov et al., 1977), the chosen sorbets oust
show little affinity toward moisture. Otherwise, the retention capacity of the
gorberits will be reached much sooner than desired.
A number of sorbents such as Tenax GG (Holzer et al., 1977; Krost et al.,
1982), various carbonaceous materials (Burghardt and Jeltes, 1975; Holzer et
al., 1977; Isidorov et al., 1977), Polisorbimid (Isidorov et al., 1977),
molecular sieves and spherisil (Ball, 1976)', and Porapak Q (Johansson, 1973)
have been successfully used. Typically, sampling is performed by drawing air
through a trdp 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 refr'.geratcd state, to
avoid sample loss.
8.1.1.2. ANALYSIS. — The method of analysis usually depends on the method
of sample collection. The earlier investigators who used plastic bags or glass
bottles for collection of grab aanple'3 used a trapping system for concentrating a
relatively large volume (1 t;> 10 £) 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 headed quickly tr: vaporize and transfer the trapped compounds
into the gas chroaiatographic (GO columns. The columns used '.r/ earlier investi-
gators (Lonnesati et al., )9t>8; Aitshuller et al., 1971) for aromatic separations
consisted of Ion*, o^en-tubuiar columns eoat.ed with m-bis( *-p le.-ioxy-phenoxy )-
benzene combined with Apiezon grease on a packed dual column with SF-9& a^ the
liquid phase 'Filar arid Graydon, 1973V.
The more recent, met.nods, which use sorbents for trapping organics, connect
the trap to a (JC syattm via multiple-port gas sampling valves. The trap is
heated quickly and the desorbed organics are passed through the chromatographic
columns. Because the collected samples contain a multitude of o^gani-x,, capil-
lary columns are rioroj-illy used for the resolution of the organics. The Grob and
Grob (1971) technique, i-ivlving th« passage of the ther-mally desorbed organics
through a small uncoated section of the capillary column cooled cryogenically, is
used. When the collection is completed, this section of the capillary is heated
quickly and the sample is separated on the remaining portion of the analytical
column. A number of coating materials for capillary columns including
8-2
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Emulphor ON-870 (Holzer el aJ ., 1977), UCON 50 HB 2000 or 5100 (Johansson,
1978), dinonyl phthalate (Isidorcv et al., 1977), A1?0? (Schneider et al., 1978),
DC-550 (Louw and Richards, 1975), OV-17 and OV-101 (Pellizzari et al., 1976) have
been used.
In one method, thermal desorption of the organics from the aorbents was
replaced by solvent desorption (Burghardt and Jeltes, 1975). In this procedure,
the organics aorbed 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'-cyanoethoxy)-propane.
The quantification of toluene separated by the GC columns is done almost
exclusively by flame ionization detectors (FID). Confirmation of the authen-
ticity of the GC peaks often is provided by coupJe'l mass spectrometers (MS), with
or without the aid of a computerized data system (Holzer et al., 1977; Pellizzari
et al., 1976; Krost et al., 1982).
A continuous automated procedure for determining toluene in the ambient air
was developed by Hester and Meyer (1979). This method needs no sample preconcen-
tration prior to analysis. In this method, a small diaphragm pump activated by a
timer automatically injects air into a 1 mi gas-sampling (GS) loop of a GC every
10 minutes. The separating column was packed with Chromosorb \f coated with N, N-
bi3(2-cyanoethyl)fonaamide. 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. PR£F£RRtD 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 deaorption efficiency of t.oluene is excellent with Tenax GC.
The generation of artifacts during therma.1 elution i-nth Tenax GC can be elimi-
nated largely by proper clean-up of the sorb»".t, °r.d by following the GC condi-
tioning procedure (Kolzer et al., 1977). The greatest advantage of the ambient
sorption-thermal elution method is its extreue 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
8-3
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(PID) may have higher sensiMvity. than flsjne ionization detectors, this higher
level of sensitivity is not required when the samples are precoricentrated by
solid sorbenta. 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-cyanoe-
tncxy)-propane are probably most suitable for* the separation of aromatic compo-
nents.
8.I.I.M. 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 (l mi) 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
normally is much higher than in ambient air. Therefore, the collection of
saaples in certain instances may not require a concentration step. The
collection of samples by the grab method has been used by a nuraber of authors
(Tokunaga et al., 1971; Chovin and Lebbe, 1967).
Soae 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., 1975), and nitrating solution (Chovin 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.
Silicb gel (Ogata et al., 1975; Tokunaga et al., 1971), activated carbon
(Esposito and Jacobs, 1977; Fracchia et al., 1977; Reid and Halpin, 1968; Fraser
and Rapoaport, 1976; NIOSH, 1977) and Tenax GC (Nimmo and 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
-------
gorbents ia 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 beentapplieJ (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 (Tokur.^aa
et al., 197't) or bis-(beta-cyanoethyl)formamide (Chovin and Lebbe, 1967). Flame
ionization detectors were used for the quantification of toluene in both cases;
however, this method is capable of analyzing toluene in work atmosphere at
concentrations cf around 10 ppm (Chovin and Lnbbe, 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 co-contaminants 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 Haipin, 1968; NIOSH, 1977; Var. Ert et al., I960), 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 desorplton efficiency with CS, (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 51 methanol to CS2 Increases the
desorption efficiency to almost quantitative value fFracchia et al., 1977).
When Tenax GC or Chromocorb 102 is used as the sorbent, elution by thermal
process is the method of choice (Nimroo and Fiahburn, 1977). Although this method
may require multiport sampling valves and a cryogenic sample trap for the trans-
fer of samplts 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.
8-5
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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., 197*0, UCC W-982 (Nimrao and
Fishburn, 1977), N,N-bis(2-cyanoethyl)fortnamide (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., 1971!). The
accuracy of the detector tubes for toluene quantification is rather poor, parti-
cularly in the presence of other organic vapor (Tokunaga et al., 1971)). There-
fore, the detector tubes are suitable for the rough estimation of toluene concen-
tration in the work atmosphere. More recently, detector tubes designed for long-
term sampling and determination of toluene have become available. A laboratory
evaluation of a few commercially available long-tern detector tubes was Bade by
Jentzsch and Fraser (1981). The results indicate that the color development of
these tubes is isore dependent upon humidity and sampling volume than the short-
term tubes.
A simple directly-combined uC-Ifi (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 fross th
-------
in the case of ambient air samples, N,N-bis(2-cyanoethyl)formaraide liquid phase
will provide one of the best separations for the aromatics.
8.1.2.4. DETECTION LIMIT — The detection limit for toluene by carbon
3orpt,ion-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 et al, 1980). For a. 100 mi eample, the Tenax GC
sorptlon-thennal desorption method showed a detection limit of 0.5 ppb (Nimmo
and Fishburn, 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 betttr
sensitivity than the method cf hot headspace analysis 'Twibell and Hose, 1977)and
has potential for use in cases where the presence of toluene needs confirmation,
such as gasoline spills.
8.1.IJ. 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 analy7ed by Brodowski et al. (1976). The method
consisted of collecting grab samples In stainless steel sampling bulbs and
injecting Q.l> m<: of tht gaa into a GC. The seoarating columns were dual stain-
less steel colictns packed witn 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 aol ? by this aethod rBrodowski et al.. 1976).
8.2. WATER
Toluene has been determined in a number of aqueous raedla 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 paraaeters are dependent on the operating process, continu
8-7
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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 (o.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
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 oust be iced or refrigerated
during transportation and storage. All such wastewater saaples should be
analyzed within 7 days of collection (Federal Register, 1979).
8.2.2. Analysis. Although direct injection (Jungclaus et al., 1978) and solvent
extraction (Jungclaus et al., 1976) methods have been used to determine the
concentration of orgar.ics 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 trie concentrativo evaporating step.
The three most commonly used methods for toluene analysis in aqueous media
are (1,1 purge and trap, (2) headspace, and (3) sorption on solid sorbents. Each
of these methods is individually discussed below.
6.2.2.1. 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;
flyan and Fritz, 1978), in wastewatera (Bellar and Lichtenberg, 1979; Rawlings and
Samfield, 1979; Jong:laus et al., 1978), and in r inwater (Seifert and Ullrich,
1976). The U.S. Environmental Protection Agency recommends the use of this
aethod 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
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
8-8
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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 al.,
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 reso ition 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 Zurcher, 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 m£ 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
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 mil) of water is
introduced into a specially designed enclosed glass apparatus (100 mJl), 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 column is
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
8-9
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Strength.in solution. Therefore, the same concentratipns of a component present
j.. 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 (Drozd et al.,
1^73) 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), arid fiyan 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-H (Ryan and Fritz, 1978). The sorbed
organics including toluene are desorbed either by solvent extraction (Pfaender,
1976) or by thermal desorption (Ryan and Fritz, 1978), and are 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 also can 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
8-10
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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
a maximum capacity, the containers must be tightly capped with contamination-
free lids to prevent loss of volatile components and to exclude possible
oxidation. The samples should be refrigerated (4°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 unlikely 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 W% when 0,1 to 3-0 |ig 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).
8.4. 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 Thomson (1982).
In this method, the acidic and basic constituents were removed by ion-exchange
chromatography prior to fractionation into groups. Alumina, chemically bonded
silica-R (NH2)2, and 2,4-dinitroanilinopropyl-silica (DNAP-silica) were used for
liquid chromatography class separation of aromatic hydrocarbons. On the basis of
8-11
-------
retention strengths and grouping tendencies, the DNAP-ailica was found to be
superior than alumina and silica-R (NH ) .
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 in blood, in urine, and in
mothers' milk 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., 197*1; Anthony et al.t 1978; Radzikowska-Kintzi and
Jakubowski, 198U. According to this method, blood is equilibriated with air in
a closed container at a fixed temperature. The headspace gas is injected into a
GC-FID system for detection of toluene. The method can be used for quantifi-
cation of coluene in blood by the standard addition method as described in
Section 8.2.2.2.
8.5.2. Uriny. 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 (Uraberger and Fioresse, 1963), UV spectrometry (Pagnatto and
Lieberman, 1967), and thin-layer chromatography (Bieniek and Wilczok, 1981);
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
hippunc acid is esterfied. with 1-p_-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 ml urine was determined to be 5 ppm.
Hippuric acid is an endogenous metabolite common in human urine, but toluene
exposure enhances jts level. However, o-cresol may be a more specific urine
metabolite and may be regarded as a better index of toluene exposure in humans
(Hansen and Dossing, 1982). A recent method (Hansen and Dossing, 1982) deter-
mined the urinary hippuric acid and o-cresol levels by a high-porfcrmance liquid
chromatographic ( HPLC) method. In this method, the hippuric acid level in urine
was determined by extracting it with acetonitrile and injecting the extract onto
8-12
-------
the HPLC column. The o-cresol level in urine was determined by digesting the
urine with concentrated sulfuric acid and extracting the digest with cyclo-
hexane. The cyhclohexane layer was first washed with a phosphate buffer and
finally extracted with sodium hydroxide. The aoiiooi ii/u« uAiut p'uaac wds injected
onto the HPLC column for the determination of o-cresol level. The HPLC system in
both cases consisted of a Lichrosorb Si 60 column and a UV detector. The
detection limits were found to 0.05 rag/mi and 0.05 ^g/mi for urine hippuric acid
and £-cresol, respectively.
8.5.3- Mother's Milk. The levels of toluene in mother's milk for populations
in the vicinity of chemical manufacuring plants and/or industrial user facili-
ties in the United States were Measured by Pellizyari et al. (1982). The
volatile compounds including toluene in the milk samples were determined by the
purge and trap method (Section 8.2.2.1.), followed by thermal desorption and
capillary GC-MS analysis. Of the total of 12 samples collected, 8 samples
qualitatively showed detectable levels of toluene. The detection limit for these
analyses was not specified by the authors.
8.6. FOODS
A headspace GC technique for quantification arid 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 p£~ billion range can be determined by this
nuthod.
8.7. CIGARETTE SMOKE
The concentration of toluene both in sidestream smoke (Jermini et al., 1976)
and mainstream smoke (Dalhamn et al., 1968a) has been determined. For the
determination of toluene in mainstream smoke, standard cigarettes w?re smoked by
machine under standardized conditions (a 2 second 35 mi. puff once every minute).
The mainstream smoke is collected in a cold trap (DaJhamn et al., 1968b). 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
smoke can be collected by drawing the smoke through a solid sorbent tube packed
with Tenax GC. The Tenax GC sorbent tube can be thermally eluted onto a glass
8-13
-------
capillary column for the determination of toluene content. Adoption of a cojd
trap for solitless 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),
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BELLAR, 7. A. and LICHTENBERG, J.J. (1979). Semiautomated headspace analysis of
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Materials, p. 108-129.
BERTSCH, W,, ANDERSON, E. and HOLZER, G. (1975). Trace analysis of organic
volatiles in water by gas chromatography-mass spectrometry with glass capillary
columns. _J. Chromatogr. JJ£: 701-718.
BIENIEK, G. and WILCZOK, T. 1981. Thin-layer chromatography of hippuric and m-
methylhippuric acid in urine after mixed exposure to toluene and xylene. Brit.
i' -Ind- Med. 38:- 304-306.
8-11
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BRODOWSKI, P.T. , WILSON, N.B. and SCOTT, W.J. (1976). Chromatographic analysis
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Chem. 18(1?) : 1812-1813.
BURGHARBT, E. and JELTES, R. (1975). Gas Chromatographic determination of
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Environ. 9_: 935-9140.
CAPEROS, J.R. and FERNANDEZ, J.G. (1977). Simultaneous determination of toluene
and xylene metabolites in urine by gas chromatography. Brit. _J. Ind. H^d .
31: 229-233.
CHOVIN, P. and LEBBE, J. (1967). Chromatography of aromatic hydrocarbons. I.
The .determination of gas chromatogr&phy of aromatic hydrocarbons in the air of
!
working environments. Occup. Health Rev. 19( 1-2) : 3-10.
DALHAHN, T. , EDFORS, M.L. and RYLANPER, R. (1968a). Mouth absorption of various
compounds in cigarette smoke. Arch. Environ. Health. 16(6) : 831-835.
DALHAHN, T., EDFORS, M.L. and RYLANDER, R. (1968b). Retention of cigarette
scvoke components in human lungs. A_rcf_. Environ. Health. 17 : 7^6-7^8.
DeVERA, E. R. , B. P. SIMMONS, R.D. STEPHENS, and D.L. STORM. (1980). Samples and
Sampling Procedures for Hazardous Waste Streams. U.S. EPA Report No. 600/2-
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through NTIS. Order No. P3 80-135353, Springfield, VA.
DOWTY, B.J., ANTOINE, S. R. and LASETER, J.L. M979). Q'-sr.t i tat, i vc zr,Z qualita-
tive analysis of purge*bli organics by high-resolution gas chromatography and
flase ionization detection. In: Measurement of Organic Pollutants in Water and
Wastevater. ASTM STP 686. Van Hall, C.W., ed. Philadelphia, PA: American
Society for Testing and Materials, p. 24-35.
8-15
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DKOZD, J., NOVAK, J. and RIJKS, J.A. (1978). Quantitative and qualitative*
headspace gas analysis of parts per billion amounts of hydrocarbons in water. A
study of model systems by capillary-column gas chromatography with splitless
sample injection. _J. Chromatogr. 156:
ESPOSITO, G.S. and JACOBS, B.W. (1977). Chromatographic determination of
aromatic hydrocarbons in ambient air. Amer. Ind. Hy_£. Assoc. 36 : H01-H07.
FEDERAL REGISTER. (1979). Purgeable Aroraatics— Method 602. Federal Register.
FETT, E.R., CHRISTOKFERSEN, D. j . and SNYDER, L.R. (1968). Routine determination
of benzene, toluene, ethyibenzene and total aromatics in hydrocarbon solvents by
a combination of liquid and gas chromatography . _J. Gas Chromatogr. 6_: 572-576.
FRACCHIA, M., PIERCE, L. , GRAUL, R. and STANLEY, R. (1977). Desorption of
organic solvents from charcoal collection tubes. Amer. Ind. J^. Assoc _J_
PHASER, D.A and RAPPA'PORT, S. (1976). Health aspects of the curing of synthetic
rubbers. Environ. Health Perspect. 17 : ^5-53.
GRIZZLE, P.L. and J.S. THOMSON. (1982). Liquid Chromatographic separation of
aromatic hydrocarbons with chemically bonded ( 2, U-dinitroanilinopropyl) Silica.
Anal. Chem. 5J*_: 1071-1078.
GROB, K. and ZURCHER, F. (1976). Stripping of trace organic substances from
water: Equipment and procedure _J. Chromatogr. 117 •' 285-29^.
GROB, K. and GROB, G. (1971). Gas-liquid chromatographic/inass spectrometric
investigat-.on of C.f-C-n organic compounds in an urban atmosphere. J. Chromatogr.
62_: 1-13. (Cited in Syracuse Research Corporation, 1980).
HANSEN, S.H. and DOSSING, M. (1Q82). Determination of urinary hippuric acid and
o-cresol, as indices of toluene exposure, by liquid chromatography on dynami-
cally modified silica. J. Chromatogr. 229: 111-1H8.
8-16
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HESTER, N.E. and MEYER, R.A. (1979). A sensitive technique for measurement of
benzene and alkylbenzenes in air. Envi ron. Sci. Technol. 1j(1) ; 107-109.
HOLLIFIELD, H.C.. BREDSH, C.V., DENNISON, J.L., ROACH, J.A. and ADAMS, W.S.
(1980). Container-derived contamination of maple syrup with methyl raethacry-
late, toluene, and styrene as determined by headspaee gas-liquid chromatography.
J_. Assoc. Off. Anal. Chen. 63.: 173-177.
HOLZER, G., ORO, J. and BERTSCH, W. (1976). Gas chromatographic-maas spectro-
aetric evaluation of exhaled tobacco smoke. J. Chrooaatogr. '\ 26 : 771-185.
HOLZER, G., CHANFIELD, H., ZLATKIS, A., BERTSCH, W., JUAREZ, P., HAYFIELD, H.
and L.IEBICH, H.M. (1977). Collection and analysis of trace organic emissions
from natural sources. J. Chromatogr. 1*42: 755-764.
ISIDOROV, V.A., ZEKKEVICK, I.G. and IOFFE, B.V. (197-7). Investigation of new
sorbents for the gas-chromatographic-ciass-spectrooetric determination of traces
of volatile organic compounds in the atmosphere. Translated froc Doiclady
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an industrial wastevater: A case study of their environmental impact. Envi ron.
Sci. Technol. 12(1); 88-96.
KRPST, K.J., PELLIZZARI, E.D., WALBURN, S.G. and HUBBARD, S. A. (1982). Collec-
tion and analysis of hazardous organic emissions. An a . 1 . Chgm . 51 : 810-817.
LINGC, R.D., MELTON, R.G.; KOPFLER, F.C., COLEMAN, W.E. and MITCHELL, D.E.
(1977). Quantitative analysis of volatile organic compounds by GC-MS. J_. Areer.
Water- Works Assoc.- 69(11, pt . 1): 605-61?.
LONSEMAN, W.A., BELLAR, T.A. und ALTSHULLER, A. P. (1968). Aromatic hydrocarbons
in the atmosphere of the Los Angeles Basin. Erv: ron. Sci . Technol.
2(1 M: 1017-1020.
LOUW, C.W. and RICHARDS, J.F. (197b'. A simple directly combined gas chromato-
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graphic-infrared spectrometri c systen for indentif ication of low molecular
weight hydrocarbons. App J . Spec t rose. 2_9: 15-2*1.
MINISTRY OF LABOUR. (1966). Methods for the Detection of Tox.c Substances in
Air, POO k let No. u : 'oen?en^, Toluene and Xylene, Styrene. London: Her
Majesty's Stationery Office, pp. 1-12.
NELlGAfi, R.E. , LEOSAM;, M.J. and BR1TAN, R.J. (1965). The gas chromatographic
detersalr.atitin of aromatic hydrocarbons in the ataosphere. Reprint of paper
presented to the Division of Water, Air, Lnd Waste Chemistry, American Chemical
Society, Atlantic City. N.J, Septemfce- 12-'' 7, 1965, 2 p.
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tants: A SynposiuE. Clear Air Society of Australia and New Zealand, p.
8-18
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NIOSH (NATIONAL INSTITUTE FOfi OCCUPATIONAL SAFETY AND HEALTH). (1977). Toluene.
In: NIOSH Manual of Analytical Methods, >nd edition. Part II. Standards Comple-
tion Prograa Validated Methods, Vol. 3. NIOSH Publication No. 77-157-C, p. 3"3-1
to 313-6. U.S. Dept. of Health, Education, and Welfare, Public Health Service,
Center for Disease Control, NIOSH, Cincinnati, OH.
NRC (National Research Council). (I960). The Alkyl Benzenes. Committee on
Alkyl Benzene Derivatives, Board on Toxicology and Environmental Health Hazards;
Assembly of Life Sciences, National Research Council. Hashinfton, DC: National
Acadeay Press.
OGATA, M., A3AKARA, H. and SAEKI, T. (1975). Sampling and analysis of some
aromatic, aliphatic and chlorinated hydrocarbon vapours in air: A gas-liquid
chromatographic ar.d colorimetric method. I^nt. Arch. Art>eitsmed. j1*: 25-37.
PAGNOTTO, L.D. and LIE8ERMAN, L.M. (1967). Urinary hippuric acid excretion as
an index of toluene exposure. Aaer. Ind. Hy_£. Assoc. ^. 28: 129-131*.
PELLIZZARI, E.D., BUNCH, J.E., BERKLEY, R.E. and MCRAE, J. ('.976). Determina-
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PELLIZZARI, E.D., HARTWELL, T.D., HARRIS, B.S., WADDELL, R.D., WHITAKER, D.A.
and ERICKSON, M.D. (1982). Purgeable organics in mother's milk. Bull. Environ.
Contaa. Toxieol. 28: 322-328.
PFAE.VDER, F.K. (1976). Analytical Methods Developed. E5E Notes. 12(j|) : 4-5.
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RADZIKOWSKA-KINTZi, H, and JAKUBOWSKI, M. (1981). Internal standardization in
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q
carbons in the parts per 10 range using glai
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q
carbons in the parts per 10 range using glass capillary columns coated with
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TOKUNAGA, R., TAKAHATA, S., ONODA, M., ISHI-I, T., SATO, K., HAYASHI, M. and
IKEDA, M. (197^). Evaluation of the exposure to organic solvent mixture.
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8-20
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U.S. EPA (U.S. ENVIRONMENTAL PROTECTION AGENCY). (1979). Chemistry Laboratory
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\
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the equilibriun vapor analysis method. Vestn. Leningr. Univ., Fiz. Khlm.
3: 132-139.
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9. EXPOSED POPULATIONS
Vhe 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 popu-
lation 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, see 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 the U.S. Census Bureau are
subject to undercounting. The result of this undercounting will be lower
population exposure 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.
The three most likely sources that may lead to dermal exposure of toluene to
the g'.?neral population are usage of vehicular fuels, toluene-containing sol-
vents, and cosmetic products containing toluene. With the recent increase of
self-service gasoline stations around the country, the number of people who may
inadvertently spill gasoline on parts of their body during filling operations
must have increased by a large number. The deliberate use of solvents for
cleaning body grease or inadvertent spillage of cleaning solvents and paint
thinners on parts of the body will a]so lead to dermal exposure to toluene.
Although the extent of exposure may be much less significant compared to the two
aforementioned sources, users of cosmetic products containing toluene are
another group of the general population that is exposed to toluene through the
dermal route. However, no estimate is available on the number of the general
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
Total
Specific
Point Sources
0
0
34
475
1,^34
6,103
19,781
39,064
95,883
269,883
34,316,299
34,748,633
195,
Number of People Exposed
Prototype
Point Sources
'59
2,841
10,200
22,700
33,900
75,200
240,000
246,000
350,000
1,229,000
0
2,210,000
637,768
From
Area
Sources
58,347
446,793
12,3^8,504
42,478,913
66,368,769
0
0
0
0
0
34,977,809
158,679,135
Source: Anderson et al., 1980
9-2
-------
population dermally exposed to toluene from these sources. The usage of other
consumer product formulations containing toluene (see Table 4-20) may cause
inhalation/dermal exposure to toluene. An estimate of the number of people
exposed to toluene from these products is also unavailable.
According to the estimate of the Department of Health, Education, and
Welfare (1977), more than 4.8 million people per year are occupationally exposed
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 estinated 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.
9.1. REFERENCES
ANDERSON, G.2., LIU, C.3., KOLMAN, M.Y. and KILLUS, J.P. (1980). Human Exposure
to Atmospheric Concentrations of Selected Chemicals, Publication No. unavail-
able. Prepared by Systems Applications, Inc., San Rafael, CA, under Contract No.
EPA 68-02-3066. U.S. Environmental Protection Agency, Research Triangle Park,
NC.
PUBLIC HEALTH SERVICE. (I930). Smoking, Tobacco end Health, A Fact Book. U.S.
Dept. of Health and Human Services, Public Health Service, Office on Smoking and
Health.
U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. (1977). National Occupa-
tional Hazard Survey, Vol. III. Survey Analysis and Supplemental Tables. U.S.
Dept. of Health, Education, and Welfare, National Institute of Occupational
Safety arid Health, Div. of Surveillance, Hazard Evaluations, and Field Studies,
Cincinnati, OH, p. 448.
o
This figure is based on the following assumptions: Of the total population of
225 million, 21.4$ are under age 13 (Dept. Commer., 1979) and do not smoke.
Teenagers in the age group 13 to 17 years constitute 7.6% of the total population
(Dept. Crmmer., 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 (P!"1,
1980).
9-3
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10. ESTIMATE OF HUMAN EXPOSURE
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 akin, during some specified time.
Exposure assessment is the qualitative estimation or quantitative determination
of the magnitude, frequency, duration, and route of exposure. Exposure estimates
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 of an absorbed dose is the amount of the intake that 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 it is not the purpose of this section 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.
To estimate human exposure, 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 routes: (1)
inhalation of air, (2) ingestion of water and foods, and (3) exposure through
skin. The next step combines the estimation of environmental concentrations with
a description of the exposed population 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 falls
under a special category, these scenarios will be discussed separately. This
section does not include toluene exposure from the use of consumer products. As
has been mentioned in Subsection 10.5., some consumer products contain high
percentages of toluene.
10-1
-------
Undoubtedly, the use of these consumer products leads to various degrees of
toluene exposure in the general population; however, no data are available to
derive estimates of toluene exposure frote consumer products. Also, the
conversion factors for expressing toluene concentrations in air at 25°C are:
1 ppm :. 3-77 rag/m-5 and in water., 1 ppm :. 1 mg/t.
10;1. EXPOSURE VIA INHALATION
\ Toluene exposure via inhalation can be estimated 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 environmental
setting. Second, the exposure can be estimated from actual monitoring data.
Estimating e^osure on the basis of monitoring data is often a preferred method,
because these data directly provide the environmental distribution of toluene;
however, this method lias 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 population exposed to
toluene. The monitoring data may not provide information on the extent of
concentration variation due to chemical reactivity (e.g., photoreaction,
oxidation in the atmosphere, etc.). These data also do not yield relationships
between materials balance of the emitted toluene and the environmental
concentration distribution in an area. Therefore, the approach toward exposure
estimation in this section has used both the available ambient monitoring data
and the theoretical dispersion modeling of toluene emission 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 ^.^.l. through
4.^.4.), (2) atmospheric reactivity of toluene, (3) meteorological data, which
are available through the U.S. or local weather bureau, and (1) a dispersion
equation to estimate concentration distribution of toluene.
10-2
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Toluene concentration downwind from a source can be estimated using the
following dispersion equation (Turner, 1969):
C(X,0,0) = . Q •
exp
2a
z
where
C(X,0,0) - concentration of toluene at various x coordinates and at zero y
and z coordinates (mg/m )
Q = emission rate (mg/s)
o - horizontal dispersion coefficient of the plume concentration
distribution
a _ vertical dispersion coefficient of the plume concentration
distribution
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)
Assuming U = 5 m/s; Q = 200 x. 10 kg/year - 6.31 x 10^ mg/s; plume height
= 10 m and 20 m; and the values of a and o from the following equation
(Anderson et al., 1980):
O (m) 0.06x(1 H- 0.0015x)~1/2
z 1 /•>
O (m) = O.OBxd + O.OOOIxT
one can calculate the concentration of toluene at different distances from the
source, as given in Table 10-1.
10-3
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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
100 500 1,000 1,500
1.36 0.45 0.15 0.12
0.003 0.31 0.13 0.1C
5,000 10,000
0.02 0.01
0.02 0.01
Source: Slimak, 1980
The calculations of the values in Tab3e 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 thst incorporates these two variables,
as well as building wake effect (enhanced dispersion due to buildings), has been
made for the estimation of spatial concenr.ration of tcluer.e from the najor
stationary sources of toluene emission (Anderson et al., I960).
The dispersion equation developed by Anderson et al. (1980) was used to
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. Included are emissions from production 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.
Thes-,' sources included emissions from gasoline marketing, from the coke-
10-1)
-------
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 sources4
; The three equations used to calculate the spatial concentration distribu-
tion of toluene from ail 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
apatial concentration range of toluene around different sources of emissions.
These values are given in Table 10-2.
TABLE 10-2
Population Distribution and Inhalation Exposure
' Levels of Toluene From Different Sources
Number of People Exposed From
Concentration
Level
(ug/m3)
>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
Specific
Point Sources
0
0
34
475
1,13"
6,103
19,781
39,064
95 , 560
269,883
34,316,299
3t.7t8.633
et al., 1980
Prototype
Point Sources
159
2,841
10,200
22,700
33,900
75,200
2tO,000
246,000
350,000
1,229,000
0
2,210,000
195,637,768
Are?
Sources
58,3t7
446,793
1 2, 348, 504
42,478,913
68,368,769
0
0
L
0
34,977,809
158,679,135
10-5
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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 estimates of
production and use of toluene, (2) the assumption that all plants operate at
the same capacity, (3) omission of certain emission sources, and CO 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 esti-
mates used by Anderson et al. (1980) will lead to higher or lower exposure
estimates. This can be done, however, by comparing these estimates with
the experimentally determined concentration patterns obtained from sources
V
that are reasonably isolated from other sources.
Concentration Pattern Errors: The concentration patterns used in the
exposure computations were obtained througn atmospheric dispersion model-
ing. Any deviations in these estimates from the true pattern (difference in
theoretical ar,d 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 impossible 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 cf exposure
scenarios. Because it may be considered impractical to measure toluene concen-
tration from all possible exposure scenarios, an atteipt has been made to develop
a few of the most prevalent ones.
10-6
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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 l.i|.H.). 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 a./Ticulty with this approach is that the
available monitoring data were often developed for sines with various degrees ot
intermixing between these exposure scenarios. Therefore, inhalation exposure
has been classified under three scenarios: the urban areas, areas containing the
user sites, and ru^al or reaote areas. In this manner, the exposure estimates
developed may be representative of a broad range of the possible exposure
scenarios. It should b-j re«eaoered that the urban areas may contain sites with
high automobile use, production and other manufacturing sites, cind coke-oven
sites.
Human exposure to toluene ttirough inhalation of urban air is shown in
Table 10-3. The concentration of toluene in urban areas in the i'nlted States in
recent years ranged froa 0.1 tiZ.'a.- to ?'ju ug/i (Ts^ie 7-1). The intake estimate
is based on a breathing rate cf 1.2 a /hour for an adult during waking hours and
O.M a"5 /hour during sleeping hours (Siimak, 1930). It is also assumed that the
sleeping period for an ad'jlt is 8 hours/day. This results in an inspire;! volume
of M.2 x 16 x 7 •» 0.^. x fc x 7) - 15C.6 n-.-'/week.
ftear user sites, the range of toluene concentration has been assumed to be
5.5 to 600 pg/i". This ranje corresponds to the measured value of Sexton and
Westberg (19t53; near- &n automotive painting slant (.Subsection 7.1.1.) ^solvent
use constitutes about 99t of total usage). The concentration of toluene at d
distance 18 kE froci the plan*, measured S5.5 ^g'm , a value 10 time« hit-h^r than
the background concentration (Sexton and Westberg, 1980). Therefore, even
workers who ctxcmute more tnan '6 km froa> the plant are suajeptible to inhaling
toluene in the concentration range of 5.5 to 600 ,ig/nr for the entire 168 hours
in a week. The to'uene concentrations near manufacturing sites range from 0.1 to
T<7 W?/m . The estimated toluene exposure ran^e from the manufact uri ng and user
sites shown in Table 10-3 is based on a concentration range of 0.1 to 600
In rural ind remote areas, the concentration of toluene has been reported to
be in the range of a trace to 3.8 ng/m^ (Table 7-D. These concentrations were
determined in 1971; the current level may be lower than this range, as indicated
10-7
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TABLE 10-3
Toluene Exposure Under Different Exposure Scenarios
Scenario
General Population
Inhalation
Urban areas
Rural and remote areas
Areas near manufacturing
and user sites
Ingestion
_. Drinking water
9 Food (fish only)
OD
Occupational Group
Inhalation
Dermal
Cigarette Smokers
Inhalation
Observed
Rar?e of
Concentration
0. V to 204 |ig/m3
trace to 3-8 |jg/m
0.1 to 600 ng/m
0 to 19 pg/Jl
0 to 1 mg/kg
377,000 tig/m3
0 to 170 ng/«,
0.1 mg/cigarette
Frequency Total Volume
of Exposed or Inhalation or
Exposure Amount Consumed Ingestion Rate
(tag/wk)
168 h/wk
168 h/wk
168 h/wk
2 i/a
6.5 g/d
40 h/d
0 to 30 min/wk
20 cigarettes/d
156.8 m3 0.02 to 32
156.8 m3 trace 0.6
156.8 m3 0.02 to 9"
14 t 0 to 0.3
45.5 g 0 to 0.45
iJS ra3 18,100
5.9 1 0 to 1.0
110 cigarettes 1U
This value is the OSHA recommended standard and represents the worst-case estimate. Ir some industries, the
exposure level rarely exceeds 10 pj/o>.
This value represents exposure to blood due to dermal contact and represent absorbed lerels.
c This value is the OSHA recommended standard.
h = hour; wk = week; d = day; min = minute
-------
by the toluene concentration reported at Grand Canyon in 1979. The estimated
tolume 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.
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 has 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 ng/S. (Subsection 7.1.2.5.). The concentration of
toluene measured in well waters in New York State was below 10 ng/fc (Subsection
7.1.2.1).). Therefore, a concentration range of 0 to 19 ng/£ has been used for
exposure assessment shown in Table 10-3. A consumption rate of .? 2./day has also
been assumed for exposure asessment.
10.2.2. 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 T.l.'O. On
the basis of these data and the assumption that the per capita consumption of
aquatic organisms in the United States is approximately 6.5 g/day (Stephan,
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 inhalation
of air containing toluene and from skin contact with toluene or other solvent
mixtures containing toluene. The concentration of toluene in the air of the work
place has 'been assumed to be 377,000 ng/m . This value corresponds to the NIOSH
(National Institute for Occupational Safety and Health) recommended workroom air
standard of 100 ppm toluene vapor as a time-weighted average (TWA) exposure for
an 8-hour work day (NIOSH, 1973). Thi-? value is reasonably close to the actual
occupational exposure levels discuised 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
10-9
-------
for 30 minutes and monitored the blood levels of toluene. A peak concentration
of 170 \ig/"i 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 proposed by NIOSH (1973) requires all workers
handling toluene to wear gloves, it is conceivable that short-tern 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 ug/J,
in blood and a blood volume of 5.9 V. for an adult male have been assumed. It has
also been assumed that the skin exposure duration does not exceed 30
minutes/week. It also should be recognized that the value for blood
concentration through dermal contact given in Table 10-3 does not -resent the
total exposure value, as it ignores exposure to other organs.
10.1*. 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 saokes 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 ESTIMATE BASED ON MONITORING DATA
As discussed earlier, exposure estimates on the basis of monitoring data
have the following listitations:
(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.
10-10
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(M) The estimate for toluene exposure to the general popula-
tion from food and drinking water as given in Table 10-3,
is very crude, Tolut,*>e 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 saitf with respect to toluene exposure
fro» food.
10.6. COMPARISON BETWEEN EXPOSURE DATA BASED ON THEORETICAL AND EXPERIMENTAL
VALUES
If the concentration values ranging from 0 ng/nr' to greater than 100 ug/rc
(Table 10-2) are combined with the value of 156.8 m for inspired volume of air
per week, an inhalation exposure estimate 33 shown in Table 10-4 can be
developed.
TABLE
Exposed Population and Exposed Amount of Toluene From Dispersion Modelling
Concentration
Level Exposed Concentration
mg/week
MOO >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
aSour ce : S 1 i mak , 1 9flO
10-11
-------
A comparison of inhalation exposure data shown in Table 10-^, 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 tig/week. The exposure
data developed from dispersion equations estimate this value to be in the range
of zero to greater than 15.7 s^/week. The cumulative inhalation exposure can be
calculated by multiplying the exposed concentrations from Table TO-M with the
appropriate exposed population given in Table 10-2.
10.7. REFERENCES
ANDERSON, G.E., LIU, C.S., HOLMAIi, H.V. and KILLUS, J. P. (1980). Human Exposure
to Atmospheric Concentrations of Selected Chemicals, Publication No. unavail-
able. Prepared by Systems Applications. Inc., San Rafael, CA, under Contract No.
EPA 68-02-3066. U.S. Environmental Protection Agency, Research Triangle Park,
NC.
NIOSH (NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH). (1973). Criteria
for a Recommended Standard. Occupational Exposure to Toluene. HEW Publ. No. HMS
73-11023 'u.3. Gov't. Printing Office, Washington, DC.
SLIMAK, M. (1980). Exposure Assessment of Priority Pollutants: Toluene. Draft
report prepared by Arthur D. Little, Inc., Cambridge, MA, for the U.S. Environ-
mental Protection Agency, Monitoring and Data Support Division, Washington, DC.
SATO, A. ar.d NAKAJIMA, T. M978). Differences follwoing skin or inhalation
exposure in the absorption and excretion kinetics of trichloroethylene and
toluene. Brit. J. Ind. Med. ^5: U3-^9.
SEXTON, K. and WES^BERG, H. (1980). Ambient hydrocarbon arid ozone measurements
downwind of a large automotive painting plant. Environ. Sci. Technol. 1jl_: 329.
(Cited in Syracuse Research Corporation, 1980).
10-12
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STEPHAN, C.E. (I960). Memorandum to J. Stara, U.S. EPA, July 3. as cited in
U.S. EPA, 1980.
TURNER, D.B. (1969). Workbook of Atmospheric Dispersion Estimates. U.S. Dept.
of Health, Education, and Welfare, Revised, 1969. (Cited in Walker, 1976).
WALKER, P. (1976). Air Pollution Assessment of Toluene. Report prepared by
Mitre Corporation. Prepared for U.S., Environmental Protection Agency.
Available through NTIS Order No. PB 256735, Springfield, VA.
10-13
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11. EFFECTS ON HUMANS
Hunan exposure to toluene primarily involves inhalation, and consequently
the effect of greatest concern is dysfunction of the CNS. As detailed in
Chapters 9 and 10, millions of individuals are exposed to toluene via inhalation
of air frcxi ambient atmosphere and cigarette smoke (ppb concentrations), and from
occupational exposures (ppm concentrations). T-'d.city 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, 196?a, 1967b; Gellman, i968; Wyse, 1973; Linder, 1975;
Faillace andGuynn, 1976; Oliver and Watscn, 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
funes, (2) 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 CNS alterations (Von Oettingen et al., 1942a,
1942b; Carpenter et al., 1944). Von Oettingen et al. (1942a, 1942b) provided
11-1
-------
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 was performed over an 8-week period. Seven of the ?2 exposures were
to pure air, and exposures to particular levels of toluene were replicated only 1
to 4 times. The effects observed 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 ppra. 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 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 ppa,- 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 "inebriation" 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' lergth 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 ?t al., 1970;-
Gamberale 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 frequenc: 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 ppa. It should be noted, however, that no other information
regarding the design of tnese experiments was presented.
11-2
-------
TABLE 11-1
Effects of Controlled 8 Hour Exposures to
Pure Toluene on Three Human Subjects3'
Concentration No. of Effects
Exposures
Ckppm (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 4 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
i of the exposure. In several instances, the pupils
were dilated, pupillary light reflex was impaired, and
the fuhdus 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).
HOO 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
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TABLE 11-1 (cpnt.)
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, 19M2b
Exposures were twice weekly for 8 weeks. The number of subjects affected is
noted in parentheses.
-------
In a more extensive study, Qamberale and Hultengren (1972) exposed 12 maJ e
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
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 TOO to 300 ppa 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 nure air (Table 11-2). V.'ith respect to reaction time, a
significant effect was noted upon exposure to 300 ppm toluene in one test (Simple
Reaction Time), and a performance aecrsnent, 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 witn 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 pptr. Because
perceptual speed was unaffected at concentrations below 700 ppm, the authors
suggested that the simpler CNS functions may be affected at lower levels of
toluene exposure than the more complex functions.
Winneke 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
11-5
-------
TABLE 11-2
a, ti
Effect of Toluene Exposure on the Performance of Perceotual Sp«ed and Reaction Tloe Testa
Mean Test Scores
Performance Teat
Ider.tical Numbers0
(minutes)
Spolces
(seconds)
Reaction Time - Simple
(neters/second)
Reaction Tim? - Choice
(asters/second)
Source: Gaaberale and
t
Concentration
(ppm)
100
300
500
700
100
300
500
700
100
300
500
700
100
300
500
700
Hultei.gren, 197?
Fsperloental
Conditions
5.62
5.25
5.13
5.19
50.5
16.7
13.6
15-1
228
236
216
253
125
129
132
112
ir*» t nrto .-, f 1AH iri(\ C
Control (Air)
Conditions
5.53
5.29
5.01
1.80
50,8
13-7
10.2
36.9
230
222
219
211
122
116
100
108
inn n r. i4 *T n /"* «. .-.™ A, .—
t-Value
+0.50
-0-39
+ 1.31
+2. 65*
-0.08
+ 1.18
+ 1.28
+2.51"
-0.31
+2.35*
+ 3.88"
+1.8l»»
+0.31*
+ 1.99
+2.91»
+3.«iS««
minute periods. The ^sts were pet ~ i^ed at each concentration Sbquentially in the order listed. The number of
times sacn test sequence was repeated waa not stated.
Perceptual speed: Identical Numbers. Subjects were Instructed tc underline the 3-d!git number, fros a total of
60 columns, that was identical to the number at the head of each column. Performance was assured as the tioc
taken to complete the test.
Perceptual speed: Spokes. Sjbjects were Instructed to connect circles located at rornJoa on four pages and
numbered froa 1 to 20 In the correct numerical order using a pen. Perfi.mnee was measured as the oean time taken
for the four assignments.
Siople Reaction Tine. Subjects were instructed tc respond to a signal from a lamp by pressing a pushbutton.
Stimuli were administered at Intervals of approxlmntely 10 aeron-tj.i, pn acoustic warning signal Mas given 3
seconds prior to onset of stimuli, and 30 stiicull were given ]n each trial. Performance was measured as the meen
reaction time for the last 20 stlnull administered.
Choice Reaction Time: Stimulus/reply test as above, but there were three pushbuttons »c.ulpp«d with Batching
stimulus lamps. Stimulus administration followed a random sequence with the number of light signals evenly
distributed among the lamps, but the trial and p-"rforffiance measurements were otherwise the s^jce as for simple
reaction time.
Degrees of freedom = 11; »P < 0.05; "f < 0.01; "«P < 0.001
-------
evaluated in t.Ms study included performance in a bisensory (auditory and visual)
vigilance task, psychomotor performance, critica] flicker frequency, and audi-
tory evoked potentials. The available abstract did not provide any additional
information on the experimental design, the r.^ture of the psyr.hrphysiological
tests, or the results of tnis 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 wel i-marked alpha rhythms when stieulated by light.
Toluene exposures of approximately 0.27 ppm (1 cig/m ) for 6 minutes apparently
caused statistically distinct changes in EEG activity fron the left tesjporal-
occipital region in all subjects; these changes persisted through a 6-minutfr
recovery period. It should be noted that the 0.27 ppm concentration is slightly
lower than the odor threshold determined for toluene in the sant experiment
0.40 ppm; see subsection 11.7.2.). Toluene concentration-; of 0.16 ppm
(0.6 mg/m ) caused no variations in the electric potentials of the EEC's. Expo-
sure sessions consisted of 10 separate observation periods in which inhalation of
toluene (5 periods) alternated with inhalation of pure air (5 periods). A single
peri-od consisted of 18 one-minute cycles. Every cycle included the sequential
presentation 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 a-.tive physical exercise (25 seconds) for recovery of normal EEG rhythm. Of
the IB minutes allotted for EEG 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.
Although the reported effects on EEG activity may represent a subtle indication
cf perception, there is no apparent toxicological significance to the finding.
It should further be noted that western studies have not 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). Host 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
11-7
-------
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 clumsiness 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 curations of the exposures were not indicated, but loss of
consciousness occurred within minutes.
Episodes of toluene abuse are characterised by the progressive development
of CNS symptoms* Toluene sniffers axperience an initial excitatory stage that is
typically characterized by drunkenness, dizziness, euphoria, delusions, nausea
and vooiting, and, less commonly, visual and auditory hallucinations (Press and
Done, 19&7a, I967b; Wyse, 1973; Lewis and Patterson, 1971*; Hayden et ai., 1977;
Oliver and Watson, 1977; Barnes, 1979). As duration of exposure increases,
symptoms indicative of CNS depression .become evident: confusion and disorienta-
tion, headache, blurred vision and reduced speech, drowsiness, muscular incoor-
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 frctn 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 ai . ( 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 seer, 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 v:ere associated With 19 other cases of acute death from
thinner intoxication (Chiba, 1969); the English abstract of this Japanese study
indicated that toluene was the major component of the inhaled thinner. Nomiyama
11-8
-------
and Nomiyama (1978) described an instance in which 1 adolescents were found dead
after sniffing 99J pure toluene in a car, but post-mortem results utrier 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, 1970; Alha et al., 1973). The sudden deaths have been
attriouted, however, to severe cardiac arrhythmia, and are discussed in Sub-
section 11,5. (Effects on the Heart).
11.1.1.2. SUBCHRONIC AND CHRONIC EFFECTS — Wilson (19^3) described the
effects of exposure to commercial toluene vapor on 100 workers (out of a total of
100C 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 ppn 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
wnether the remaining 900 workers evidenced any symptoms of toluene exposure.
The concentration of toluene was determined shortly after any dxnosed 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 60J 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 30J of the patients) - headache, nausea, bad
taste in the mouth, anorexia, lassitude, slight but definite impairment of coor-
dination and reaction time, and momentary loss of memory.
500 to 1500 ppm (approximately 10? 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 (197D noted symptoms of
stupor, nervousness, and insomnia in one worker who was employed for "diverse"
11-9
-------
years in preparing a toluene-containing mixture for use in the manufacture of
V-belts. The mean atnospheric concentration of toluene in the mixing department
was 250 ppai, with extremes of 210 ppm and 300 ppcn. No CNS effects were observed,
however, in 1? other workers who were exposed to 125 ppm toluene (range, 60 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 ppai pure toluene (<0.3J 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 t:^an 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 variation in the balance of two metal plates; a
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
iiOO 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 tne end of their shifts indicate expo-
sure to toluene levels of at least 300 ppna 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 unclear, however, when
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
11-10
-------
Schnilde (1973)i who tested the effects of "extreme" concentrations of 11 fre-
quently used organic solvents in humans with the Sphallograph and fc fid only
minimal effects. This would argue that the Sphallograph is not a sensitive test
for determining CNS 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 paychosyndrome" in
21$ of a group of printers exposed on the average to 300 ppra toluene for 18 years
(mean age, 42 years), and in 40% of a group of printers' helpers exposed to
430 ppm for 12 years (mean age, 414 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 95J of the cases.
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, Lindstroeia 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 tx?en 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 (4U) , 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, psychonotor 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 Rorsctiach 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
11-11
-------
40 years (mean, 14.8 JK 8.5 years), but, as detailed in Table 11-3, toluene was
present in the greatest amount (30.6 ppm).
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
i White Spirit 4.9
Methyl Isobutyl Ketone 1.7
Isopropanol .2.9
Ethyl Acetate 2,6
Acetone 3.1
Ethanol 2.9
g
Source: Hanninen et al., 1976
Sampling Period = 1 hour; Number of Car Repair Garages = 6;
Nunber of Samples = 54.
A battery of tests included 1 test for verbal intelligence, 3 visual tests, 5
memory or learning tasks, 4 tests of psychotnotor performances, and the Rorschach
test for measuring personality changes (Tables 11-4 and 11-5). Results of this
study showed significant differences between the exposed and reference group ir,
almost all intellectual performances arid memory tasks. Impairments in visual ;?r: j
verbal intelligence and in memory, as well as a reduction of emotional reactivity
as indicated by the Rorschach test, were the predominant effects of solvent
exposure (Tables 11-4 and 11-5). Differences in psychotaotor 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
11-12
-------
TABLE 11-H
Perfornance Testa: Meana, Star.dard Deviations, and Significances Between the Croup Means (Age-Matched) Croups*
I
LO
' Means and Standard Deviations
Test
WAIS8 Similarities test0
WAIS Picture Conpletiond
WAIS Block Design"
Figure Identification
WAIS and WHS8 Digit Spanh
WHS Logical Matory1
HMS Aaaoclate Learning^
Benton Test for Visual Reproduction
Benton Teat for Vl.iual Retention
SADT - right handk
SADT - left nandk
SADT - coordination with both hands'1
Finger Tapping - right hand
Finger Tapping - left hand
Reaction Time (Simple) - right hand
Reaction Time (Simple) - left hand
Reaction Tioe (Choice)
Mlra Teat0
Mira Test"
Exposed (N = 100)
19.1 *_
11.9 »
31. 6 *
32.0 +
10.6 £
11.7 i
15.3 t
21.1 +
8.2 +
11.7 +
12.3 *
29-0 +
202.5 i
186.7 *
12.1 +
12.1 +
9.1 +
18.8 +
2.2 «
3.1
2.9
7.0
9.0
1.6
3-7
3-6
3-1
1.5
5.7
5.1
5-1
29.2
28.5
2.9
3.0
1.8
3.8
1.0
Nonexpoaed (N = 150)
2.9 *
16.2 _*
39.6 »
36.7 *
11.5 +
13.9 «
•7.1 +
22.6 »
8.7 *
17.5 +
U3.6 +
31.5 +
Z'09.6 +
196.1 »
11.9 «
11.7 +
9.1 *;
.?0 . 3 +
2.0 +
2.1
2.3
5.6
9-8
1.8
3-1
2.6
2.3
1.3
5-8
5.1
5.7
23-8
22.1
1.1
1.1
1.2
1.6
0.8
Significance
of Differences
(t-teat)
• «•
1.1
in
• ••
in
ill
• ••
• •i
•
• •
• n
l
«n
i
Source: Hanninen et al., 1976
Tiechsler Adult Intelligence Scale.
Measures verbal intelligence and abstraction.
Veasurea visual Intelligence and observation.
'"'Measures visual intelligence and abstraction.
Measures speed of perception and memory for visual details.
^Wechsler Memory Scale.
Measures memory for digits.
Measures verbal memory.
'rlfasurea verbal memory and learning.
Santa Ana Dexterity Test; measures psychomotor speed.
Measures motor speed.
Te.3t for nsychomotor behavior and psychomotor ability;" two variables tested.
"paired t-teat.
•P c 0.05; «P < 0.01; ««P < 0.001
-------
TABLE 11-5
Rorschach Personality Test Variables: Means, Standard Deviations, and
Significances Between the Group Means— (-Age-Matched Groups)
J Oi ,._... Significance
Means and Standard Deviations „,. n
-------
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 excess 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 ar;d coworkers (1976) for neurophysiological
effects. Results of EEC analysis on 102 sol vent-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 EEG 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. EEG 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 EEG abnormalities. This difference was not statistically
significant (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
concentrations of toluene (>250 ppm) 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;
frequencies ranged from 1 to 30 per second. Evaluated a? a normal response was
the occurrence of EEG 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 EEG 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; Weisenberger,
11-15
-------
1977; Keane, 1978; Sasa et al., 1978; Tarsh, 1979; Malm and Lying-Tunell, 1980;
Metrick and Brenner, 1982). Boor and Hyrtig (1977) described a case of cerebral
involvement in an optician who regularly used toluene occupationally to clean
eyeglasses and contact lenses in a small, unventilated room, and optic neuropathy
has been observed (Xeane, 1978; Mai in and Lying-Tunell, I960; Metrick and Brenner,
1982). 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 encephalopathic 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 has, however, on-occasion led to permanent encephalopathy and brain
atrophy as evidenced by EEG and neuroradiological (pneumoencephalogram,
angiograia) changes (Knox and Nelson, 1966; Boor and Hurtig, 1977; Sasa et al.,
1978). Pontomedullary atrophy and abnormal brainsteni auditory evoked potentials
were recently observed in two chronic toluene abusers (Metrick and Brenner,
1982).
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 i
5.2 years) who had been exposed to a glue containing mainly toluene and "slight"
gasoline for an average Duration of 3 years and b 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 + 0.8Z mg/ml versus 0.35 + 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
11-16
-------
TABLE 11-6
Encephalopathic Effects of Chronic Toluene Abuse
Subject (Age)
Exposure History
Effects and Diagnosis
Reference
Male (33 years)
Hale (30 years)
Fenale (19 years)
Male (25 years)
Pegularly sniffed toluene for I1) years.
Subject purchased a gallon of pure
toluene every 1-6 weeks, and Inhaled the
toluene on an almost 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 common ingredient In all
the brands sniffed. Previous 1-year
history of multiple drug and solvent
abuse.
10-year history of lacquer thinner (99J
toluene) abuse; during the last 5 years he
had spent virtually all his making hours
Inhaling the vapors (1 gallon used every
2 weeks)
Patient Initially examined after 6 years by
Grsbskl; signs Included ataxla, Intention
tremors, pyramidal signs and psychosis which
were concluded to be consistent with cerebellar
degeneration. After 8 acre years of abuse, Knox
and Nelson reexamlned the patient and concluded
that the syndrome was primarily a diffuse
cerebral disorder based on findings of ataxla,
treaors, Hob incoordinatlon, emotional lability,
marked snout reflex, and positive Babinski toe
reflex; cerebral atrophy waa confirmed by EEG
and pneumoencephalography.
Recurrent headaches, "inappropriate" speech,
brief episodes of menory loss, increased
Irritability, and exaggerated swings in mood.
Unremarkable clinical and neurological exam,
but nonspecific EEG changes were found that
were regarded as consistent with diffuse
encephalcpathy.
Ataxia, intention tremors of hands and feet,
incoordination, hallucinations, Nonsal EEG,
brain scan, arterlography, and pneumoencephalo-
graphy. The diagnostic impression was
cerebellar dysfunction secondary to scoe toxic
factor in the paint. Objective neurological
Improvement 5 months after sniffing was
discontinued.
Abasia, mildly slurred speech, r.ystagmus , and
bllatsral Babinski. signs. Normal EEG, nuclide
brain scan, electromyogram, and nerve conduction
studies, but a computerized brain scan-showed
diffuse widening of the cortical and cerebellar
suJci. Subjective improvement in condition
following abstinence from exposure, but a
neurolugical exam after 9 months was
ensentially unchanged.
Grabskl, 1961;
Knox and Nelson, 1966
Satran and Dodson, 1963
Kelly, 1975
Boor and Hurtig, 1977
-------
Table 11-6. (cent.)
Subject (Age)
Exposure History
Effects and Diagnosis
Reference
Male (59 years)
Hals (age not stated)
Hale (27 years)
•J* Hale (20 years)
cx>
Hale (25 years)
Female (18 years)
Optician who freo.tiently but Inter-
oittep.My used 99i toluene In a small
ur.ventilated roor to clean eytgl-asnes
end contact lenaes. Unable to smell
toluene because of chror.lc anosnia.
Duration of exposure not stated.
Habitual Inhalation of paint thinner
(toluene) on tha job. Duration not
stated.
Sniffed unspecified glujs and paint
thinners for 10 years. From age 25,
toluene was involved ^-5 times per week
(200-300 ml/week used), and from age 26,
he inhaled 1-7 times per day (100 mi/day
used.
3-year history of dally aerosol spray
paint inhalation. Product contained
copper, toluene, and xylene as solvent.-)
and isobutane propane and roethylene
chloride as propellants.
Sniffed toluene for 1 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 us»?d
per month). Sniffed more heavily th?.ii
usual during the last 2 months.
Fatigue and clumsiness of the left side which
got progressively worse. Oocaiional staggering
and mildly slurred speech, disturbed concen-
tration and memory. Normal neurological exam,
EEC, and brain scans. Dally improvement without
specific treatment following cessation of exposure.
Slzzare behavior prior to hospital admission.
Admitted In an agitated, violent, nearly catatonic
state.
Ann and neck trenors, ataxla, incoordination,
and equilibrium disorders. Wo abnormal
psychiatric symptoms. Pneuooencephalographlc
and anglographical evidence of mi dbraln and
cerebrum atrophy. Degeneration of the
cerebellum suspec'.ed.
Reduced vision, poor color perception, con-
stricted visual fields, normal optic fundl, im-
paired papillary response, ataxia, and nystagmus.
Symptoms slowly subsided following cessation
of paint sniffing.
Delusions and unpredictable behavior.
Largactil prescribed because he was thought to
have a schizophrenic Illness. Symptoms dis-
appeared and did not recur following termina-
tion of anlffing.
Personality changes (apathy, Irritability,
emotional lability, carelessness), vooitlng,
jlfflculty in walking, and slurred speech
1-2 weeks before admission. Gait ataxia,
Incoordination, dysarthrla, downbeat nystagmus,
bilateral positive Bablnskl sign, visual and
colu" sense loss, impaired concentration and
abstracting ability upon admission. Symptoms
consistent with mainly cerebellar-braln stem
involvement and possibly optic neuritis.
Symptoms decreased when she did not Inhale
toluene, and disappeared after 8 months.
Boor and Hurtig, 1977
Welsenberger, 1977
Sasa et al., 1978
Keane, 1978
Tarsh, 1979
Main and LyIng-Tunell, 1980
-------
TABLE 11-7
Results of Neurological and Muscular Function Tests
of Toluene-Exposed Female Shoemakers
Testb
Abnormal tendon reflex:
. Biceps and triceps
Patellar
Ankle
Pathological reflex
Grasping power (dominant hand)
i
Tapping tempo (M + S.D.)°
I
Cold pressure test
Postural hypotension
Cuff test (upper arm)
Dermatographism
Blocking test (M + S.D.) (seconds)
Numbers investigated
Exposed Group
6(16)
14(37)*
7(18)"
U 3)
11(29)**
162.9 ± 16.6
6(16)
2( 5)
5(13)
5(13)
68.2 + 13-3
38(100)
Cor. ^rol 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)
Source: Matsushita et al., 1975
Numbers of subjects with abnormal scores reported. The percentage of
subjects affected is indicated in the parentheses.
HJnit of measurement not stated.
Statistical significance (Chi Square- and t-tests): *P < 0.05; **P < 0.1;
M = mean; SD = standard deviation.
11-19
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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 labora-
tory. 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; Tov»fighi et al., 19V6; 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 electro-
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_n-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., 1974; Suzuki et al., 1974) as
the cause of glue sniffers' neuropathy. The following observations have been
offered as evidence to indicate that _n-hexane plays an important role in its
etiology: (i; in many of the reported cases, neuropathy did not develop until
11-20
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the patients began to sniff glue products that contained jn-hexane, and (2) it is
known that continuous occupational exposure to n-hexane under poor ventilation
conditions produces a neuropathy among workers that is clinically and patholo-
gically similar to that observed among the glue sniffers. From a recent outbreak
of polyneuropathy among 18 glue thinner sniffers in West Germany, however,
Altenkirch et al. (1977) presented data that implicate methyl ethyl ketone (MEK)
as the causative agent and argue against n-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 _n~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$) had been added; the amount
of toluene was noc significantly changed (29$).
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 4 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
11-21
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question whether _n-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
cerebral dysfunction following prolonged inhalation of 99? pure toluene (Boor
and Hurtig, 1977).
11.2, EFFECTS ON THE.BLOOD AND HEMATOPOIET1C 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., 19^2; 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
C<0.3J benzene) in 1955; earlier, workers were typically exposed to toluene that
was derived from coal tar and contaminated with as much as 20? benzene.
Greenburg et al. (19^2) found mild depression of erythrocyte levels, abso-
lute lymphocytos^s, macrooytosis, and elevation of the hemoglobin level and the
mean corpuscular hemoglobin concentration in 61 airplane painters who had been
exposed to 100 to 1100 ppm toluene for periods extending from 2 weeks to 5 years
(Table 11-8)- Exposure was also associated with liver enlargement in 13 of the
61 painters (Section 11.3.), but not with abnormal granulocytic leukocyte
counts, differential granulocytic leukocyte counts, reticulated erythrocyte
counts, basophilic aggregation estimates, platelet counts, erythrocyte sedi-
mentation rates, coagulation time, hematocrit values, erythrocyte fragility, or
serun bil"irubin levels. Approximately 75% of the painters were exposed to
concentrations of 500 ppn. or less, and the group had no known prior exposure to
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 such as ethyl
alcohol, ethyl acetate, butyl alcohol, and petroleim 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
11-22
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TABLE 11-8
Results of Blood Examinations Performed on Toluene-Exposed Airplane Painters3'
Toluene-Exposed
Workers
Unexposed
Workers
Erythrocytes ,
counts <5.2 x 10 /mm
Lymphocytes
counts >5000/mm
Mean Corpuscular Volume
>100 ^
Hemoglobin
_>l6g/100 mJi
Mean Corpuscular Hemoglobin
>35 picograms
Mean Corpuscular Hemoglobin
Concentration
% of cases 2.35g/100 mfc
13.1$ (N = 61)
20.^ (N = 59)
34.4$ (N = 61)
5.2? (N =
1.1% (N = 395)
21.3? (N = 61) 7.2$ (N = 111)
29.5? (N = 61) 2.4? (N = 81}
13-1? (N = 61) 0? (N = 73)
2.5? (N - 81)
Source: Greenburg et al., 1942
Percent abnormal cases reported.
11-23
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TABLE 11-9
Analysis of Paint Used by Painters3
Percentage
in Mixture
Spray painters
Primer (75$ of paint used):
Zinc chromate
Magnesium silicate
Synthetic resin
Driers (lead and cobalt compounds)
Xylene
Toluene
Nonvolatile:
Resin, titanium oxide, zinc oxide,
ultramarine blue, ferrocyanide
blue, iron oxide, diatomaceous
earth, amorphous silica, carbon
black
100.0
Lacquer 1 (15$ of paint used):
Volatile portion:
Ethyl alcohol 7.0
Ethyl acetate 18.0
Butyl alcohol 7.0
Butyl acetate 15.0
Petroleum naphtha 3.0
Toluene 50.0
100.0
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 25.0
Xylene 33-0
Petroleum naphtha ^2.0
100.0
-------
TABLE 11-9 (cont.)
Percentage
in Mixture
Brush painters
Dope:
Volatile portion:
Ethyl acetate 16.5
Ethyl alcohol 3.2
Butyl acetate 16.5
Butyl alcohol 5.6
Pttroleum naphtha 13,7
Toluene 114.5
100.0
Nonvolatile:
Nitrocellulose, glycol sebacate,
aluminum, cadmium sulfide, barium
sulfate
Brush wash:
Acetone
Ethyl alcohol
Toluene
100.0
aGreenburg et al.,
Dip painters used a primer only of the same composition as given
for spray painters.
11-25
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to 3 weeks, 100 showed symptoms attributable to toluene intoxication. Ten of the
100 workers had been exposed to concentrations in excess of 500 pprn and showed
signs of serious CNS toxicity (Section 11.1,1.2.). In most of these 10 cases,
all blood elements remained normal except for the red cell count, which was
"usually" reduced (=2.5 x 10 /mm^). in 2 of the 10 cases, leukocytes (2500 to
3000/mrr) and platelets were reduced as well, and differential counts showed
decreased polymorphonuclear cells and reticuloeytes, 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 . (19423, 19M2b) 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 0.01J 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
between exposures, and the experiments were conducted over a period of 8 weeks
(Section 11.1.1.1.). Erythrocyte counts were not made.
Parmeggiani and Sassi (195^) 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
2^00 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, 3^? reportedly showed slight anemia (2000/mm ), and 45J showed a decrease in blood platelets (<150,000/mmJ)
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
11-26
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inks reportedly contained only traces of benzene (<0.3$); when 5 samples of the
toluene were examined by Banfer, no traces of benzene were found, but the method
of analysis and detection limits were not stated. Analysis of the room air for
toluene was performed by infrared spectroscopy, but limited to 5 samples taken
from different sites.on a single day. Ambient toluene concentrations were not
specified, but three of the samples were determined to be below the "MAK-Wert,"
the fourth sample was at the "MAK-Wert," and the fifth sample, taken near one of
the presses, exceeded the "MAK-Wert" by 400 ppm. A translation of this study by
NIOSH (1973) indicates that the "MAK-Wert" was 200 ppm. Hematologic examina-
tions of the workers and controls did not roveal any significant changes in the
total number of leukocytes, lymphocytes, granulocytes, or erythrocytes, or hemo-
globin levels (Table 11-10). Sternal biopsies from 6 printers with white cell
counts of less than 5000/mm were normal.
TABLE 11-10
Henatologic Examination of 889 Rotogravure Workers3
Printers
(N = 889)
Controls,
Group 1
(N = 155)
Controls,
Group 2C
(N = 323)
Erythrocytes ,
counts <4 x 10 /mm-1
Leukocytes, total
counts > 8500/mo
counts <5000/mm
counts
counts <4000/nm-3
Lymphocytes
<35$ total leukocytes.
total counts <5000/mm:
Granulocytes __
total counts >2000/mnr
Hemoglobin
value <13g/100mJi,
16 (1.79$)
78 (8.77$)
74 (8.32$)
28 (3.15$)
3 (0.33$)
25 (2.81$)
889 (100$)
3 (1.93$)
7 (2.10?)
11 (7.09$) 26 (8.04$)
18 (11.61$) 38 (11.76$)
4 (2.58) 12 (3-71$)
1 (0.64$) 1 (0.30$)
3 (4.16$)
155 (100$)
4 (2.58$)
4 11.32$)
323 C.00$)
889 (100$) 155 (100$) 323 (100$)
4 (1.23$)
Source: Banfer, 1961
Unexposed management workers from the same plant
Q
Unexposed individuals not enployec! at the plant
11-27
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I
Capellini and AjLessio (1971) performed hematological examinations on 17
workers who had been exposed for "diverse" years to 125 ppm toluehe (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 CNS
toxicity and conjunct!val 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 (<0.3% benzene) and an unexposed control group of equal
size from the same plant. Analysis of air samples collected from the workplace
reportedly indicated that the potential exposure to toluene ranged from 200 to
400 ppm. Blood analyses (hemoglobin, erythrocyte, leukocyte, thrombocytes, dif-
ferential analysis) demonstrated no unusual frequency of abnormalities in either
the exposed or control groups.
Matsushita et al. (1975) found no alterations in the specific gravity of
whole blood, hemoglobin content, ftematocrit, or white blood cell counts in a
group of 3& female shoemakers who had been exposed to toluene (60 to 100 ppm
average) and, in a "few" working places, gasoline (range, 20 to 50 ppm) for an
average duration of 3 years and 4 months. Tne hematological test results from
the shoemakers were compared with tho^e from an unexposed control group of 16
female workers. A significantly increased number of "Mommsen's" toxic granules
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 +_ 5.6) compared with 1 of 16 controls (mean number per neutrophil, 3.8
t 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 ho clinical effect on the
leukemic process.
11-28
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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; Kassengale et al., 1963; Barman et al.,
1964; Press and Done, 1967b), there were no instances of anemia or lymphppenia, a
single report of neutropenia, and 6 cases of eosinophilia of greater than 5%.
Christiansson and .Karlsson (1957) aldo 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
42 of the patients, and noted the frequent occurrence of poikilocytosis (25
i
cases), anisocytosis (20 cases), hypochromia (14 cases), and polychromasia (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.
Powars (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 subjects
showed a reduced number of red blood cells, but no other hematologic abnormali-
ties were found in these workers. The benzene content of the toluene was not
reported.
11-29
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\
11.2.3. Phagocytic Activity of Leukocyt.es. 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
Hungarian study did not detail any of the exposure information or mention the
benzene content of the toluene.
Friborska (1973; cited in NRC, 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. Immunoeompetence. 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/Jl, 0.08 to 0.23 mg/2,, and 0.12 to 3.0 mg/£,
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 were not identified.
11.3. EFFECTS ON THE LIVER
Greenberg et al. (1942) found enlarged livers in 13 of 61 airplane painters
(21J) who were exposed to 100 to 1100 ppra 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
11-30
-------
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
toluene1, 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 tender. 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 coworkers' ( 1942) finding of hepatomegaly has not been sub-
stantiated in subsequent studies of workers with histories of occupational
toluene exposure. Parmeggiani and Sassl (1954) found a comparable incidence
(21%) of enlarged livers in a group of 11 paint and pharmaceutical projection
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 a mean atmospheric concentration of 125 ppm
toluene (range, 80 to 160 ppm) in a plant manufacturing V-belts for industrial
machinery. Liver function in this study was evaluated by determinations of total
serum protein and protein electrophoresis.
M-ore 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
-------
investigated. Blood .alcohol determinations before arid 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 test-^J; approximately half
of the tested subjects had levels between 0,01 and 0.1J. The significance of the
elevated blood alcohol levels is unclear, however, because of the small number of
subjects tested, because only single biood alcohol del.erminations were performed
on each subject, and because the data were presented ambiguously.
Other studies have reported significant effects on indices of liver func-
tion in groups of toluene-exposed workers. In an examination of 9^ rotogravure
printers with a history of exposure to 18 to 500 ppm toluene and of a reference
group of 30 municipal clerks, Szadkowski et al. (1976) found significant reduc-
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 inten-
sity of exposure to toluene. The mean exposure levels, durations of exposure 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 = 4) - ^26 ppm, newly
appointed on day of investigation, 2^.3 years; Group 3 (N - 11) - 82 ppm, 5.6 +_
5.2 years, ^2.9 years; Group 4 (N - 11) - 18 ppm, 8.5 +_ ^.4 years, 35.8 years.
Blood alcohol levels ranged from 0.02? to 0.07$ in the exposed workers.
Trevisan ana Chiesura (1978) performed the following hepatic function tests
on ^7 subjects who were exposed occupationally to toluene via inhalation: bili-
rubin, SCOT, GGT, alkaline phosphatase (AP).ornitnine-carbamyl transferase
(OCT.), Uuick's test, and protein measurement. All tests gave normal results with
the exception of GGT, which was reportedly above normal (28 n/m£) in 3^% of the
cases. In a group of 12 subjects controlled before and after toluer.e entered in
the working operation, mean GGT activity increased 2-fo]d after exposure.
Although GGT has proved to be a very sensitive screening enzyme for slight
changes in liver function (Dragoslcs et al., 1976), it should be noted that the
data from this study were published in abstract form, and that information on
exposure or type of occupation and detailed results of the hepatic function tests
were not presented.
The mean serum activities of four liver enzymes (aspartate transaininase,
alanine aminotransferase, OCT, GGT) did not differ between a group of 102 car
painters who were exposed to a mixture of organic solvents, and an age-matched
unexposed reference group of 102 men (Kurppa and Ilusman, 1982). The exposed
11-32
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\
subjects were exposed mostly to low levels of toluene (30.6 ppra detailed in Table
11-3) for 1 tO HO years (mean, 14.8 •«• 8.5 yrs), and the age of the painters ranged
from 20 tO 65 (mean 35 +_ 11 yrs). Abnormal intellectual/psychomotor performance
(Hanninen et al. 1976), abnormal neurophysiological effects (Seppalainen et al.,
1978) and an increased frequency of lens changes (Raitta et al., 1976), however,
have been observed in thf.se workers. Abnormally slow motor and sensory
conduction velocities and/or prolonged motor digital latencies were suggested in
12 of ^9 car painters studied (Section 11.1.2), and ophthalmological examination
revealed lens opacities in 48 of 92 car painters (Section 11.7.1). Kurppa and
Husman (1982) found that, the liver enzyme activities of these two
"solvent-affected" subgroups were similar to those of the car painters with no
corresponding abnormalities.
English summaries of two Polish studies of women with histories of occupa-
tional exposure to toluene indicated abnormalities in the glycoprotein, 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). Although these changes may be
indicative of liver dysfunction, clinical signs of liver function impairment
were not observed in these subjects. The concentrations of toluene, durations of
exposure, and the possibility of exposure to other chemicals were not discussed
in the available 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 sulfobrotnophthalein 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; Bam an et al., 196-'J; Press and Done,
1967a, 1967L). 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
11-33
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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? toluene (other components not known)
coupled with alcohol ingestion (O'Brien et al, 1971); the hepatic effect was
indicated by elevated serum bilirubin and AP.
11.1*. 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 ppm
toluene for 2 weeks to 5 years (Greenburg et al., 1942). Urinalysis consisted of
specific gravity, albumin, and sugar determinations, arid examinations for formed
elements. Exposure to mean concentrations of 60 to 100 ppm toluene and 20 to
50 pptn gasoline in a "few" working places for an average duration of 3 years and
4 months did not result in abnormal urinalysis findings as determined by standard
methods (protein, sugar, urobilinogen, bilirubin, occluded blood, keton body),
except for excretion of hippuric acid, in 38 female shoemakers (Matsushita
et al., 1975). Gloraerular filtration rate (as measured by Cr-EDTA clearance
from plasma) was not reduced in a group of 3^ rotogravure workers when compared
with 48 non-exposed male controls (Askergren et al., 1981), but the toluene
exposures were not characterized. 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 45J toluene and 21% DDT (Lurie, 1949).
Reisin and coworkers (1975) published a report regarding the development of
severe myoglobinuria and n:>n-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
hoaodialysis 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-
based glues (Christiansson and Karlsson, 1957; Massengale et al., 1963; Sokol and
Robinson, 19&3; Barman et al., 1961; Press and Done, 1967a, 1967b). The clinical
11-34
-------
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
observed in glue sniffers, are generally transient, and follow closely the inten*-
sive exposures (Press and Done, 196?b).
0'Brj°n 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 ppjo. In addition to diminished urine output, evidence of renal damage
included hematuria, proteinuria, and elevated serum creatinine. The effects of
these exposures 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., 197^; Fischman and Oster, 1979a; Kroeger et al., 1980;
Bennett and Forman, I960; Moss et al ., 1980). The cases of acidosis described '.j
these investigators (Table 11-12) are characterized by serious electrolyte
abnormalities (hypokalemia, hyperchloretnia), 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,
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.
11-35
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TABLE 11-11
Renal Funqtion Investigations of Glue Sniffers
a,b
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
ND
0
12
1
5/13
Clearances
ND
ND
ND
PSPd
0/13
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. , 196U
1963
Press and Done, 1967b
Source: Press and Done, 1967b
Exposures 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.
Pnenosulfonphthalein clearance in 2 hours.
ND = not determined
-------
TABLE 11-12
Toluene Induced Metabolic Acidosis
Subject (Age)
Exposure History
Symptoms
Clinical Findings
Reference
Kale (23 yr)
Feoale (20 yr)
Female (17 yr)
Feaal« (21 yr)
Z. Fco4l« (25 yr)
I
CO
~j
Hale (23 yr)
Fenale (27 yr)
Four Indlvlducls
(ages and sexes
not stated)
Male (2? yr)
Sniffed glue and pure toluene
Intermittently for 6 yr.
Two 3 to 5 d episodes of sniffing
aerosol paint containing 60)
toluene within
-------
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 an:on 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 CMS, and that altered pH and electrolyte balance may be more commonly respon-
sible for the manifestations of toluene abuse than is usually recognized (NRC,
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
effect on the heart rates or 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 8 hours (Von Oettingen
et al., 19^2a, 19l;2b) 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 100 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 \.o 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; AIha et al., 1973).
Toluene, benzene, arid gasoline have been individually implicated in a small
number of these deaths (10, 6, and H cases, respectively), but the volatile
hydrocarbons most frequently involved were trichloroethane and fluorinated
11-38
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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
i Subjective complaints of dysmenorrhea were reported by 19 out of 38 Japanese
female shoemakers (mean age, 20.7 years) who were exposed to mean toluene concen-
trations of 60 to 100 ppm for an average duration of 3 years and 4 months
(Matsushita et al., 1975). In an vinexposed control group of 16 women from the
same plant, this effect was noted by 3 individuals (19J). It should be noted
that these women were concomitantly exposed to 20 to 50 ppm of gasoline in a
"few" working places. In this study, the presence or absence of 15 subjective
symptoms was ascertained by questionnaire; in addition to dysmenorrhea, a
significant number of workers reported "uneasy feelings" about the solvent
vapor;, and itching and dermatitis of the hands.
Michon (1965) reported disturbances of menstruation in a group of 500 women
(age 20 to 40 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, 31 ppfli (100 mg/m ) for benzene, 67 ppm
o •?
(250 mg/m-5) for toluene, and 58 ppm (250 mg/m^) for xylene). When the menstrual
cycles of the exposed women were compared with those of 100 w\nen from the same
plant with- no exposure to these hydrocarbons, prolonged and more intense
menstrual bleeding was reportedly found in the exposed group. The regularity of
the cycle was not affected.
It has a] so been noted in the English summary of a Russian study that
cccupational exposure to average concentrations of 6 to 93 ppro (25 to 350 mg/m )
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" om.et of nursing. Although the above studies suggest that occupa-
tional exposure to aromatic hydrocarbons may be associated with menstrual
disturbances, it should be emphasized that a specific effect of toluene could not
11-39
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be determined from the available data, Information on the possible reproductive
effects of toluene in males is not available.
11.7. EFFECTS ON THE RESPIRATORY TRACT AND THE EYES
11.7.1. Effects of Exposure. Carpenter et al. (1944) observed that 2 male
subjects who were exposed to toluene for 7 to 8 hours experienced transitory rHd
throat and eye irritation at 200 ppm, and lacrimation at 400 ppm. Parmeggiani
and Sassi (195*0 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.
(1942a,b) and Wilson (1943), 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 ppra 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-
tiva! irritation and corneal damage, with no loss of vision, was observed in
three workers who were accidentally splashed with toluene (Mclaughlin, 1946;
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 cc al., 1942); results were not published, but it was noted
that the examinations in each case consisted of a "history of ocular complaints,
visual acuicy, 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 (Hanninen et al., 1976; Seppalainen et al., 1978) and liver function
(Kurppa and Husman, 1982) of the car painters (see Sections 11.1. and 11.3).
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
11-40
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mainly of lens opacities and/or nuclear sclerosis. To 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).
TABLE 11-13
Frequency of Lens Changes and Distribution by Exposure Time
I in 69 Age-Matched Pairs of Car Painters and Railway Engineers3
Pesult
Car painters had fewer
changes than the engineers
No noticeable difference
between the pairs
Car painters had more
chknges than the engineers
Frequency of
Lens Changes
(no. pairs)
4
38
27
Distribution
by Years
£ 10 11
3
22
6
of Lens Changes
of Exposure
to 20 >21
1 0
13 3
i
17 4
Source: Raitta et al., 1976
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 by this Russian investigator to be within
0.40 to 0.85 ppm (1.5 to 3.2 mg/m ), 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. (1976). "Toluene
concentrate" is a hydrocarbon mixture containing 15.89? toluene, 38.69? paraf-
fins, 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).
11.8. 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 uncornif.ied (soft)) were observed in 6 of 16
cabinet makers who were dermally exposed to a thinner mixture that contained 30J
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 2 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 CNS.
Single 8-hour experimental (Von Oettingen et al., 1942a, 1942b; Carpenter
et al., 1944) and subchronic occupational (Wilson, 1943) exposures to toluene in
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 to?uene have also caused objective increases in reaction time at 200
11-42
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I
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 EEC 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 accident;,! -workplace (Lurie, 1949; Browning, 1965; Longley
et a!,, 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 CFS depression progressively
develop, and, in extreme cases, collapse, loss cf consciousness, 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
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 CNS symptoms and impaired performance on tests for intellectual and
psychomotor ability and memory in car painters (Hannir.en 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.
11-43
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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 (firabski, 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 encephaiopathy and brain atrophy
(Kno* and Nelson, 1966; Boor and Hurtig, 1977; Sasa et al., 1978). Reports of
\
polyn'europathies 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 (Matsunmra et al., 1972; Takenaka
et al., 1972; Goto et al., 1974; Shirabe et al., 1974; Suzuki et al., 1974;
Korcbkin 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 myclotoxic effects to toluene (Greenburg et al. 1942; Wilson, 1943), but
the majority of recent evidence indicates tnat 'toluene is not toxic to the blood
i
or bone marrow (Von Oettingen et al., 1942a, 1942b; Parmeggiani 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;
Msssengal* et al., 19&3; 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, 1966), and increased enzyme concentrations in leukocytes and
lymphocytes (Fribor-ska, 1973) of workers who were exposed to toluene. Decreases
In serum icmunoglobin 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 (Parmeggiani and Sassi,
1954; Suhr, 1975). Chronic occupational exposure to toluene has generally not
11-44
-------
been associated with abnormal liver function (Greenburg et al., 19^2}
Parmeggiani and Sassi, 1954; Capellini and Alessio, 1971; Suhr , 1975; Kurppa and
Husman, 1982), although reductions in serum bilirubin and alkaline phosphatase
(Szadkowski et al., 1976) and increases in gamma glutamyl tranapeptidase
(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., 1964; Boor and Hurtig, 1977; Press
and Done, 1967a, 1967b).
Exposure to mean concentrations of 100 tc 1100 ppm toluene for 2 weeks to
5 years (Greenburg et al., 1942) or 60 to 100 ppm toluene for over 3 years
(Matsushita et al., 1975) did not result in abnormal urinalysis findings in
airplane painters or female shoemakers, respectively. Glomeruiar filtration rate
was reduced in rotogravure worker." with uncharactsrized toluene exposures
(Asker'gren et al., 1981), but clinical case reports have described proteinuria
and hematuria (Lurie, 1949; O'Brien et al., 1971) and myoglobenuria and renal
failure (Reisin et al., 1975) in workers who were accidentally overexposed to
toluene. Pyria, hematuria, and proteinuria have been the most frequently
observed signs of renal dysfunction associated with the deliberate inhalation of
toluene-based glues, but these effects have not been universally 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., 1974; Fischman and Oster, 1979a; Koeger et
al., 1980; Bennett and Forman, I960; Moss et al., 1980).
Acute experimental exposure to toluene within the range of 50 to 800 ppm
have not caused any definite effects on heart rate or blooci pressure
(Von Oettingen et al., 1942a, 1942b; 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.
Subjective complaints of dysmenorrhea have been reported by a significant
number of female shoemakers exposed to 60 to 100 ppm toluene and concomitantly to
20 to 5C ppm gasoline in a "few" working places for an average duration of
3 years and 4 months (Matsushita et al., 1975). Disturbances of menstruation
11-45
-------
have also been reported in women exposed concurrently to toluene, benzene, and
xylene in the workplace (Michon, 1965), and in women exposed occupationally tp
toluene and other unspecified solvents (Syrovadko, 1977), but a specific effect
of toluene could hot be determined from the available data. Information on the
possible reproductive effects of toluene in males is not available.
Minimum perceptible concentrations of toluene have been determined to be
0.^0 to 0.85 ppn (Gusev, 1965) 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., 19^; Partneggiani and 5ass.i, 195^; Capellini
and Alessio, 1971), but no complaints of respiratory tract discomfort were
recorded in volunteers or workers exposed to levels as high as 600 to 1500 ppm
for 8-hour periods in other studies (Von OettiP^cn et al., 19^2a,b; Wilson,
19^3)- No complaints of respiratory tract or eye irritation were recorded in men
accidentally exposed to 10,000 to 30,000 ppm toluene for brief durations
(Longley et al., 1967).
Transient epithelial injury to the eyes that healed within ^8 hours was
observed in workers who were accidently splashed with toluene (McLaughlin, 19^6;
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., 13^2), but Raitta et al. (1976) found lens chenges ir. 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
contact may cause skin damage due to its degreasing action (Gerarde, 1960;
Browning, 1965; Malten et al., 1966).
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11-56
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12. ANIMAL TOXICOLOGY
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 (see Sections 10.3 and 10.f). However, for those rare exposures
to high levels of toluene, 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 the 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 are irritation of the mucous membranes, incoordination, mydriasis, nar-
cosis1, tremors, prostration, anesthesia, and death. Cats appeared to be more
resistant than dogs and rabbits; rats and mice are 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. (1976a) reported 100? mor-
tality in rats that were exposed for 4 hours to 12,000 ppm of "toluene concen-
trate" (a mixture of paraffins, naphthenes, and aromatics that contained 45.9?
toluene and 0.06? benzene). Treu.ors 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 4 hours'
exposure to 3300 ppm. A calculated LC of 8800 ppm for a 4-hour period of
inhalation of "toluene concentrate" was reported. 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., 1976b).
In a study by Smyth et al. (1969a), inhalar.ion 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, and subsequently narcosis and mild twitching. A drop in body
temperature followed by death, occurred after 3 day.", of exposure. At necropsy, a
severe cloudy swelling of the kidneys was found. In this study, no effects on
12-1
-------
TABLE 12-1
Acute Effects of Toluene
ro
l
rv>
Route
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
4 nUnl -* *- , — —
Species
rats
rats
rats
rats
rats
rats
« n *• _
Dose
2^,^00 ppra for 1,5 h
12,200 ppm for 6.5 h
13,269 ppm
4,000 ppm for H h
12,000 ppm for 4 h
("toluene concentrate")3
8,800 ppm for 4 h
("toluene concentrate")3
£ *inr\ ~ <*_ ~. h v.
Effect
60? mortality
50? mortality
Lethal dose
1/6 dead
Lethal dose
LC50
I I n « rJ *- _ «— , n _. n J -, 1 Vi
Reference
Cameron et al
Cameron et al
Faustov, 1958
Smyth et al . ,
Carpenter .et
Carpenter et
., 1938
,, 1938
1969a
al.,. 1976b
al., ?976b
-iT 1 nTC v.
("toluene concentrate")''
inhalation rats 3,300 ppm for l4 h
("toluene concentrate")0
inhalation rats 1,700 ppm for *4 h
("toluene concentrate")0
inhalation mice 24,^00 ppm for 1.5 h
inhalation mice 12,200 ppm for 6.5 h
inhalation Swiss mice 5,320 ppm for 7 h
(less than 0.01?
benzene present)
Prostration in 2 h, normal
3 h after exposure
Slight loss of coordination Carpenter et al., 1976b
No-effect-level
10? mortality
100J mortality
LC50
Carpenter et al., 1976b
Cameron et al., 1938
Cameron et al., 1938
Svirbely et al.,
-------
TABLE 12-1 (cont.)
Route
inhalation
inhalation
inhalation
inhalation
Species
mice
mice
mice
rr t r •.
Dose
6,942 ppm for 6 h
(99. 5J purity)
6,634 ppm
9,288 ppm
8,600 ppm or 15,000 ppm
Effect
LC50
LSo
Lethal dose
SOJ reduction respiratory
Reference
Bonnet et al . ,
Faustov, 1958
Faustov, 1958
Carpenter et al
1979
., 1976b
inhalation
Inhalation
rvj
i
OJ
inhalation
inhalation
inhalation
inhalation
cats
("toluene concentrate")1
5,OUO ppra
("toluene concentrate")c
7,800 ppra for 6 h
("toluene concentrate")'
guinea pigs 4,000 ppm for 4 h
rabbits 5,500 ppm
dogs 850 ppm for 1 h
dogs
760 ppm "toluene con-
centrate" t h/d x 2 d
rested for 4 d, exposed
again for 3 d
rate
No-effect-level for
respiratory rate
Progressive signs: slight
loss of coordination,
roydriasla, slight hyper-
sensitivity to light within
20 min, prostration within
80 min, anesthesia within
2 hours.
One death during 14 d
observation period
2/3 dead within a few days
Lethal within 40 .min
Increased respiration rate,
decreased respiration
volume
Weight ]or,s of 1.1 kg in
1 of 2 dogs, otherwise normal
Carpenter et al., 1976b
Carpenter et al., 1976b
Smyth and Smyth, 1928
Carpenter et al , , 1944
Von Oettingen et al.-,
Carpenter et al . , 1976b
-------
TABLE 1?-1 (cent.)
Route
Species
inhalation -dogs
oral
rats
Dose
1,500 pprc "toluene con-
centrate" 6 h/d x 3 d
7.53 g/kg (6.73 to 8.43)
Effect
Reference
51ight laci imatlon and head Carpenter et al., 1976b
tremors (2 dogs exposed)
LDt
Smyth et al . , 19&9a
oral Wistar rats
adult
oral Sprague-Dawley rats
(150 to 200 g)
oral rats
14 d old, both sexes
young adults
ro
£T
i.p.
i .p.
i .p.
older
rats
rats
rats
adults
and mice
i.p. rats (both sexes)
i.p. mice (male)
7.0 g/kg
5.58 g/kg
(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 ma/kg (1.7 g/kg)
0.75 mil/kg (0.7 g/kg)
1.75 to 2.0 rat/kg
(1,5 g/kg to 1.7 g/kg)
800 oig/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)
LD
50
LD50
LD
LD
LD,
50
50
50
Lethal dose
Apathy
Death from respiratory
failure
Approximate lethal dose
LD,
.0
Observed for 24 h
Cause of death:
respiratory failure
Wolf et al., 1956
Withey and Hall, 1975
Kimura et al., 1971
Cameron et al . , 1938
Batchelor, 1927
Batchelor-, 1927
Keplinger et al., 1959
Koga and Ohmiya, 1978
i.p.
mice (female)
g/kg
LD
50
Ikeda and Ohtsuji, 1971
-------
TABLE 12-1 (cont.)
Route
i.p.
i .p.
Species
mice
guinea pigs
Dose
4 g/kg
2.0 mfc pure solvent
Effect
Lethal dose
6/10 dead after 2 h
Reference
Tsuzi, 1956
Wahlberg, 1976
s .c.
i.v.
dermal
(single
application)
dermal
dermal
derrcal
(1.7 g)
rats and mice 5 to 10 rod/kg
(4.3 to 8.2 g/kg)
rabbits 0.15 mi/kg (.13 g/kg)
0.20 m!./kg (.17 g/kg)
rabbits 14.1 md/kg
rabbits uncovered application
to abdomen
rabbits 10 to 20 applications of
undiluted toluene to
rabbit ear and bandaged
to shaved abdomen
guinea pigs 1 IT.!, for 16 h
All dead after 6 h
Lethal dose
13* mortality
100$ mortality
LD
50
Slight irritation
Cameron et al., 1938
Braier, 1973
Smyth et al., 1969a
Smyth et al.,. -1969a
Perceptible erythema, Wolf et al., 1956
thin layer of devitalized
tissue which exfoliated
No effect on gross appearance,
behavior, or weight
Karyopyknosis, karyulysis,
perinuclear edema,
spongiosis,
junctional separation,
cellular infiltration in
derrois,
no liver or kidney damage
K.ronevi et al., 1979
-------
TABLE 12-1 (cont.;
Route
dermal
Specifis
guinea pigs
Dose
Effect,
Reference
;\0 rot, covered Completely absorbed by 5th
to 7th d
No mortality up to 4 wk
Weight less than controls
for wk 1 to 3. no difference
at wk IJ
Wahlberg, 1976
to ,
i corneal
corneal
cCrneal
rabbits
rabbits
rabbits
C.005 -nl.
0.005 E!
: drc™
Moderately severe injury
Moderately severe injury
Perceptible irritation of
conjunctival membranes
No corneal injury
Smyth et al., 1969a
Carpenter and Smyth, T9lifc
Wolf et al., 1956
h = hour; nin = minute; d r day; wV' : week; i.p- = irtrnperi toneal; s.c. = subcutaneous;
i.v. = intravenous; n i number; ns = not specified
"toluene concentrate" is 3 mlxt^re oT paraffins, naj-lithcnea and arotr.aticp that contained ^5-9? toluene
and 0.06% benzene.
-------
TABLE 12-2
Subchronic Effects of Toluene
Species Route
Dose
Effect
Reference
Rat Inhalation 1600 ppm
18 to 20 h'd
Initial effect of instabilitj-
and incoordination, conjunc-
tivitis, lacrimation, and
sniffles; then narcosis
Batchelor, 1927
Rat Inhalation 1600 ppm
18 to 20 h/d x 3 d
Mild twitching; drop in body
temperature; death. Histology:
severe cloudy swelling of
kidneys, no effect on liver,
heart, or testes
Batchelor, 1927
Rat inhalation 1250 ppm
18 to 20 h/d
Slight instability and
incoordination; mucous
membrane irritation
Batchelor, 1927
Rat Inhalation 620 ppm or 1100 ppm
18 to 20 h/d
No-effect-level for symptoms;
hyperpiasia of bone marrow
Batchelor, 1927
Rat
Inhalation
1000 ppm solvent mix-
ture (50 to 60$
oenzene, 30 to 35$
toluene, *l? xylene)
7 h/d x 5 d x ?b wk
No effect on body weight;
lymphopenia followed by leuco-
cytosis and lymphocytes is; tran-
sient changes in blood picture
before or after each daily
expooure; splenic hemosiderosis
greater than that found after
inhalation of benzene only:
si ight to moderate reduction
2-1/2 wk after exposure. Nar-
rowing of peri-follicular collars
of cells in spleen, no fat in
livers and kidney; iron-negative
pipjnent in kidneys of a few animals.
Svirbely et al.,
-------
TABLE 12-2 (cent.)
Species Route
Dose
Effect
Reference
Rat Inhalation 240, iJ80, or 980 ppm
"toluene concentrate"
6 h/d x 5 d/wk x 65 d
No effect on red blood cell
count, white blood cell count,
hematocrit, hemoglobin, total
and differential white count,
blood urea nitrogen, SuOT,
SGPT, alkaline phosphntase,
or body weight.
Carpenter et al., 1976b
Rat
Inhalation
3184
4 h/d x 30 d
CD
Increased levels of SCOT,
SGPT, 0-lipop^oteins
Decreased levels of gluta-
thione, catalase, peroxi-
dase, total cholesterol
Khinkova, 1971
Rat
Inhalation
200 ppm or 600 ppm
No narcosis; body weight
change in HBC 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, or bone marrow
Von Oettingen et al,,
-------
TABLE 12-2 (cont.)
Species
Route
Rat
Inhalation
Dose
2500 ppra or 5000 ppm
7 h/d x 5 d x 5 wk
5 d/wk x 15 wk
Effect
Reference
Transient decrease in body
weight; hyperactivity, marked
incoordination, recovery after
cessation of exposure; mor-
tality in 5000 ppm group 18/25;
increased bleeding time; blood
•picture: total leucocytes
reduced after each exposure;
pulmonary lesions occurred
earlier than in group exposed
to 200 or 600 ppm; casts in
renal tubules in all rats
within 2 wk of exposure; rest
of histology saine as 200
and 600 ppra
cytochrome P-J450, ethoxy-
coumarin 0-deethylase increased;
UDP glucuronslytrarisf erase in-
creased only at end of exposure
von Oettingen et al.,
Rats
Inhalation
CFY rats Inhalation
(both sexes)
7 consecutive cycles
daily, 5 d/wk x 8 wk:
each cycle, 10 min to
12,000 pprc followed by
20 min toluene-free
internal
265 ppm 6 h/d x
5 d/wk z 1, 3 or
6 mo
Depression of body weight gain;
increased SCOT, LDH levels;
no effect on BUN levels
Depression of kidney, brain,
and lung weights. Histology:
no effect on brain, lung, liver
heart, or kidney, no sign of
lipid vacuolation in liver
Bromsulphthalein retention
decreased; Cytochrome P-450
increased independent of
period of exposure; SGOT
and SGPT activity unaffected
Bruckner and Peterson,
198la
Ungvary et al., 1980
-------
TABLE 12-2 (cont.)
Specious
Rom e
Dose
Effect
Reference
CFY rats Inhalation 929 ppm H h/d x
1-bot n sexes) 5 d*'wi; x -i wk,
6 w-' f. mo
ro
I
CFY rats
(.raaler)
Inhalation 398, 796, 1592 ppm
8 h/d x 5 d/wk x
It . . i .
Cytochrome P-150 increased
independent of exposure
period; no effect on SCOT
or SGPT; aniline hydroxylase
and aminopyrine N - dern ethyl as e
activity increased; cytochrome
bc concentrations increased.
KIstological 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
wi th dose
Rat, guinea Innalation 1G7 ppro continuously
pig, clop, for 90 d, cr 1085 ppm
monkey 8 h/cj, v d/wk x 6 wk
Nc effect on leukocytes, hemo-
globin, or hematocrit; no effect
on liver, kidney, lungs, spleen
or heart; ro effect or. brain or
spinal cord of dogs and monkeys
Jenkins et al ., 1970
-------
TABLET12-2 (cont.)
Species Route
Dose
Effect
Reference
Mice Inhalation 7 consecutive cycles
daily, 5 d/wk x 8 wk:
each cycle, 10 min. to
12,000 ppm followed
by 20 min. toluene-
free interval
Depression of body weight gain;
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.
Bruckner and Peterson,
198la
Mice Inhalation 4000 ppm 99.9% pure
toluene for 3 h
No effect on LDH activity
significant increase of
SGOT 24 h post exposure only
Bruckner and Peters-on,
198lb
Mice Inh?lation 4000 ppm 99.9$ pure
toluene for 3 h/d x
1, 3, or 5 d
SGOT levels increased after 1
and 3 days of treatment; no
effect 24 h after 5 d
Bruckner and Peterson,
198lb
Mice Inhalation 4000 ppm 99.9$ pure
toluene for 3 h/d x
5 d wk x 8 wk
Depression of body weight gain
during first 7 wk; increased
liver-to-body weight ratio after
4 wk exposure, no effect at 1, 2,
or 8 wk; no increase in kidney,
brain, or lung weights; SGOT activity
increased after 4 wk of exposure
and 2 wk post-exposure, but not
after 2 wk or 8 wk of exposure;
no change in BUN. Histology: no
effect on heart, lung, kidney,
brain and liver
Bruckner and Peterson,
198lb
-------
TABLE 12-2 (cont.)
Species
Route
Dose
Effect
Reference
Mice
Inhalation 1, 10, -100 or 1000 ppm No effect on body weight; 1
6 h/d x 20 d and 10 ppm caused increase of RBC
count on 10th day, recovery on
day 20; 100 ppiu, 1000 ppm -
decrease of RBC count; all doses -
increase CJO 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.
Horiguchi and Inoue, 1977
Guinea pig Inhalation 1250 ppm 4 h/d x
6 d/wk (18 exposures)
1000 ppm 4 h/d x
6 d/wk (35 exposures)
Prostration, marked liver
and renal degeneration,
marked pulmonary inflammation
No symptoms; slight toxic
degeneration in liver and
kidney
Smyth and Smyth, 1928
-------
TABLE 12-2 (cont.) .
Species
Route
Dose
Effect
Reference
Dogs
2 experimental,
1 control
Inhalation 2000 ppm 8 h/d x
6 d/wk x l) mo, and
then 2660 ppm 8 h/d,
6 d/wk x 2 mo
Death on days 179 and 180; slight Fabre et al.t 1955
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;
hyperemic renal glomeruli; albumin
in urine
Dogs
ro
i
Inhalation 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
No effect on circulation, spinal
pressure; increase of respiratory
rate, small increase of minute
volume, decrease of respiratory
volume
von Oettingen et al.f
Dogs
Inhalation 400 ppm; 7 h/d x 5 d Moderate temporary lyraphocytosis von Oettingen et ai.,
Rats
Oral 113 mg/kg/d,
354 mg/kg/d,
590 mg/kg/d x T38
No effect on
body and organ weights,
adrenals, pancreas, femoral
bone marrow, lungs, heart,
liver, kidney, spleen,
testes, bone marrow, BUN,
blood counts
Wolf et al.,. 1956
-------
TABLE 12-2 (cont.)
Species ~Route
Dose
Effect
Reference
Rats
Subcutaneous
1 cc/',:g x 21 d
Slight induration at injec-
tion site; 5 to 1H% 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
Batchelor, 192?
Guinea pig Subcutaneous
0.25 cc/d x 30 to 70 d
I
Jr
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
Sessa, 1948-
-------
TABLE 12-2 (cont.)
Species
Route
Dose
Effect
Reference
Rabbit
i
~^
>ji
Subcutaneous 1 cc/kg x 6 d
cc/kg
Transient slight -granulo-
penia followed by ^ranulo-
cyt6sis; no change in bone
marrow
More marked effect on
granulocytes; all rabbits
dead by end of secord day;
no effect on bone marrow
Braier, 1973
h = hour; d = day; wk = week; SCOT = serun glutamic oxalacetic transarainase; SGPT = serum
glutamic pyruvic transaminase; WBC = white blood cell; RBC = red blood cell; HDP = uridine 5'-phosphate;
BUN = blood urea nitrogen; mo = month.
-------
the liver, heart, or testes were observed, although hyperplasia of the bone
marrow was noted, suggesting possible contamination of the solvent with benzene,
Cameron et al. (1938), found that 24,400 ppm of toluene produced a
•nortality of 60$ and 10? in rats and mice, respectively, after 1.5 hours of
exposure. In another group of rats and mice exposed to one-half the above
concentration for a longer period, 6.5 hours, the mortality was 50$ and 100$,
respectively. These two species are probably equally sensitive. Other studies
of mice include that of S^irbely et al. (1943), in which the 7-hour LC in
Swiss mice was determined to be 5320 ppz, and that of Bonnet et al. (1979), in
which a 6-hour LC of 694? ppm for mice was noted.
In the study of Carpenter et al. (1976b), 4 of 4 cats initially survi"ed
exposure to inhalation of 7800 ppm "toluene concentrate" for 6 hours. During
Qvprtcur-o »hp cats showed progressive si mi of tcxicity, including slight loss of
coordination, mydriasis, slight hyperdensitivity to light within 20 minutes,
prostration within 80 minutes, and light anesthesia within 2 hours. Only 1 cat
died during the 14-day observation period.
/
Inhalation of 4000 ppm toluer" (purified by distillation) for 4 hours daily
was lethal within a few days to 2 of 3 guinea pigs.. The third animal was severely
prostrated. Under the same regimen, animals exposed to less than one-third of
this concentration (1250 ppm) for 6 days a week survived 3 weeks of exposure,
although they were severely affected. At 1000 ppm, guinea pigs were not affected
even after 35 exposures, although there were slight toxic degenerative changes
ia the liver and kidney (Smyth and Smyth, 1928).
Carpenter et al. (1944) reported that inhalation of a .concentration of
about 55,000 ppm was lethal to 6 rabbits in about 40 minutes (range of 24 to
62 minutes).
Von Oettingen et al. (1942b) observed that inhalation of 650 ppm toluene
containing 0.01$ benzene for 1 hour by 6 dogs produced an increase of respiratory
rate and a decrease of respiratory volume. Exposure to 1500 ppn of "toluene
concentrate" for 6 hours daily for 3 days produced only slight lacrimation and
head tremors in dogs. Reduction of the concentration of "toluene concentrate" to
1000 ppm did not alleviate tne head tremors (Carpenter et al., 1976b).
Bruckner and Peterson (198la,b) found an age-dependent sensitivity in rats
anl Bice. Mice, 4 weeks of age, were found to be more susceptible to exposure of
2600 ppm toluene vapor for 3 hours than 8 or 12 week old animals.
12-16
-------
12.1.1.2. ACUTE ORAL TOXICITY — An LD^ 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 LDc0 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™ of 2.6 g/kg body weight, 5.5
g/kg body weight, and 6.4 g/kg body weight for each group, respectively. This
age-dependent sensitivity was also noted by inhalation exposure (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. Thirty-three
percent of a group of 12 nine day old rats survived 5.25 hours of exposure to air
saturated with toluene, but 100$ mortality was observed in a group of adult rats
exposed for the same duration.
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 of 0.002 g/kg bw for a single oral dose. This was obtained by
dividing the dose that elicited the first observable gross signs of CNS toxicity
by 1000.
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. Koga and Ohmiya (1978) determined an LD^ of
1.15 g/kg body weight for male mice from administration of toluene graduated
between 0.79 and 1.65 g/kg and diluted in olive oil. Respiratory failure was the
main cause of death in these animals. An LD™ of 1.64 g/kg was reported for
female mice by Ikeda and Ohtsuji (197D. The reason for the disparity in the
above data (e.g., interlaboratory differences or sexual differences in
sensitivity) has not been ascertained. In rats an i.p. injection ->f 0.65 g/kg
toluene produced apathy, while 1.5 to 1.7 g/kg produced death from respiratory
failure (Batchelor, 1927); 1.7 g/kg was a lethal dose in rats, mice (Cameron
et al., 1938), and guinea pigs (Wahlberg, 1976)*
Savolainen (1978) observed that the concentration of radioactivity in the
•)!(
CNS was highest in the cerebrum after an intraperitoneal injection of methyl C-
toluene. Label was iirrJetectable in the CNS by 24 hours post-injection, which is
consistent with the time course of clinical signs of acute toluene intoxication.
12-17
-------
A temperature-dependent sensitivity to toluene was observed in adult rats
of both sexes by Keplinger et al. (1959). The lethal dose at 26°C was 800 mg/kg,
while at 8°C and 36°C, lethal aoses were 530 mg/kg and 225 mg/kg, respectively.
The toxicity of toluene is greater in hot and cold environments. It is unknown
whether increased susceptibility to toluene is caused by the stress of altered
environmental temperature, or by altered, physiological processes (e.g.,
absorption, diffusion, distribution, or metabolic rate) .
12.1.1.4. ACUTE EFFECTS FROM SUBCUTANEOUS INJECTION — Subcutaneous
injection of 1.1 to 1.25 g/kg and 4.3 to 3.7 g/kg toluene have been reported to
produce mortality in rats and mice, respectively (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 ar.d 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 toluene to the raDbit ear or shaved skin of the
abdomen produced slight to moderate irritation (Wolf et al., 1956; Smyth et al.,
1969a) ai;d increased local capillary permeability (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
within 16 hours (Kronevi et al., 1979; Wahlberg, 1976). Application to the
abdominal skin of the rat produced hemoglobinuria (Schutz, 1960). Slight
irritation of conjunct!val membranes but no corneal injury (Wolf et al., 1956) or
moderately severe injury (Carpenter and Smyth, 1946; Smyth et al., 1969a), have
been observed following direct application of toluene to the eye.
12.1.2. Subchrcnic and Chronic Exposure to Toluene. Subchronic or chronic
studies of toluene have not indicated, with the exception of the high exposure
level study of Fabre et al. (1955), evidence of major toxic effects.
Fabre ct al. (1955) exposed 2 dogs for 8 hours daily, 6 days a week, to
2000 ppm pure toluene via inhalation for 4 months, and subsequently to 2660 ppm
for 2 months. Slight nasal and ocular irritation occurred at the lower concen-
tration, and motor incoordination that preceded paralysis of the extremities
occurred in the terminal phase. Death occurred un days 179 and 180. There was no
effect on gain in body weight, on the bone marrow, or on the adrenal., thyroid, or
12-18
-------
pituitary glands. Congestion in the lungs, hemorrhage in the liver, a decrease
of lymphoid follicles, and hemosiderosis in the spleen were observed. Glomeruli
of the kidney were hyperemic, and albumin was found in the urine.
Svirbely et al., (1944) found that repeated inhalation of 1000 ppm of a
solvent mixture containing 30 to 35% toluene, 50 to 60% benzene, and a small
amount of xylene for 28 weeics (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
•fat was not found in the liver or kidneys; however, narrowing of perifollicular
collars was observed in the spleen (Table 12-2). Splenic hemosiderosis was
greater than that found ai'ter exposure to benzene (Svirbely et al., 1944).
Continuous exposure to 107 pptn toluene for 90 days or repeated exposure to
1085 ppm toluene for 6 weeks (6 hours'day, 5 days/week) did not adversely affect
the liver, kidney, lungs, spleen, or heart in 30 rats, 30 guinea pigs, 4 dogs, or
6 monkeys. In addition, treatment-related effects were not seen in the brain or
the spinal cord of dogs or monkeys. No significant change was observed in
hematoiogic parameters (hemoglobin, hematocrit, or leucocyte count). All
animals with the exception of 2 of 30 treated rats survived exposure, and all
gained body weight with the exception of the monkeys (Jenkins et al., 1970).
Repeated inhalation of 240, 460, or 980 ppm of "toluene concentrate" for
13 weeks (6 hours/day, 5 days/week) produced no treatment-related organ damage
in rats or dogs. Serum alkaline phosphatase (SAP), serum glutamic pyruvic
transaminase (SGPT), serum glutamic oxaloacetic transaminase (SCOT), and blood
urea nitrogen (BUN) activities were normal. Prior treatment with toluene did not
render the animals either more susceptible or more resistant to a subsequent
challenge dose of 12,000 ppm (Carpenter et al., 19?6b).
The results of an unreviewec subchronic inhalation study with rats that was
performed by Bio/dynamics for the American Petroleum Institute (1980) are
available. 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 toluene. 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, SAP,
glucose), urinalysis, and neurohistological examination of tissue was performed.
The only treatment-related sign was increased incidence of dry rales and staining
of the ano-genital fur in the high level treatment group. Significant changes in
the blood and urine were not found with the exception of a dose-related decrease
12-19
-------
in blood glucose levels and a dose-relatfcd increase in SGPT levels in female
»
rats. Body weights were significantly higher in the high-dose male rats than in
the control rats, but this was not considered a toxic effect. Treatment-related
neurohistopathological changes were not found.
Inhalation exposure to 1000 ppcn toluene for 6 hours a day, 5 days a week for
6 months had no treatment-related effects on male OFA rats (Gradski et al.,
1981). Twenty-four rats/treatment and control group were examined, and body
weight gain, hematologic parameters (BBC and -W3C counts, hemoglobin, mean
corpuscular volume, hematocrit, sedimentation rate), and tissue histology
(lungs, liver, spleen, kidney, genitals, and other unspecified "principal"
organs) were assessed.
In a chronic inhalation study conducted by Industrial Bio-Test Labora-
tories, Inc. for the Chemical Industry Institute for Toxicology (CUT), groups of
120 Fischer 344 rats of each sex were exposed to 30, 100, or 300 ppm of high
purity (>99.98J) toluene for 6 hours/day, 5 days/week for 24 months (CUT,
I960). All animals were weighed at the beginning of the study, weekly for the
first 6 months, every other week from 6 to 24 months, and immediately prior to
sacrifice. Hematology. blood chemistry, urinalysis, opthamology, and pathology
determinations were conducted on randomly selected rats that were sacrificed
after 6, 12, or 18 months to determine progression of toxic effects (Table 12-3).
All remaining rats were sacrificed for study after 24 months, but histopatno-
logical examinations were conducted only on tissues from rats in the high
exposure (300 ppa) and control (0 ppm) groups.
Unscheduled deaths occurred in 140 rats (14.6J of 960 animals) over the
2-year course of the study, but mortality in the treated rats reportedly did not
differ significantly from controls (CUT, 1980). The body weights of the treated
males were found to be significantly heavier than the control males throughout
the study, although a clear dose-response relationship was not apparent
(Table 12-4). A similar effect was noted for the females but the effect
disappeared during the final 4 weeks of the study. There were, however, no
significant differences among the groups in absolute organ weights (brain,
liver, heart, kidneys, lungs, and testes or ovaries were weighed). The battery
Pf clinical chemistry tests, hematologic studies and urinalyses (Table 12-3)
revealed normal levels in the treated rats except for two hematologic parameters
in females. Females exposed to 100 or 300 ppm toluene showed slightly, but
significantly, reduced hematocrits, and the mean corpuscular hemoglobin concen-
12-20
-------
TABLE 12^3
Number of Rats Per Sex and Treatment Group
Examined at Each Interval
Interval
6 Months 12 Months 18 Months 24 Months
Hematologya
Blood Chemistry
Urinal ysisc
Ophthamology
r
Pathology
5
5
5
5
5
5
5
5
5
5
20
10
10
25e
20
10
10
10
58-66
68-76g
Hemoglobin concentration (HgB), hematocrit (HcT), total
erythrocyte count (RBC), and total and differential leukocyte
counts (WBC) were determined; mean corpuscular volume (MCV), mean
corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin
concentration (MCHC) were subsequently calculated.
Blood urea nitrogen (BUN), serum glutamic pyruvic transaminase
(SGPT) activity, and serum alkaline phosphatase (SAP) were
determined.
c
Appearance, specific gravity, protein or albumin, pH, ketones,
glucose, and presence of microscopic particles were determined.
d
Ophthalmological examinations were conducted on all animals
scheduled for interval and final (24-month) sacrifice, except
animals also scheduled for blood collection at the final
sacrifice.
20 rats/sex/group were originally scheduled for sacrifice, but
an additional 5 rats/group were examined so that they could be
used as replacement animals should any of the firit group not
survive until the final sacrifice date.
f
Histologic examinations were conducted on 38 tissues taken from
the high exposure (300 ppm) and control (0 ppm) rats only. All
scheduled sacrifices, as well as rats that were sacrificed ir\
extremis (8-17 rats/sex/group) or died during the course of the
study (2-7 rats/sex/group), were examined grossly.
ff
All surviving animals at the end of the 24 months were sacrificed
for pathologic examination.
12-21
-------
tration was slightly, but significantly, increased in females exposed to 300 ppc
(Table 12-5). A variety of inflammatory, degenerative, prcliferative, and
neoplastic lesions were observed in various tissues (see Section 14.1), but the
lesions occurred with equal frequency in all control and treatment groups; CUT
(I960) concluded that no tissue changes can be attributed to toluene inhalation.
There were no significant differences among the groups; absolute ophthalsologic
examinations did not reveal any toluene-induced changes in the eyes of the rats.
\
TABLE 12-4
24 Month Chronic Exposure of Fischer 344 Rats Exposed
6 Hours/Day, 5 Days/Week, to Toluene by Inhalation
Group
Hales
Control '
30 ppm
100 ppm
300 ppm
Females
Control
30 ppm
100 ppm
300 ppm
i
•
Number
Animals
69
69
89
90
90
90
90
90
Mean
Body Weight in Grans
Weeks of
0
141
141
141
142
109
109
109
109
26
340
349«
3q 1.**
341
203
191"
194
195"
52
384
396"
140*4"
403"
213
211
211
211
Exposure
76
426
445"
4i47«»
446"
214
246"
248«»
248"
ICO
430
456"
4b4"
451"
260
272"
272"
271"
104
43C
454"
452"
445
265
273*
275
272
Total
Weight
Change
286
31U"
312«*
304"
156
164
166
163
Source: CUT, 1980
•Statistically significant difference from control (P <0.05)
"Statistically significant difference from control (P <0.01)
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 determined 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.
12-22
-------
TAKLK I. -•
Mematology Measurements
21* Month Chronic Exposure of Fischer 344 Rats txpoaed 6 Hours/Day, 5 Days/Wvek, to Toluene by Inhalation
ro
Group
Control
30 ppm
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
20
20
20
20
10
10
10
10
20
20
20
20
10
10
10
10
(103
6
9
6
6
7
8
8
7
it
4
3
4
4
5
5
4
WBC
/cu mm)
.03
.96*
.54
.53
.51
.66
.13
.50
.04
.59
.91
.21
.93
.40
.74
.87
,R3C
(10 /cu
18 Months
8.757
8.766
8.700
8.894
24 Months
9.666
8.736
9.925
9.407
18 Months
8.022
7.956
7.915
8.010
24 Months
8.397
8.274
8.076
8.090
HgB HcT
mm) (g/DL) (?)
of Exposure
16.56
16.61
16.47
16.80
of Exposure
18.91
16.58
18.47
18.33
of Exposure
15.67
15.77
15.75
15.78
of Exposure
16.46
15.89
15.94
15.86
(Males)
43.10
42.42
41.93
42.34
(Males)
51.78
46.51
51.61
47.35
(Females)
41.70
41.25
40.83
41 .20
(Females)
44.99
43.06
42.47»
42.02S«
MCV
(Cu. Mic.)
50
49
49
43
51
52
50
50
53
52
52
52
54
53
53
53
.4
.6
.5
.8"
.2
.5
.7
.9
.0
.8
.7
.4
.7
.3
-9
. 1
MCH
(we,)
18.87
13.90
IS. 91
18.35
19.24
19.05
18.67
19.44
19.49
- 19.77
I9.S5*
19.63
19.50
19. 11
19.68
19.52
MCHC
38.
38.
33.
39.
37.
36.
38.
39.
3T.
37.
38.
37.
36.
36.
37.
37.
04
82
93
30"
87
33
34
33
26
90«
24»
98
10
42
08
46»
Source: CUT, 1980
•Statistically significant difference froa; control (P <0.05)
••Statistically significant difference from control (P <0.01)
WBC = white blood cell count; RGB = red blood cell count; HgB ; henoglobin concentration; DL = 100 milliliters;
HcT = hematocrit; MCV = mean corpuscular volume; Mic. = micron; MCH = me.nn corpuscular- hemoglobin; MCHC -
mean corpuscular hemoglobin concentration.
-------
12.2.1. Liver
Histological damage was not observed after subchronic or chronic inhalation
of 1000 ppm of a solvent mixture containing 30 to 35? toluene for 26 weeks,
980 pfffl of "toluene concentrate" for 12 weeks, 1085 pptL of toluene for f weeks,
or 300 ppm of 99-98? pure toluene for 24 months in a variety of species in the
studies described in Section 12.1.2. (Svirbely et al., 1944; Carpenter et al.,
1976b; Jenkins et al., 1970; CUT, I960). Furthermore, no liver damage was
detected in female rats after daily oral doses of 590 mg/kg toluene 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 designed to zinic
solvent "sniffing", male rats and mice were exposed to 12,000 ppm toluene for 7
ten-minute periods (interspersed with 20-minute toluene-free periods),
5 days/week for 8 weeks. No organ pathology was found. Lactic dehydrogenase,
SGPT activity, BUN level, 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 as indicated by a battery of toxicological tests (SCOT
activity, BUN level, urinary glucose and protein concentration, and urinary cell
count), and histopathological examination of the liver, kidney, and lung
(Bruckner and Peterson, 1976).
Intraperitoneal injection of reagent grade toluene (corn oil vehicle) at
doses of 150, 300, 600, or 1200 mg/kg had no effect on serum ornithine carbamyl
transferase activity in adult male guinea pigs, when assayed 24 hours after
injection (Divincenzo and Krasavage, 1974). Histological examination revealed
no liver abnormalities or lipid accumulation with the exception of the highest
dose, where there was evidence of .lipid accumulation.
Two hours after male rats (weighing 150 to 300 g) were administered
239-5 mg/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 demethy-
lase, nicotinamide adenine dinucleotide phosphate (NADPH), neotetrazolium reduc-
tase, or lipid conjugated diene content of microsomes (Reynolds, 1972). Inhala-
tion of 3CO ppm toluene (6 hours/day, 5 days/week) for 15 weeks slightly
increased cytochrome P-450 content in tlie liver, appreciably enhanced ethoxycou
oarin o-deethylase, and at the end of exposure, increased UDP glueuronyltrans-
12-24
-------
ferase activity. The com.pnr, of .toluene in osrirenal fat tended to decrease
during continued evDo.snre. wMle presence in the! brain was detected throughout
exposure. The d.lr"ini'at-ion r,f toluene content in perlrenal fat at the same tine
that drug met.?ho.i .< r.i.nc pn^vrnps increased suggests an adaptation to continued
presence of the soi.vpr.t-. fFV>«sara et al.. 1979).
ntpnpono contact with a dose of 1.7 g (2.0 i-.i) toluene, whicn
was completely ahso'-he'l "'vti-'in 5 to- 7 days, .produced no change in liver
i"orpho5 ogy (Wahlberc, lpr-e ?^e others that suggest a slight toxic effect. In a
sU^y by von Oettjpcpri f-f ;•! . M^Pb), inhalation of 600 to 5000 ppm toluene that
contained 0.01S ben-7pne for S wpeks (7 hours/day, 5 days/week) by rats caused an
enlargement of the ] ivpr f increase of weight and volume) in a dose-dependent
manner To hours after the last exposure. Histologically there was a progressive
decrease- of cytoplasm density in the liver cells as the concentration of toluene
i
increased, but hyperemia was not noted. These observations were not seen in rats
sacrificed 2 wee^s after the ]ast exposure. Matsumoto et al . (1971) reported an
increase in liver wei eht and liver weight to body weight ratio in rats exposed
9 hours/day. 6 days/week for ^3 weeks to 2000 ppm toluene vapor. This was not
noted at lower doses (100 pr-m or 200 ppm).
In the inhalation study of Fabre et al . (1955), 2 dogs exposed for U months
(8 hours/day, 6 days/week) to 2000 ppm pure toluene and, subsequently, to
?£66 ppm for 2 months . hari 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 the same laboratory revealed no effect on SCOT
activity or BUM level in mice or rats, a recent report by Bruckner and Peterson
(198lb) noted an increase in SOOT activity in these species during intermittent
exposure to 12,000 ppra 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 ratio was
found.
Histological changes in the liver were found when male CFY rats were
injected intraperitoneally with O.U3 or 0.87 g/kg body weight of analytical
grade toluene for up to ^ weeks (Ungvary et al . , 1976). There was a dose-
12-25
-------
dependent increase in the number of mitochondria per unit of cytoplasmic area in
the liver. Total area, nuclear density, and nucleus/cytoplasm ratio increased at
the higher dosage. Dose-dependent decreases in nuclear volume were seen after
intraperitoneal or subcutaneous injection, witn subcutaneous injection being
less effective than intraperitoneal injection. The authors suggested that the
considerable accumulation of mitochondria was related to increased metabolism by
the liver, and that oxidative detoxification of the solvent might involve mito-
chondrial enzymes as well as hepatic microsomal enzymes. In an earlier paper,
Ungvary et al. (1975) found that intraperitoneal or aubcutaneous 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
discontinuation of exposure, the hepatic changes indicating increased load on
detoxification processes (increased succinate dehydrogenase (SDH) activity,
increase of mitochondria and smooth endoplasmic reticulum, decreased glycogen
content) as well as degeneration (dilation of endoplasmic reticulum,
accumulation 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 ai. (19&U), male CFY rats were exposed
via inhalation to 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
exposures a week for up to 6 months). Growth was inhibited in males at the
higher concentrations, and in the females. No abnormal nistological changes were
found in the liver, but liver weight was increased by treatment. Signs of
adaptive compensation included proliferation of smooth endoplasmic reticulum,
increased cytochrcme P^50 and cytochrorae b, activity, increased aniline
hydroxylase activity, and increased aminopyrine N-demethylase activity. These
changes were dose-dependent and reversible, but 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 histological effects of inhalation
exposure to toluene were corroborated by the earlier intraperitoneal or subcuta-
neous studies, with the exception that necrotic areas were not found after
inhalation. Whether or not this reflects the different route of exposure or the
12-26
-------
higher concentration of toluene administered intraperitoneally has not been
ascertained.
12.2.2. Kidney. Histological effects of renal toxicity were not seen in
subchronic inhalation studies (Table 12-2) mice exposed to 1000 ppm for 20 days
(Horiguchi and Inoue, 1977)i in rats, guinea pigs, dogs, or monkeys exposed to
1085 ppm for 6 weeks (Jenkins et al., 1970), in rats and mice exposed to 4000 ppm
toluene for 8 weeks (Bruckner and Peterson, 1981b), or in chronic inhalation
studies in rats exposed to 300 ppm for 24 months (CUT, 1980). Toluene did not
elicit an observable effect in renal histology after daily subchronic oral dosing
at a level of 590 mg/kg for 138 days in rats (Wolf et al., 1956).
Pathological renal changes, however, have been observed in somfe studies.
von Oetvir.^en et al. (1942b) 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 were observed in dogs following inhalation exposure to 200 to
i
600 ppm for approximately 20 daily 8-hour exposures, subsequently to 400 ppm for
7 hours/day, 5 days/week for 1 week, and finally to 850 ppm for 1 hour.
Matsumoto et al. (197D reported that inhalation exposure to toluene at a level
of 2000 ppm for 8 hours/day, 6 days/week for 43 weeks produced hyaline droplets
in the renal tubules of rats. There was an increase in kidney weight and the
ratio of kidney weight to body weight.
Inhalation of 2000 ppm toluene 8 hours/day, 6 days/week for 4 months,
followed by exposure to 2600 ppm during the remaining 2 months, produced
hyperemic renal glomeruli and albuminuria in dogs (Fabre et al., 1955). In
guinea pigs, inhalation of 1000 ppm distilled pure toluene (4 hours/day,
6 days/week for a total of 35 exposures) produced slight toxic degeneration :n
the kidney (Smyth and Smyth, 1928). Eighteen exposures at a higher levels of
1250 ppm produced more marked degeneration. Degeneration of convoluted tubular
epithelium in guinea pigs exposed to toluene by the subcutaneous route was
reported in an abstract of a paper by Sessa (1948).
12.2.3. Lungs. Histological lung damage was not seen after inhalation of
1000 ppm toluene for 20 days in mice (Horiguchi and Inoue, 1977), after
inhalation of 1085 ppm for 6 weeks in rats, guinea pigs, dogs., or monkeys
(Jenkins et al., 1970), after inhalation of 4000 ppm for 8 weeks in rats and mice
12-27
-------
(Bruckner and Peterson, 198lb), after inhalation of 300 ppm for 24 months in rats
(CUT, I960), or after daily ingestion of 590 mg/kg for 133 days in rats (Wolf
et al., 1956).
Irritative effects on the respiratory tract, however, have been reported
(Browning, 1965; Gerarde, 1959; Fabre et al., 1955; von Oettingen et al.,
19t2b). Marked pulmonary inflammation was seen in guinea pigs after inhalation
of 1250 ppm distilled pure toluene for ^ hours daily, 6 days/week, for
18 exposures (Smyth and Smyth, 1928). Hemorrhagic, hyperemic, and sometimes
degenerative pulmonary changes were observed in guinea pigs after a subcutaneous
injection of 0.22 g of toluene daily for 30 to 70 days as reported in an abstract
(Sessa. 1948). Repeated exposure to concentrations of 200 to 600 ppm toluene
produced congestion in the lungs of dogs, and pulmonary lesions were elicited in
rats after 1 week of inhalation of 2500 ppm (7 hours/day, 5 days/week)
(von Oettingen et al., 1942b). Congestion in the lungs was noted by Fabre et al.
(1955) in dogs exposed for 8 hours a day, 6 days a week to 2000 ppm toluene for
4 months, and subsequently to 2660 ppm for 2 months.
12.3. BEHAVIORAL TOXICITY AND CENTRAL NERVOUS SYSTEM EFFECTS
Excessive depression of the CNS has been associated 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 cf 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 that appeared within 5 minutes of exposure, and prostration that
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 (Batchelor, 1927).; no symptoms were seen at 1100 ppm. Carpenter
et al. (1976b) reported that rats were unaffected by inhalation exposure to
1700 ppm of "toluene concentrate" for 4 hours, and suffered only slight
incoordination at 3300 ppm. Dogs were unaffected by exposure to 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, but no mortality.
Bruckner and Peterson (198lb) observed that the onset of narcosis and the
depth of CNS depression was dose-dependent in mice exposed via inhalation to
12-28
-------
12,000 ppm, 5200 ppm, or 2600 ppm toluene. Recovery was rapid. Aftf>: exposure
to 12,000 ppm for 20 minutes, mean performance levels scored prior to exposure
were restored within approximately one-half hour in 1-week-old rats.
A single intraveriqus injection of 0.06 g toluene per kg body weight caused
generalized rigidity with hyperextension of the back within 10 seconds in an
experiment with 1 dog (Baker and Tichy, 1953). Recovery occurred within
12 minutes. When a series of 10 doses of 0.06 g toluene/kg was given intra-
venously every 3 t° 5 days to another dog, rigidity and twitching of the
extremities were induced. Recovery occurred in 5 to 10 minutes. At necropsy,
cortical and cerebeliar atrophy was found. Marked shrinkage and hyperchro-
maticity of many cortical neurons, patchy myelin pallor and fragmentation,
especially in perivascular areas, were found. Multiple fresh petechiae,
especially in the white matter, were 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 CNS effects on
humans (Section 11.1.), inhalation of readily available thinners by young adults
has been described as a prevalent practice that typically affects the CNS.
Inhalation of solvent mixtures containing toluene in the laboratory rat have
i , 1
demonstrated similar effects. Inhalation of a mixture of solvents containing 25?
methylene chloride, 5% methanol, 1)3% heptane, and 23% toluene for 10 minutes (60
to 226 mg/Jl) 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? 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 (DRL 20). In
this test, the animal is rewarded for a bar press separated from the last
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,
12-29
-------
responses in rats that had a period of rest after exposure did not differ from
controls (ColoUa et al., 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 pptn toluene for 3 hours decreased over time of exposure, and 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 concentration
(10,615 ppm) was consistent with the pattern elicited by the lower concent-
ration, longer duration exposure. Recovery of behavioral performance 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 with
i
blood concentrations of HO to 75 ^ig/g, 75 to 125 ng/g, 125 to 150 ng/g and
>150 ng/g, respectively, as measured by the air bleb method.
A study was conducted by Peterson and Bruckner (1978) with mice to mimic the
conditions typical of human solvent-sniffing abuse. Intermittent exposures to
10,615 ppm for approximately 3 hours (5 minutes of exposure followed by
10 minutes without, toluene, or 10 minutes of exposure followed by 20 minutes
without toluene), or to 11,9^2 ppm for approximately 3 hours (10 minutes of
exposure followed by 20 or 30 minutes without toluene) were conducted. Reflex
performance became progressively lower throughout the experimental periods in
the regimens that included toluene-free intervals of 20 minutes or less, A 30-
minute, toluene-free interval between exposures permitted almost unimpaired
perfrrmance, 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
12-30
-------
TISSUE LEVELS
tu
800-,
600-
400-
ioo-
—I
4
0 1 2 3 t 2 3
HOURS OF EXPOSURE HOURS POSTEXPOSURE
100 -,
o
er
ui
0.
NORMALIZED TISSUE LEVELS
— BRAIN
LIVER
BLOOD
I
1
0 1
HOURS OF EXPOSURE
II
3
HOURS POSTEXPOSURE
UJ
z
UJ
O
o
600-
400-
200-
BRAIN CONCENTRATION VERSUS
CHANGE IN PERFORMANCE SCORE
BRAIN
APERFORMANCE
I I T
0123
HOURS OF EXPOSURE
i
2
-5 u,
4 2
re
_ IL.
1 a
r 1 uj
b~ °"
3 4
HOURS POSTEXPOSURE
Figure 12-1. Toluene Levels in Tissue and Behavioral Performance (Mice were con-
tinuously exposed for 3 hours to an intoxicating concentration cf
3980 pprn toluene. Groups of animals were analyzed for air bleb con-
centration, reflex performance, and tissue levels after 15, 30, 60,
120, and 180 minutes of exposure and 1, 2, and t( 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 H hours postexposure, in which case, N = 6. (Pt-.terson and
Bruckner, 1978)
12-31
-------
course of treatment, while performance scores of rats exhibited a progressive
decline. The authors speculate that ,the rapidity of recovery in mice might be
attribu'.ed to the higher circulatory, metabolic, and respiratory rates of mice;
the increasing CNS 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 1 hour post exposure had been noted by
the same authors in ah earlier paper (Bruckner and Peterson, 196la).
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 (Bruckner and Peterson,
198la). Depression of body weight gain was observed in both rats and mice during
the 8 weeks of intermittent toluene exposure. An increase in SCOT levels was
noted in rats and mice, but the increase in mice was net statistically
significant. An increase in LDH was seen in rats at all sampling intervals, but
this effect was not noted in mice. 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 depression in gain of
organ weights (kidney, brain, lung) was noted in both species.
12.3-2. Effects on Simple and Complex Behavioral Performance. After a single
exposure to 800 ppsn toluene for 4 hours, unconditioned reflexes and simple
behavior (corneal, grip, and righting reflexes, locomotor activity, and coor-
dination) began to fail (Krivanek and Mullin, 1978; Mullin and Krivanek, 1982).
In these studies, male rats were exposed to concentrations of 0, 800, 1600, 3200,
and 6^400 ppm and tested at 0.5, 1, 2, and k hours during exposure and 18 hours
after exposure (Table 12-6).
Concentrations of toluene as low as 1 ppa 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 20
daily exposures. However, alterations-in blood elements were observed in animals
exposed to 10, 100, or 1000 ppm (Table 12-7).
The positive findings at 1 ppm reported by Horiguchi and Inoue (1977), and a
report of changes in motor nerve chronaxies in rats exposed continuously to ^ ppm
toluene for 85 days (Gusev, 1967; cited by NRC, 1980). are at variance with
negative effects observed in other experiments at much higher levels and may be
12-32
-------
TABLE ^-6
Behavioral Effects of Toluene
I
U)
txl
Species
Wistar rats
Sprague-Dawl ey
rats
Rats (scale)
Rats
Rats (oalej
Rats (male)
Rats (eile)
Sprague-Dawiey
rata
Mice
Mice
Mice (sale)
Mice
Mice (male)
Route
Inhalation
Inhalation
Inhalation ,
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
I. p.
Dose
571*, 1118, 2296, and
1595 ppa
150 ppm for 0.5, 1 , 2 or
« h
550 to 800 ppu for
« h/d x 2 wk
"4000 ppto 2 h/d x 60 d
3UOO ppm for ->4 It
1000 ppm for b h
3200 ppm for "4 h
1600 ppa for 1 h
800 ppm for 1 h
23,000 ppm for 1/2 h/d x 7.6 d
3980 ppn for 3 ^
10,615 ppa for 10 mln
4,000 ppo for 3 h/d x
5 d/wk for 8 wk
1, 10, 100, 1,000 ppa for
6 h/d- » 10 d
2650 ppm
0.96 g/kg
Effect
Deficit In multiple
response schedule
Initial stimulation
followed by depression In
multiple response schedule
No effect on avoidance
response
Multiple response schedule
No effect on CRF or FR30
Deficit In DHL 12 sec
schedule
Deficit In conditioned
avoidance response
No effect level
Deficit conditioned
avoidance response
No- effect- level
Deficit in unconditioned
reflexes and simple
behavior
Induced forced turning
1/eficlt in visual placing,
grip strength, wire maneuver
tail pinch, righting reflex
Deficit on an accelerating,
rotating bar
Deficit in wheel-turning
Causes mice to fall on side
Loss of righting reflex in
5/7 In 20.6 + 1.6 Bin
Interval froo loss of
righting reflex to re-
covery 35.0 + 8.2 nin.
1t.3J lethality in 2M h
Reference
Colotla et el.,
1979
Celler et al., 1979
Bat tig and Grandjean, 1964
Ikeda and Mlyaka, 1978
Shlgeta et al., 1978
Krlvanek and Hullin, 1978;
Mullin and Krivanek, 1982
Krivanek and Mullin, -1978
Hullin and Krivanek, 1982
Ishlkawa and Schaldt, t973
Peterson and Bruckner,
1978
Bruckner and Peterson,
1976
Horiguchl and Inoue, 1977
Fausto», 1956
Koga and Ohalya, 1978
r s hour; d = day; wk 5 week; i.p. = Intraperltoneal; Bin = minute; sec = second.
-------
TABLE 12-7
Myelotoxicity Effects of Toluene
Species
Route
Dose
Effect
Reference
Rats
Rats,
Guinea pigs,
Dogs,
Monkeys
Rats
I
(A)
Inhalation 200, 600, 2500 or
f.OOO ppm for 7 h/d,
'5 d/wk x 5 to 6 wk
Inhalation 107 ppm continuous
exposure for 90 d,
or 1085 ppm for 8 h/d,
5 d/wk x 6 wk
Inhalation 30, 100 or 300 ppra for
6 h/d x 5 d/wk x 24 mo
Rats,
Dogs
Inhalation
240, 480, or 980 ppm
for 6 h/d x 5 d/wk
x 65 d
A temporary decrease of
lympho-ytes and total at
the highest doses
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
CII'i, 1980
Carpenter et al., 1976b
-------
TABLE 12-7 (cent.)
Species Route
Dose
Effect
Reference
Rats
Inhalation
200, 1000 or 2000 ppm
for 8 h/day x 32 wks
ro
t
oo
Ul
Rat
Rats
Inhalation
Oral
112 ppm for
4 h/d x ij mo
Significantly retarded weight
gain at 2 higher doses during
initial 4 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 J) weeks and then
recovered; increase of
Mommsen's toxic granules.
Leukocytosis and chromo-
some damage in bone marrow
118, 354 or 590 mg/kg/d Normal bone marrow,
x 138 d spleen, bone marrow
counts, blood count
Takeuchi, 1969
Dobrokhctov and
Enikeev, 1975
(cited in U.S. EPA, 1980b)
Wolf et ai., 1956
-------
TABLE 12-7 (cont.)
Species Route
Dose
Effect
Reference
Rats
Rat
Rat
tlice
u>
Dogs
Dogs
Subcutaneous 0.8? g/kg/g
x 1U d
Subcutaneous 1 g/kg/d x 12 d
Dermal
Inhalation
Inhalation
Inhalation
10 g/kg/d
1, 10, 100 or 1000 ppm
for 6 h/d x 20 d
Normal leukocyte count,
spleen, and bone marrow
11.5$ chromosome damaged
cells vs. 3-9? in controls
Impaired leukopoiesis
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
ppm for 7 h/d x 5 d No change in blood picture;
temporary lymphocytosis
2000 ppm for 8 h/d x
6 d/wk x i\ mo, and
then 2600 ppm for 8 h/d
x 6 d/wk x 2 mo
No effect on bone marrow
Gerarde, 1960
Lyakalo, 1973
Yushkevich and Malypheva,
1975
Horiguchi and Inoue, 1977
Von Oettingen et al.,
Fabre et al., 1955
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.
-------
regarded as spurious. For example, Takeuchi et al. (1991) reported that exposure
to 1000 ppm toluene for 16 weeks (12 hours/day) did not produce evidence of
peripheral (tail) nerve injury (as determined by nerve condition velocity, mixed
nerve conduction velocity, and distal latency measurements) in Wistar rats.
Ikeda and Miyake (1978) did not find any effect on spontaneous activity in
studies of repeated exposure to 4000 ppm toluene in rats. However, the
behavioral tests of the latter authors were carried out 4 days after final
exposure, and rapid recovery of behavior after exposure (Shigeta et al., 1978;
Peterson and Bruckner, 1978; and Ishikawa and Schmidt, 1973) may explain in part
the disparate results.
A single exposure to 3000 ppm toluene for U hours disrupted established
timing of bar pressing in a conditioned avoidance response test with 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 1 hour after exposure. Krivanek and Mullin
(1978) reported a decrease in conditioned avoidance reflexes in male rats after
inhalation of 3200 ppm toluene for & hours, but they reported no effect at dose
levels of 1600 or 800 ppm.
In another study of operant behavior, Colotla et al., (1979) used rats that
had been trained to reinforced bar pressing in a multiple schedule that consisted
of fixed ratio (FR) 10 and differential reinforcement of low rates (DRL) 20-
second components with a 60-second time out between reinforcement periods. Five
trained adult Wistar rats were exposed to concentrations of 57^, 1H»8, 2296, or
^595 ppm toluene, and test sessions were 36 minutes long. Control sessions
intervened between solvent exposure sessions to assess recovery. A decrease in
rate of response of the FR component and an increase of freouency rate of the DRL
component were observed with all doses in a dose-dependent manner. No residual
effects were observed.
Exposure to a lower concentration of toluene (150 ppm) for periods of 0.5,
1, 2, or H hours affected performance on a multiple fixed ratio-fixed interval
schedule of reinforcement in ; male Holtzman Sprague-Dawley rats. An initial
enhancement of FR and FI rates occurred during the shorter exposure periods,
followed by a decrease in rates during longer exposure periods (Geller et al.,
1979); however, only a small number of animals was used, and the response was not
uniform. Battig and Grandjean (1961!) found no effect on acquisition or consoli-
12-37
-------
dation of an avoidance response in 6 adult male rats after inhalation of toluene
that varied in concentration from 550 to 800 ppm, fpr 4 hours/day for 2 weeks.
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
i
(FR 30). schedule performance where every 30th response is reinforced. The
exposure impaired learning on a third operant schedule, however, in which
acquisition of a differential reinforcement of a low rate of responding (DRL 12
seconds) schedule required rats to allow at least 12 seconds between responses to
receive a reward. Impaired performance was present 60 days after final exposure.
Exposure to toluene appears to affect more seriously higher levels of cognition.
Histoiogicai examination of the brain did not reveal any changes (Ikeda and
Miyake, 1976).
Inhalation of 1*000 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 curing 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 exposure r.o approximately
23|000 ppm (4 to 5 mi. in kO to 50 4. of air) for one-half hour per day. After 15,
21, or 3*1 days of recovery, the rats were reexposed daily to toluene. When only
15 days of recovery had elapsed, the number of exposures required t'o elicit
forced turning was significantly let>s than the nuinter required to acquire the
behavior originally. This effect was not seen when a longer period of recovery
had elapsed. Thus, toluene has a residual effect and the effect is reversible.
This turning was not associated with any histological lesions in the brain
(Ishikawa and Schmidt, 1973).
^•So. 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 via trachea.l cannulation to
7000 to 52,000 ppm (approximate) concentrations of toluene for 10-minute periods
a day, 7 days a week for *40 days; exposures were started at 7000 ppm and were
12-38
-------
increased by increments of approximately 7000 ppm (with 10-minute recoveiy
intervals between exposures) each 10 minutes until electrical and behavioral
changes appeared. During the first seconds of acute intoxication at 12,000 ppm,
the behavior consisted of restlessness, polypnea, coughing; sneezing, and vege-
tative responses consisting of salivation, mydriasis, and lacrimation. Itaxia
appeared 2 minutes later, ending with postural collapse. Changes of electrical
actisvity at this point were found in the anterior lobe of the cerebellum, the
amygdala, and the visual cortex. There was no behavioral responsa to light,
sound, or pain stimuli (Table 12-8). The threshold dose for restlessness war,
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 approx-
imately 27,150 ppm, hypersynchronous rhythms spread from the amygdala to the
reticular formation, visual cortex, and cerebellum, and electrical activity
appeared in the gyrus cingvli 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).
Takeuchi and Hisanaga (1977,) found that 1030, 2000, or UOCO ppm toluene
administered for 4 hours to groups of 4 or 5 male Wistar rats elicited changes in
the sleep cycle, altered cortical and hippoceapal ERG rhythms, and increased
pulse rates. All phases of sleep were disturbed at concentrations of 2000 and
4000 ppm; 1000 ppro deterred the onset of the slow-wave phase of sleep, but
facilitated onset of 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 1)000 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 upon
reexposure. At 2000 ppm only increased excitability was observed, and 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.
12-39
-------
TABLE 12-8
Central Nervous System Effects of Toluene
Species
Route
Dose
Effect
Cats
Inhalation ca. 7,000 to 52,000 ppm
10 min/d x 40 d
Rats
Inhalation 1000, 2000, or ^000 ppm
for H h
ro
Jr
O
Rats (male) Inhalation 2000 ppm toluene for
8 h/d x 1 wk
Sprague-Dawley Inhalation 500 ppm 6 h/d x 3 d
Rats (male) Killed 16 to 18 h after
exposure
1000 ppm 6 h/d x 5 d
decapitated 4 h after
exposures
Reference
Rats
Inhalation 1000 ppm x 6 h/d x
6 d/wk x J! wks
Rats, mice Inhalation 265 ppm
Restlessness
Autonomic nervous system
stimulation, ataxia,
collapse
EEG changes
Seizures
EEG changes
Increased excitability
Changed sleep cycle
Increased pulse rate
Decreased threshold for
Bern egride-induced
convulsions
Increase of catecholamines
in lateral palisade
zone of median eminence
Increase of catecholamines
in subependymal layer of
median eminence
Increase of FSH
Increased spontaneous activity
during light period after
repeated exposure. Single
exposure did not influence
cir^adian rhythm.
Threshold affecting CNS
Contreras et al., 1979
Takeuchi and Hisanaga,
'.977
Takeuchi and Suzuki,
1975
Andersson et al., 1980
Ikeda et al., 1981
Faustov, 1958
min = minute; d = day; h = hour; -wk = week; EEG - electroencephalogram; FSH - follicle-stimulating hormone; CNS = central
nervous system.
-------
Convulsion threshold after intraperitoneal injection of Bemegride was,
decreased significantly by preexposure to 2000 ppm toluene for 8 hours/day in
6 Sprague-Dawley tale rats. The change was noted after 1 week of exposure, and
convulsion threshold continued to decrease over 6 weeks of exposure. After 8
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 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.^« Effect on Neuromodulators. Andersson et al. (1980) reported an increase
of dopaioine 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 periventricular and paraventricular hypothalamic nuclei. A significant
increase of plasma levels of follicle-stimulating hormone (FSH) and a non-signi-
ficant elevation of prolactin and corticosterone were also noted.
i Yamawaki et al. (1982) found a decrease in specific serotonin ( H)-5HT
binding to synaptic membrane fractions from whole brains, and from the hippo-
campus and pons/medulla oblongata regions of rats that were exposed 15 minutes a
day to 7000 ppm toluene for 14 days. These results indicate that serotonergic
mechanisms may have contributed to some of the observed behavioral effects of
exposure (i.e., hindlimb abduction, resting tremor, head weaving).
12.3.5. Minimal Effect Levels. Although most acute as well as chronic studies
indicate minor effects of toluene at concentrations under 1000 ppm and most
reviews (NIOSH, 1973; U.S. EPA, 1980a; NRC, 1980; Benignus, 198la, 198lb) have
emphasized the negligible effects of toluene on the CNS at this level, several
foreign studies suggest that lower level exposures may not be innocuous.
Horiguchi and Inoue (1977) found a decrement in simple task performance during
exposure to 1 ppm toluene, Gusev (1967) reported lengthened motor nerve
chronaxies at 4 ppm, Colotla et al. (1979) noted a decrement in operant behavior
at concentrations of 57*J 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 that regulates many vegetative, as well as
reproductive, functions. Although the results of the lower exposure level
12-41
-------
studies (Horiguchi and Inoue, 1977; Gusev, 1967) are inconclusive, these
findings indicate that effects of toluene' on the CNS at levels below 1000 ppm
cannot be totally ignored,
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's 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 myeiotoxicity, although several have indicated a positive effect (see Table
12-7).
One of the first studies that used pure toluene was that of von Oettingen
et al. (1942b). Exposure 01' rats to 200 to 5000 ppm toluene contaminated with
less than 0.01J 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 that was
characterized by a decrease of lymphocytes and total white blood count, with a
moderate increase of segmented cells (Table 12-9). Exposure of dogs to 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). Fabre et al. (1955) also found that
exposure of dogs to high concentrations of toluene containing less than 0.1J
benzene (2000 ppm for 8 hours daily, 6 days weekly for 4 months, and
subsequently 2600 ppm for the 2 remaining months) had no effect on the bone
marrow.
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 94.4J pure toluene at levels of 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 (CUT, I960)
(see Table 12-4); there were also no changes in the bone marrow or spleen.
Male Wistar rats administered a daily subcutaneous dose of 0.87 g/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).
12-42
-------
TABLE 12-9
Weekly Blood Picture of formal Rata and Rats Exposed to 600 and
2500 ppn of Toluene 7 Hours/Day, 5 Days/Week, for 5 Weeks
'
Weeks
Preexposure period:
First
Second
Exposure period:
First
Second
Third
Fourth
Fifth
2 Weeks After
Exposure
Preexposure period:
First
Second
Exposure period:
First
Second
Third
Fourth
Fifth
2 Weeks After
Exposure
Preexposure period:
First
Second
Exposure period:
First
Second
Third
Fourth
Fifth
2 Weeks After
Exposure
Nuaibei of Animals
5
15
20
—
20
20
20
20
20
20
20
20
20
9
9
15
5
20
—
20
—
20
__
20
20
20
20
20
10
10
10
10
20
20
20
20
20
20
20
20
20
20
20
10
10
-------
\
Speck and Moeschlin (1968) noted that subcutaneous injection of 300 or
700 rag/kg pure toluene administered daily to rabbits for 6 and 9 weeks, respec-
tively, had no myelotoxic effects. There were no changes in DNA-synthesis of
bone marrow cells as measured by incorporation of ^H-methylthymidine or1 in peri-
pheral blood elements (leucocytes, thrombocytes, reticulocytes, or erythro-
cytss).
Braier (1973) reported that subcutaneous injection of 862 mg/kg toluene
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
.eno of 6 days (i.e., 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. Andrews et al. (1977) found that benzene
59
inhibited the incorporation of Fe into erythrocytes of mice, although intra-
peritoneal injection of toluene alone did not (see Section 15.1).
The studies suggesting a myelotoxic effect include that of Horiguchi and
Inoue (1977), who exposed groups of 6 male mice to toluene vapor at concentra-
tions of 1, 10, 100, or 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 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 (19&9) 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-nour 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
eight-hour daily exposures to benzene prior to sacrifice and histopathological
examination. The-adrenal weight to body weight ratio was depressed significantly
in all groups that had been exposed to toluene. Histologically, the zona
glonierulosa 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 the
unexposed controls, all groups exposed and unexposed to toluene were also exposed
-------
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 ^ weeks
increased adrenal weight and eosinophil counts and decreased corticosteroid con-
centration 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 aosage of 1 g/kg toluene daily had no effect (Yushkevich
and Malypheva, 1975).
Leukocytosis and chromosomal damage in the bone marrow (Section 1^.2.3-3.)
was noted in rats that had been exposed via inhalation to 112 ppm of toluene,
4 hours daily for 4 months (Dobrokhotov and Enikeev, 1975). Recovery from
leucocytosis occurred 1 month after termination of exposure, but the chromosomal
damage was unchanged. It was also reported that 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.
Further; benzene caused leukocytopenia, but the mixture caused leukocytosis. It
should be noted, however, that the results of this study should be regarded as
inconclusive because Russian reports of toluene-induced chromosomal aberrations
have not been corroborated by western investigators (Section 1i(.2.3.?.).
In the studies by Katsumotc 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 by NEC
(1980) that the positive findings may indicate subtle unrecognized hematopoietic
responses is sound. For example, the effect of tcluene on hematocrit and mean
corpuscular hemoglobin concentration in female Fischer rats and not in male rats
(CUT, I960) 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 decrease in erythrocyues, hemoglobin content, white blood cells
and mean corpuscular hemoglobin concentration, and increase in mean corpuscular
volume in the female was simulated in the estradiol propionate-treated orchi-
dectomized male.
12-45
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There was no increase of erythrocyte fragility in 6 rats that inhaled
20,000 ppn "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 Oettingen et al. O942b).
12.4.2. Cardiovascular Effects. Several animal studies have shown that massive
doses of toluene cause a number of electrocardiographic changes* In addition, a
sensitization of the heart to low oxygen levels has been observed.
Inhalation of glue fumes containing toluene for 1 minute significantly
slowed sinoatrial heart rate and slightly lengthened the P-R interval in 8 ICR
mice. .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 five-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. Subcutaneous injection of
two doses of 0.87 g/kg body weight daily for 6 weeks elicited repolarization
disorders, atrial fibrillation, and in some of the rats, ventricular extra-
systoles (Morvai et al., 1976).
Intravenous injection of 0.01 mg/kg epinephrine into dogs following inhala-
tion of toluene vapors elicited ventricular fibrillation (Chenoweth, 1946).
This observation is of interest, because the "sudden death" ayndrome 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 0.5 mg/kg body weight of toluene into rats reduced
arterial blood pressure; however, injection of the same dosage by the intra-
peritoneal or subcutaneous route had no effect on blood pressure (Morvai et al.,
1976). No effect on blood pressure was seen in the chronic inhalation study 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, no
effect was observed on blood pressure, heart rate, venous pressure, spinal
pressure, respiratory rate, minute volume, or respiratory volume.
12.4.3. Gonadal Effects. Matsumoto et al. (197D 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,
12-46
-------
serum total protein, or cholinesterase activity. However, at the higher dose,
degeneration of germinal cells of the testes was found in H 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 animals is on the CN3. Acute
\exposure to high levels of toluene has been linked with depression of the CKS,
but vapor levels of approximately 1000 ppm appear to have little or no effect on
gross manifestations of this parameter. A dose-related response of instability,
incoordination, and mild narcosis has been observed in rats exposed daily to
toluene vapor at concentrations of 1250 and 1600 ppm, but no effect was noted at
1100 ppm (Batchelor, 1927). Inhalation of 1000 ppm toluene vapor for b hours did
not increase rearing reactions (standing on hind legs) in rats (Takeuchi and
Hisanaga, 1977). Operand behavior (conditioned avoidance response) was
'unaffected by exposure to 1000 ppm (Snigeta et al. 1978) or 800 ppm (Krivanek
and Mullin, 1978) toluene. 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 study (CUT, I960). Smyth and Smyth (1928) noted tnat
daily inhalation of 1250 ppm for ^ 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) found that exposure to 2000 ppjs toluene for
8 hours daily, 6 days weekly for 4 months produced only slight nasal and ocular
irritation after 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,
Carpenter et al. (1976).
The use of more sensitive methods of detection have, however, revealed an
effect on simple behavioral parameters and the CNS at lower levels. EEC changes
were seen in rats after inhalation of 1000 ppm toluene (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 a
multiple response schedule at 571) ppm in rats (Colotla et al., 1979), and in
wheel-turning in rats at 1 ppm (Horiguchi and Inoue, 1977). Neuromodulator
content in the hypothalamus was affected at 500 ppm (Andersson et al., 1980).
12-147
-------
Early studies suggested a myelotoxic effect of toluene. However, several
studies done since the early 1940's Using toluene of greater purity have indi-
cated an absence of toluene-induced injurious effect on blood-forming organs in
rats and dogs (von Oettingen et al., 1942a,b; Gerarde, 1959; Wolf et al., 1956;
Fabre et al., 1955; Jenkins et al., 1970; Carpenter et al., 1976b; CUT, 1980).
Nonetheless, there is no unanimity on this point. Leukocytosis, impaired
leukopoiesis, and chromosomal damage in the bone marrow have been observed in
some foreign studies (Horiguchi and Inoue, 1977; Dobrokhotov and Enikeev, 1977;
Lyapkalo, 1973; Yushkevich and Malypheva, 1975).
Inhalation of concentrations up to 1085 ppn> toluene for 6 weeks or 300 ppm
for 24 months, or 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
et al., 1970; CUT, 1980; Wolf et al., 1956). Exceptions were the studies of
von Oettingen et al. (1942b), in which inhalation of 600 ppm toluene caused
increases of weight and volume in the liver of rats, Fabre et al. (1955) in
which hemorrhagic livers we^e found in dogs, and Ungvary et al. (1976) in which
intraperitoneal injection of 0.43 or 0.82 g/kg toluene produced histological
changes in the liver. However, in a more recent study by Ungvary et al. (1980),
male CFY rats were exposed by daily inhalation to 265 ppm or 929 ppm analytical
grade toluene and female rats were exposed to lower doses five times a week for
up to 6 months. No abnormal histological changes were found in the liver,
although growth was inhibited at the higher dose in males and at the lower dose
in females; specific hepatoxic effects were not noted, although signs of adaptive
compensation were observed.
Renal changes consisting of casts in collecting tubules of rats were
observed by von Oettingen et al. (1942b) after inhalation of 600 ppm toluene.
Hyperemic renal glomeruli and albuainuria 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 has been
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 (Jenkins et al., 1970), after repeated inhalation
of 300 ppm for 24 months in rats (CUT, 1980), or after repeated ingestion of
590 mg toluene/kg body weight for 6 months in rats (Wolf et cJ.., 1956).
Irritative effects were noted in the respiratory tract of dogs, guinea pigs,
and rats following exposure to toluene vapor (Browning, 1965; Gerarde, 1959;
12-48
-------
Fabre et al., 1955; von Oettingen et al., 1942b; Smyth and Smyth, 1928; Sessa,
1918). Sensitization of the heart after inhalation of toluene has been observed
in mice, rats, and dogs (Taylor and Harris, 1970; Morvai et al., 1976; Chenoweth,
19*6).
The acute oral LD5Q of toluene is in the range of 6.0 to 7.5 g/kg in rats
(Kimura et al., 1971; Smyth et al., 1969b; Withey and Hall, 1975; Wolf et al,,
•1956). An acute dermal LD^ of 14.1 mg/kg has been determined for rabbits (Smyth
et al., 1969b). Slight to moderate irritation of the rabbit and guinea pig skin
was elicited by acute or subacute application of toluene (Kronevi et al., 1979;
Wolf et al., 1956), and application to the rabbit cornea has caused slight to
moderate irritation (Wolf et al., 1956; Smyth et al., 1969; Carpenter and Smyth,
1916).
The inhalation LC for mice is in the range of 5500 to 7COO ppm toluene for
an exposure period of 6 to 7 hours (Svirbely et al., 1943; Bonnet et al., 1979),
An LC of 8800 ppm of "toluene concentrate" for 4 hours (4,038 ppm toluene) was
determined for rats (Carpenter et al., 1976b). In guinea pigs, inhalation
'exposure to 1000 ppra toluene for 4 hours caused death in 2 of 3 animals (Smyth
and Smyth, 1928).
Subchronic treatment of rats (von Oettingen et al,, 1942b) and rats, guinea
pigs, dogs, and monkeys (Jenkins et al., 1970; Smyth and Smyth, 1928) at levels
of 200 and 1085 Ppm, respectively, did not have a deleterious effect on
hematology and organ pathology. Horiguchi and Inoue (1977) did report, however,
that mice showed changes in blood elements at levels as low as 10 ppm. Oral
administration of toluene at a level of 590 mg/kg/day for 6 months was tolerated
by rats with no adverse effects (Wolf et al., 1956).
The only chronic study of toluene was the study performed for CUT (1980) in
which rats were exposed for 24 months via inhalation to toluene at levels of up
to 300 ppm. No effect on hematology, clinical chemistry, body weight or histo-
pathology was noted except for two hematologic parameters in females; females
exposed to 100 or 300 ppm showed reduced hematocrit levels and increased mean
corpuscular hemoglobin concentration at 300 ppm toluene.
12-49'
-------
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tion of joint toxic action: Twenty-seven industrial chemicals intubated in rats
in all possible pairs. Toxicol. Appl. Pharmacol. 14(2): 340-347.
SMYTH, H.F., JR., CARPENTER, C.P., WEIL, C.S., POZZANI, U.C., STRIEGEL, J.A. and
NYCUM,. J.S. (1969b). Range-finding toxicity data. VII. Amer. Ind. Hyg. Assoc.
J. 30(5): 470-476.
SMYTH, H.F. and SMYTH,. H.F., JR. (1928). Inhalation experiments with certain
lacquer solvents. J_. Ind. Hyg. 10: 261-271.
SPECK, B. and MOESCHLIN, S. (1968). Effect of toluene, xylene, chloramphenicol,
and thiouracil on bone marrow. Experimental autoradiographic study with thymi-
dine-3hh Schweiz. Med. Wochenschr. 98(42): 1683-1686.
12-57
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SVIRBELY, J.L., DUNN, R.C. and VON OETTINGEN, W.F. (1943). The acute toxicity
of vapors of certain solvents containing appreciable amounts of benzene and
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1945.
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37-46. Taken from: Chem. Abst. 38_: 4696, 1944.
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rats after "i week inhalation exposure. Acta Pharmacol. 4 1 (*t): 78.
TAKEUCHI, Y. (1969). Experimental studies on the toluene poisoning—chiefly on
the findings of peripheral blocd and adrenal gland. Ind. Health^ ]_: 31-45.
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dience-phalon-hypophysis adrenal cortex system in exposure to toluene vapor.
Sangyo Igakus 14(6): 543-553.
I
TAKEUCHI, Y. and HISANAGE, N. (1977). The neurotoxicity of toluene: EEC
changes in rats exposed to various concentrations. Brit. J^. Med. 34(4);
314-324.
TAKEUCHI,.Y. and SUZUKI, H. (1975). Change of convulsion threshold of the rat
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TAKEUCHI, Y.; ONON, Y.; and HISANAGA, N. (1981). An experimental study on the
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! ~ ~ L
TSUZI, K. (1956). Convulsion caused by phenol compounds. Kumamoto Med. j):
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12-58
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UNGVARY, G., HUDAK, A., BORS, Z. and FOLLY, G. (1976). The effect of toluene on
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12-59
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12-60
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13. PHARMACOKINETIC CONSIDERATIONS IN HUMANS AND IN ANIMALS
13.1. ROUTES OF EXPOSURE .AMD ABSORPTION
For hmnans, the most common routes of exposure to toluene are through the
respiratory tract and the skin. Toluene is absorbed readily through the respira-
tory tract. In experimental exposures of humans to toluene conducted by Astrand
and coworkers (1972; also reported in Astrand, 1975), toluene was detected in
\
arterial blood during the first 10 seconds of exposure. Toluene was supplied in
the inspired air 'at 100 or 200 ppm through a breathing valve and mouthpiece.
Unless otherwise specified, in the experiments reported here, human subjects
breathed toluene vapor from some type of respiratory apparatus. In resting
subjects, the concentration of toluene in arterial blood increased rapidly
during the first 10 minutes of exposure and then began to level off, approaching
an apparent steady state by 30 minutes. The concentration of toluene in alveolar
air (i.e.; an air sample taken at the end of a normal expiration) increased
concoinitantly.
Alveolar and arterial concentrations of toluene were proportional to the
concentration in inspired air. At the end of 30 minutes of exposure to 100 or
200 ppm (0.375 or 0.750 mg/2,) toluene, the concentration of toluene in alveolar
air (mg/X,) was 18$ of that in inspired air (mg/R,), while the concentration in
arterial blood (mg/kg) was 270$. of that in inspired air (mg/£) (Astrand et al.,
1972; Astrand, 1975). The ratio between arterial blood ana alveolar air concen-
trations was 15, which is similar to the _in vitro blood/air partition coeffi-
cients (at 37°C) of 14.6, 15.6, and 15.6 reported for human blood by Sato et al.
(197^a), She>"wood (1976), and Sato and Nakajima (1979a), respectively.
According to Veulemans and Niasschelein (1978a), subjects' lung clearances
(i.e., the virtual volume of inspired air from which all available toluene is
absorbed per unit time) decreased during exposure at rest, reaching an apparent
steady state 9 to 13 minutes from the beginning of exposure. Lung clearance
(C.-C )/C. x V where C. is the concentration of toluene in inspired air (mg/JZ,),
1616 1
C is the concentration of toluene in expired air (mg/2,), and V is the respira-
C 6
tory minute volume (fc/min). Lung clearance varied less among individuals than
did the concentration in expired air.
Nomiyama and Nomiyama (197^a) measured the pulmonary retention ((C.-C )/C.
x 100) of volunteers exposed to about 115 ppm toluene for H hours. The subjects
13-1
-------
may have been fairly sedentary because the authors did not mention exercise.
Retention at the end of 1 hour was approximately 52? and decreased to 37$ at the
end of 2 hours, remaining constant at that "".evel for the remaining 2 hours.
These results suggest a slower approach to steady-state concentrations in
expired or alveolar air than was indicated by the time courses obtained for lung
clearance by Veulemans and Masschelein (1978a) or for alveolar air concentra-
tions by Astrand et al. (1972). The results also suggest a lower percentage of
uptake or retention than was reported by Veulemans and Masschelein (1978a) and
others as will be presented subsequently. The reasons for these discrepancies
are unclear.
Eyercise affected the absorption of toluene through the respiratory tract.
In the experiments of Astrand and coworkers (Astrand et al., 1972; Astrand,
1975), exercise greatly increased the concentrations of toluene in arterial
blood and alveolar air of the subjr-c,ts during exposure, and these concentrations
did not level off as soon in exercising subjects as in resting subjects. The
concentrations of toluene in arterial blood and alveolar air were approximately
the same at 30 minutes of exposure to 200 ppm during rest as at 30 minutes of
exposure to 100 ppm during light exercise (50 watts). At 30 minutes exposure to
100 or 200 ppm (0.375 or 0.750 mg/X,) toluene, the concentrations in milligrams
per liter expressed relative to the concentration in insplrad air (mg/fc) were 33?
for alveolar air and 620? for arter.lal blood at exercise of 50 watts, and 47? for
alveolar air and 725? for arterial blood at exercise of 150 watts. The ratio of
arterial to alveolar concentration remained about the same as at rest. Thus,
alveolar concentrations appeared to reflect arterial concentrations during
exposure to 100 to 200 ppz toluene at rest and various intensities of exercise.
The inhalation of 4? C0? by resting subjects during exposure to 100 ppm
toluene increased their alveolar ventilation (£/min) and the concentrations of
toluene in their arterial blood and alveolar air (Astrand et al., 1972). The
increased toluene concentration in blood and alveolar air were similar to those
obtained with a corresponding increase in alveolar ventilation during exercise.
Because exercise increased both alveolar ventilation and heart rate while CQ
increased only alveolar ventilation, the effect of exercise on toluene absorp-
tion appears to be due to increased alveolar (or pulmonary) ventilation.
In the experiments of Veulemans and Masschelein (1978a), the "steady state"
lung clearances of 6 different subjects during exposure to 50 ppm toluene at rest
and at workloads of 25 and 50 watts on a bicycle ergometer correlated well
13-2
-------
o
(r = 0.96) with their respiratory minute volumes. Lung clearance was deter-
i
mined from the regression line to be equal to 0.47 tf . The uptake rate in
milligrams per minute, which equals lung clearance times the inhaled
concentration, therefore was equal to 0.47 tf C. (where C. is expressed in mg/£)
61 X
and total uptake in milligrams equaled 47$ of the total amount inhaled. Lung
clearances and respiratory minute volumes doubled with an exercise intensity of
25 watts and tripled with an exercise intensity of 50 watts over the
corresponding values at rest (Veulemans and Masschelein, 1978a).
Carlsson and Lindqvist (1977) found that the uptake of toluene by 7 male
subjects exposed to 100 ppm for 30 minutes (0.375 mg/Jl) during rest or various
levels of exercise (50, 100, and 150 watts on a bicycle ergometer) correlated
inversely (r = 0.72) with the alveolar concentration determined at the end of
30 minutes exposure, as described by the following equation:
1 U tak - n 6^ alveolar concentration (mg/fc) x 100 + 72.9
inspired concentration (mg/L)
This relationship is logical and applies to other solvents as well (Astrand,
1975; Ovrum et al., 1978). Percent uptake was determined on the basis of the
total amount of toluene inhaled and exhaled during the entire exposure period
(i.e., the expired air was collected continuously throughout exposure, and thus
was a mean value). The uptake ranged from about 47 to 67$ at rest and from about
36 to 57$ at an exercise level of 150 watts. This group of men comprised 3 thin,
1 slightly overweight, and 3 cbese subjects (Carlsson and Lihdquist, 1977).
Similar uptake values were also more recently reported by Carlsson (1982) for a
group of 12 subjects who were exposed to 80 ppm toluene during rest (=50$), and
during a fourth consecutive 30-minute period of 150W exercise (=30$).
Cvrum and coworkers (1978), monitoring four workers exposed to toluene in a
printing plant, found good agreement between the value for percent uptake
determined directly from the total amounts of toluene inspired and expired during
a sampling period and the value determined indirectly from the instantaneous
concentrations in alveolar and inspired air, using the equation given in the
preceding paragraph. Percent uptake determined by the direct method was 47$ and
by the indirect method was 51$. The total uptake of toluene that would occur
during exposure to 80 ppm (0.3 mg/£.) for an 8-hour work day was calculated using
the mean value for pulmonary ventilation of 16 H/min measured for these 4 workers
and a percent uptake of 50. The total uptake amounted to approximately 1150 mg
(Ovrum et al., 1978).
13-3
-------
\
The percent uptake values determined by Carlsson and Lihdquist (1977),
Ovrum et al. (1978) and Carlsson (1982) are in reasonable agreement with those
previously reported in abstracts from the foreign literature: 51)? average uptake
during 5 hours' exposure to 271 to 1177 Hg/£ (Srbova and Teisinger, 1952) and 72/6
initial retention decreasing to 57$ retention towards the end of 8 hours of
exposure to 100 to 800 ng/S, (Piotrowski, 1967).
Another factor, in addition to exercise, that has been reported to affect
the absorption of toluene through the respiratory tract is the amount of adipose
tissue in the body (Carlsson and Lindquist, 1977; Carlsscn and Lindquist, 1982).
Carlsson and Lindquist (1977) found that mean alveolar air concentrations were
slightly higher in 3 thin men than in 3 obese men at the end of 30 minutes of
exposure to 100 ppm (0.375 mg/K.) toluene during rest or exercise. The ranges,
however, overlapped. Conversely, the total uptake of toluene duri.ig 30 minutes
of exposure (determined as previously described) was lower for the thin subjects
than for the obese ones (Table 13-1).
TABLE 13-1
f
Uptake of Toluene in Thin and Obese Men Turing Exposure
to a Toluene Concentration of 375 mg/m (100 ppm)a'
Number of
Subjects
Thin (N = 3)
Mean
Range
Slightly overweight
(N = 1)
Obese (N = 3)
Mean
Range
Adipose
Tissue
(kg)
6.0
1.4-10.7
22.8
44.0
35.1-49.0
Rest
61
55-69
71
84
72-73
Uptake
50 W
148
133-158
179
198
183-206
(mg)
Exercise
100 W
193
168-211
246
258
237-275
150 W
228
181-271
299
319
258-358
Source: Carlson and Lindquist, 1977
b
The subjects were exposed during one 30-minute period of rest and three
consecutive 30-minute periods of exercise in order of increasing intensity.
A 20-minute pause without exposure occurred between rest and exercise.
Expired air was collected continuously during exposure.
-------
The thin subjects had a mean adipose tissue content of 6 kg and the obese ones
had a mean adipose tissue content of M kgr It appears, from Figure 6 in the
Carlsson and Lindquist (1977) paper, that the obese men inspired a greater total
quantity of toluene than did the thin men. Because the concentrations of toluene
in the inspired air were the same for both thin and obese subjects, pulmonary
ventilation must have been greater in the obese ones. Thus the differences in
uptake between the thin and obese men may have been at least partially due to
greater ventilation (respiratory minute volume) in the obese subjects rather
than to their adipose tissue per se. Veulemans and Masschelein (1978a) reported
finding no correlation between a subject's content of adipose tissue and uptake
of toluene during exposures to 50 to 150 ppm toluene lasting about 4.hours.
Astrand and coworkers (1972) stated that they found no systematic differences
between male subjects (N - 11, adipose tissue 5.7 + 1.5 kg, mean + S.D.) and
female subjects (N = ^, adipose tissue 13-3 kg, mean; 9-6 to 20.2 kg, range) in
alveolar air and arterial blood concentrations of toluene.
Dahlmann and coworkers (1968a, 1968b) investigated the absorption of
toluene contained in cigarette smoke through the mouths and respiratory tracts of
volunteers. The uptake of toluene from smoke that stayed in the subject's mouth
for 2 seconds or less and was not inhaled was ?9J; uptake when the smoke was
inhaled into the lungs was 93$. It is unclear whether each subject was exposed
to a single puff of smoke, the smoke from 1 cigarette (8 puffs), or the smoke
from 2 cigarettes.
During inhalation exposure of resting subjects, the concentration of
toluene in peripheral venous blood (from the cubital vein of the arm) attained
apparent steady state more slowly than did lung clearance or concentrations in
alveolar air or arterial blood and was more variable among subjects than were the
above mentioned values (Veulemans and Masschelein, 1978a; 1978b; Astrand et al.,
1972; Sato and Nakajima, 1978). Peripheral venous concentrations appeared to
level off during the second or third hour of exposure. Von Oettingen (19^2a,
19^2b) had observed that toluene concentrations in subjects' peripheral venous
blood at the end of 8 hours of exposure were roughly proportional to the
concentrations of toluene (200 to 800 ppm) in the atmosphere of the exposure
chamber.
Similar results were obtained when the toluene concentrations in peripheral
venous blood of 19 workers at the end of a work week v:ere correlated with toluene
concentration in workplace air; the data points showed considerable scatter, but
13-5
-------
a positive correlation (rc = 0.78) was observed. (Apostoli et al.^ 1982). IJlood
was sampled at the end of the work shift Friday afternoon and air was sampled for
20-25 minutes with personal sampling devices once during the same afternoon. The
concentrations of toluene in venous blood ranged from 3^ to 572 ng/& and in
workroom air from 15 to 182 \ig/i (57-686 ppm). The ratio of toluene
concentrations in peripheral venous blood (ng/£.) to that in air (|ig/Z) was =3.
The authors calculated similar yalues from the data of otherp for both
experimental and occupational human exposure (Astrand et al., 1972; Veulemans
and Masschelein, 1978b; Ovrum et al., 1978; Angerer and Behling, 1981).
Veulemans and Masschelein (1978b) reported that the steady-state
concentrations of toluene in peripheral venous blood were correlated with the
rate of uptake at different inspired concentrations (50, 100, and 150 ppm)
(r2 = 0.73) arid at different levels of rest and exercise (r2 _ 0.74). In both
instances, the relationship between peripheral venous concentrations and uptake
rate was:
Venous concentration (mg/2,) = 0.3 min/X, x uptake rate (mg/min).
The concentration of toluene in peripheral venous blood of exercising subjects
i
increased more rapidly and appeared to reach steady-state values sooner than in
resting subjects (Astrand et al., 1972; Veulemans and Masschelein, 19?8b).
Absorption through the respiratory tract has been studied less extensively
in experimental animals than in humans. The initial uptake of a relatively low
concentration of toluene was found to be approximately 90% in dogs inhaling
toluene (Egle and Gochberg, 1976). Varying the ventilatory rate from 5 to
HO inhalations per minute, the tidal volume from 100 to 250 m£, or the concentra-
tion of toluene from 0.37 to 0.82 ^g/i (approximately 100 to 220 ppm) had no
significant effect on the animals' initial respiratory uptake. Toluene was
readily absorbed from the upper as well as from the lower respiratory tract. The
dogs were anesthetized with sodium pentobarbital for these experiments and
breathed toluene from a recording respirometer for 1 to 2 minutes. The percent
uptake was calculated from the total amounts of toluene inhaled and exhaled
during the 1 to 2 minute exposure.
von Oettlngen and coworkers (1942b) found that the concentration of toluene
in the peripheral venous blood of dogs at the end of 8 hours of exposure was
proportion.il to the concentration of toluene (200, 400, or 600 ppm) in the air of
the exposure chamber. As previously described, similar observations had been
made with humans.
13-6
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Mice exposed singly to an extremely high initial concentration of methyl-
C-toluene. in a closed chamber for 10 minutes retained about 60? of the radio-
activity when removed from the chamber at the end of the exposure (Bergman,
1979). This value is a rough approximation of absorption because some of the
toluene may have been adsorbed to the animals' fur. A substantial portion of the
retained dose appears to have been absorbed, however, as shown by its subsequent
excretion in the urine (Section 13-4.). The initial concentration of toluene in
the chamber (10 [ii evaporated in a volume of about 30 m&, or about 77,000 ppm)
would have been above the saturation concentration even if the temperature had
been as high as 30°C (saturation concentration = 48,900 ppm at 30°C)
(Verschueren, 1977). Bergman (1979) noted that exposure to toluene under these
conditions markedly reduced the respiratory rate of the mice and attributed this
reduction to irritation. It seems more likely that the decreased respiratory
rate was due to narcosis.
Absorption of toluene also occurs through the skin. Dutkiewicz and Tyras
(1968a, 1968b), in experiments with humans, measured the absorption of liquid
.toluene into the skin of the forearm and found the rate of absorption to be 14 to
,23 mg/cm /hr. This rate was calculated from the difference between the amount of
toluene introduced under a watch glass affixed to the skin and the amount
remaining on the skin at the end of 10 to 15 minutes. Absorption of toluene from
aqueous solutions during immersion of both hands was 160 to 600 [ig/cra /hr and was
directly proportional to the initial concentration of toluene (180 to 600 mg/ii).
From these results, Dutkiewicz and Tyras (1968a, 1968b) calculated that the
absorption of toluene through the skin of both hands during contact with a
saturated aqueous solution of toluene for 1 hour could be in the same range as
absorption through the respiratory tract during 8 hours of exposure to 26.5 ppm
CO. 1 mg/JL) toluene.
Sato and Nakajima (1978) found, however, that the maximum toluene concen-
tration (170 |ig/£) in the blood of subjects who immersed one hand in liquid
toluene for 30 minutes was only 26% of the concentration (650 ng/2.) in blood of
subjects who inhaled 100 ppm toluene vapor for 30 minutes. Blood was collected
from the cubital vein of the (unexposed) arm at intervals during and after
exposure. Sato and Nakajima (1978) suggested that some of the toluene that
penetrates the stratum corneum may be subsequently given off into the air, rather
than entering the systemic circulation. Toluene appears to pass slowly from the
skin into the bloodstream after penetrating the skin. Guillemin et al. (1974)
13-7
-------
reported that the elimination of toluene in alveolar air sometimes increased
during the first 20 minutes after the termination of exposure of both hands to
liquid toluene, and Sato and Nakajima (197?) noted that the maximum levels of
toluene in venous blood were maintained for about 15 minutes after the end of
exposure.
Jakobson et al, (1982) monitored the concentration of toluene in the
arterial blood of anesthetized guinea pigs following epicutaneous exposure. In
2
this study, a 3-1 cm area of clipped back skin was continuously exposed to
liquid toluene by means of a sealed glass ring. It was found that the concen-
tration of toluene in the blood increased rapidly within 1 hour to. a peak of
-1.3 Jig/mi, and then decreased in spite of the continuing exposure to a plateau
concentration of =0.5 ng/m2. after 6 hours. A similar pattern of uptake was
observed with other lipophilic solvents (i.e., carbon tetrachloriue, hexane,
tetrachloroethylene-, 1,1,1-trichloroethane, and trichloroethylene).
Absorption of toluene vapor through the skin does not appear to result in a
significant contribution to the body burden of toluene as compared to absorption
through the respiratory tract. In experiments conducted by Riihimaki and Pfaffli
(1978), volunteers wearing light, loose-fitting clothing and respiratory protec-
"oT." i
tion were exposed to 600 ppra toluene for 3-5 hours. The subjecJS^emained at
rest except for 3 exercise perio-ds, each lasting for 10 minutes, which occurred
at 0.5, 1.5, and 2.5 hours of exposure. The exercise was sufficient to stimulate
perspiration and raise the skin temperature slightly, conditions which are
thought to enhance percutaneous absorption. The concentration of toluene in
peripheral venous blood, measured at the end of 1, 2, and 3 hours of exposure,
Was constant at approximately 100 (ig/i.
Riihimaki and Pfaffli (1978) compared total uptake through the skin
(calculated from the amount of toluene exhaled assuming that 16$ of absorbed
toluene is exhaled) with theoretical uptake through the respiratory tract
(assuming pulmonary ventilation of 10 Jl/min and retention of 60?) at the same
(600 ppm) level of exposure. They estimated that uptake through the skin was
approximately 1$ of the theoretical uptake through the respiratory system.
In similar experiments conducted by Piotrowski (1967, reviewed in NIOSH,
1973)i subjects exposed dermally to 1600 mg/m-' Ci27 ppm) toluene for 8 hours had
no increase in urinary excretion of a metabolite (benzoic acid) of toluene.
Based on this result, Piotrowski (1967) concluded that absorption of toluene
13-8
-------
through the skin would not exceed 5% of absorption through the respiratory tract
under the saine conditions.
The absorption of toluene from the gastrointestinal tract appears to occur
more slowly than through the respiratory tract, but appears to be fairly complete
based on experiments with animals. The concentration of radioactivity in the
blood of adult male rats reached a maximum 2 hours after gastric intubation of
100- \jJi 4-%-toluene in 400 u& peanut oil (Pyykko et al., 1977). The oil may
have retarded absorption. Based on the percentages of the dose excreted
unchanged in the expired air and as hippuric acid in the urine of rabbits,
toluene appears to be completely absorbed from the gastrointestinal tract
(El Masri et al., 1956; Smith et al., 195*4).
13.2. DISTRIBUTION
Toluene is highly soluble in lipid and sparingly soluble in water, as
indicated by the partition coefficients in Table 13-2. Judging from the
fluid/air partition coefficients for water, plasma, and blood, much of the
toluene in blood may be associated with the lipid and lipoprotein components,
including the cellular elements. The tissue/blood partition coefficients for
fatty tissues were very high (113 for adipose tissue and 35 for bone marrow); for
other tissues, they ranged from about 1 to 3.
Little is known about the tissue distribution of toluene in humans. During
inhalation exposure to 50 to 200 ppm toluene, the slow approach to steady-state
of peripheral venous concentrations as compared to arterial concentrations
(described under absorption) indicates that equilibration with the tissues may
take at least 2 to 3 hours. Concentrations in peripheral venous blood do not,
however, reflect the dii. harge of toluene to the tissues as fully as would
concentrations in central venous blood. A teenage boy who died from sniffing
glue had the following levels of toluene in his tissues: heart blood, 11 mg/kg;
liver, 47 mg/kg; brain, 44 mg/kg; and kidney, 39 mg/kg (Winek et al. 1968; also
reported in Winek and Collum, 1971).
Several laboratories have investigated the tissue distribution of toluene
and its metabolites in animals exposed by inhalation to relatively high concen-
trations of toluene. The concentrations of toluene in liver, brain, and blood of
mice exposed to 3950 ppm (15 mg/fc) toluene for 3 hours in a dynamic exposure
Chamber rose continuously throughout the exposure period, as shown previously in
Figure 12-1. Concentrations of toluene reached 625 mg/kg in liver, 420 mg/kg in
brain, and 200 mg/kg in blood at the end of exposure (Peterson and Bruckner,
13-9
-------
fABLE 13-2
Partition Coefficients for Toluene at 37 °C
Partition Coefficient Reference
I. Fluid/Air or Material/Air
Water
Oil, olive
Blood, Human
Fat, human, peritoneal
Oil, olive
Lard
Blood, human
Blood, human
Blood, rabbit
Plasma, rabbit
II. Tissuea/Blood (Rabbit)
Liver
Kidney
Brain
Lung
Heart
Muscle, femoral
Bone narow, red
Fat, retroperitoneal
2.23
492
15.6
1296
1380
1270
15.6
K.64
10.41
16.99
2.58
1.54
3.06
1.92
2.10
1.18
35.43
113.16
Sato and Nakajima, 1979a
Sherwood, 1976
Sato et al., 1974a, 1974b
Sato et al., 19?4a, 1974b
Homogenatfcs.
20 J fat by volume.
-------
1978; Bruckner and Peterson, 198la). Exposure of mice to 10,600 ppm (40 mg/£)
toluene for 10 minutes resulted in lower tissue and blood concentrations.
Intermittent exposure to 10,600 ppm in cycles of 5 minutes on, 10 minutes off or
10 minutes on, 20 minutes off for a total of 3 hours produced tissue and blood
levels approximately 3 times-higher than those produced by the single 10-minute
exposure to 10,600 ppm and similar to those produced by the 3-hour exposure to
T.0,600 ppm. The intermittent exposures were an attempt to simulate solvent abuse
(e.g., glue sniffing) by humans (Peterson and Bruckner, 1978; Bruckner and
Peterson, 198lb).
From an analysis of the time course of toluene levels in central venous
blood and in brain of rats during and after whole-body exposure of the aniials to
575 ppm toluene, Benignus et al. (1981) concluded that their data fit a one-
compartment model. Groups of rats were killed at intervals from 15 to
240 minutes during exposure and at intervals from 15 to 2^0 minutes after
exposure. Blood samples were taken from the posterior vena cava at sacrifice.
According to the one-compartment model analysis of Benignus et al. (1981),
asymptotes (steady state levels) during exposure to 575 ppm toluene were
10.5 ppm toluene in blood and 18 ppm toluene in brain, and concentrations of
toluene in these tissues reached 95? of these estimated asymptotes in approxi-
mately 55 minutes. Visual inspection of the experimental data, however, shows
that the mean toluene concentrations in the blood and brain of rats exposed for
120 and 2^0 minutes were above the predicted asymptotes and, particularly i;i the
brain, may still have been increasing appreciably during' this interval. The
authors mention that this observation "could be construed as an indication that a
multicompartment model ought to have been fitted." The elimination of toluene,
estimated by one-compartment model analysis, occurred at a slightly faster rate
from the brain than from central venous blood. The experimental data of Eenignus
et al. (1981) for rats are similar to those of Peterson and Bruckner (1978) for
mice, previously discussed.
After adult male rats were exposed by inhalation to radioactively-labeled
toluene, the highest concentrations of radioactivity were found in their white
adippse tissue (Carlsson and Lindquist, 1977; Pyykko et al., 1977). In the
experiments of Pyykko and coworkers (1977) the concentration of radioactivity
reached a maximum in all tissues, but white adipose tissue within 15 to
30 minutes after the end of 10 minute? of exposure to ^600 ppm ll- H-toluene. The
concentration in white adipose tissue reached a maximum 1 hour after the end of
13-
-------
exposure. In the experiments of Carlsson and Lindquist (1977)F a similar
increase in the concentration of radioactivity in white adipose tissue occurred
during the first hour after cessation of exposure for 1 hour to 550 ppra
(1.950 mg/O methyl- C- toluene. No such increase occurred in other tissues.
Carlsson and Lindquist (1977) found that after white adipose tissue, the
next highest concentrations of radioactivity occurred in adrenals and kidneys,
followed by liver, cerebrum, and cerebellum. At the end of exposure, white
adipose tissue contained a 6-fcld higher concentration of radioactivity than did
cerebrum or cerebellum. Pyykko et al. (1977) reported that after white adipose
tissue, the next highest concentration of radioactivity was found in brown
adipose tissue, followed in order of decreasing concentrations by adrenal,
stomach, liver and kidney, brain and other tissues, blood, and bone marrow. The
loss of radioactivity from adipose tissue and bone marrow appeared to occur more
slowly than the loss from other tissues (Pyykko et al., 1977). Radioactivity in
the tissues presumably represented toluene and its metabolites.
Bergman (1979), using three-stop whole-body autoradiography, investigated
the distribution of toluene, its metabolites, and covalently bound reactive
ill
intermediates in mice exposed to an extremely high concentration of methyl- C-
toluene. This work was briefly described in a previous report (Bergman, 1978).
The mice were exposed singly to a very high initial concentration of toluene for
10 minutes in a closed chamber, as described in Section 13.1., and sacrificed at
intervals thereafter. Low temperature autoradiography, performed at -80°C,
allowed the detection of both volatile radioactivity (representing toluene) and
non-volatile radioactivity (representing metabolites). In a second step,
sections were dried and heated to remove volatile material before
autoradiography, thus permitting detection of non-volatile metabolites only. In
the third step, sections that had been dried and heated were then extracted to
remove water-soluble and lipid-soluble i-adioactivity, presumably leaving on] y
the radioactivity that was covalently bound to proteins and nucleic acids.
Lov; temperature autoradiography performed immediately after exposure
revealed high levels of radioactivity in adipose tissue, bone marrow, and soinal
nerves, with some radioactivity also present in the brain, spinal cord, .liver,
and kidney (Bergman, 1979). Bergman reported that the adrenal did not contain
high concentrations of radioactivity, but he did not discuss whether radio-
activity was found in the stomach.
-------
The only radioactivity visible in dried, heated sections appeared in the
liver, kidney, and blood (Bergman, 1979). This indicates that significant
amounts of metabolites had already been formed by the end of exposure, and that
the radioactivity in fat and nervous tissue was due to the parent compound,
Similarly, as early as 8 minutes after intraperitoneal injection of 290 \ig
C-toluene/kg into mice, the majority of radioactivity in the kidney (78$) and
liver (64J) and about half the radioactivity in blood C<8J) was reported to
represent non-volatile metabolites, while most of the radioactivity in brain and
virtually all in the adipose tissue was volatile and thus represented toluene
itself (Koga, 1978). The methods used in Koga's study are unclear because the
t?xt of the paper is in Japanese, with only the figures, tables, and summary in
English. Bergman (1979) reported that no radioactivity was detected in auto-
radiograms prepared from dried, heated, and extracted sections, indicating an
absence of covalent binding.
As nad been observed in the studies of Pyykko et al. (1977) and Carlsson and
Lindquist (1977), radioactivity disappeared from the tissues relatively quickly
after exposure was terminated. The distribution patterns observed in mice killed
more than 4 hours after exposure were the same on low temperature autoradiograms
as on dried, heated sections. Thus, the radioactivity remaining in the tissues
at this time represented non-volatile metabolites. At 8 hours after exposure,
only the kidney and the intestinal contents had detectable radioactivity
(Lergmam, 1979).
Oral a-dainistration of iJ- H-t.oluene (100 \il toluene in 400 uE, peanut oil by
intubation) to aault male rats produced a pattern of tissue distribution similar
to that produced by inhalation exposure (Pyykko et al., 1977). Distribution
appeared to be delayed, however, by absorption from the digestive tract. Maximum
tissue concentrations occurred 2 to 3 hours after administration for scat
tissues and 5 hours after administration for adipose tissue.
In sunmary, toluene was preferentially accumulated in adipose tissue and
was retained longer in adipose tissue and bone marrow than in other tissues,
which is reasonable on the basis of the high tissue/blood distribution
coefficients of these tissues. Toluene and its metabolites were found in
relatively high concentrations in tissues active in Its metabolism and excretion
(i.e., liver and kidney). Levels in the brain relative to those in other tissues
Were perhaps lower than woull be expected on the basis of the tissue/blood
13-13
-------
distribution coefficients reported by Sato et al. (197^a, 197^b). Tissue
distribution was similar after inhalation and oral exposure.
13.3. METABOLISM
Toluene is thought to be metabolized in humans and in animals by the
pathways outlined in Figure 13-1. Some of the absorbed toluene is excreted
unchanged in the exhaled air, but the major portion is metabolized by side-chain
oxidation to benzole acid, which is conjugated with glycine to form hippuric acid
and then excreted in the urine. Small amounts of benzoic acid may be conjugated
with glucuronic acid. Minor amounts of toluene undergo ring hydroxylation,
probably via are.rie oxide intermediates, to form o-cresol and p-cresol, which are
excreted in the urine as sulfate or glucuronide conjugates.
Hurans exposed to toluene by inhalation exhaled about 16? of the absorbed
toluene after exposure was terminated, according to Nomiyama arid Nomiyaaa
(197^) and Srt-ova and Teisinger (1952, 1953), - or 4J, according to Veulemans and
Masscheleir. (1978a:. Volunteers inhaling 50 to 150 ppm toluene for about t hours
during rest or exercise excreted 60 to 70% of the absorbed dose as hippuric acid
in the urine during and after exposure (Veulemans and Masschelein, 1979). A
siarilar va^ue was obtained when subjects were exposed to toluene (67 ppm) and
xyleris (85 ppa) simultaneously for 3 hours; 68J of the absorbed toluene was
excretec as urinary hirDuric acid during and after exposure (Ogata et al., 1970).
Srbava and Teisin.ger (19l~3) reported that although most of the benzoic acid in
tre urine of subjects who inhaled 72 to 532 ppm (0.271 to 2.009 mg/fc) toluene was
excretec.as nippuric acid, 10 to 205 was excreted as a glucuronide conjugate.
The excretion of hippuric acid in the urine was elevated within 30 minutes
of the initiation of inhalation exposure, indicating that the metabolism of
Uluci.-e is rapid (Noraiyama and Norciyama, 1975; Ogata et al., 1070; Veulemans and
Masschelein, 1979). The maximum rate of hippuric acid formation from benzoic
acid was reporter by Amsel and Levy (1969) to be about 190 [jmol/nin, and it
appeared to be limited by the availability of glycine (Amsel and Levy, 1969;
Quick. 1931). Assuming retention of 60? of the inhaled concentration, Riihimaki
(1979) estimated that uptake of toluene may saturate the conjugation capacity at
a toluene concentration of 760 ppm (32 mmol/m-1) during light work (pulmonary
ventilation of 10 fc/roin) or 270 ppm (11 mmol/m-1) during heavy work (pulmonary
ventilation of 30 Z/min).
o-Cresol, a cocpound that is not detected often in normal urine, has been
identified in the urine of workers exposed to 7 to 112 ppm toluene (Angerer,
-------
EXHALED
UNCHANGED
CH-,
o
TOLUENE
CHjOH
o -
BENZYL ALCOHOL
i-CRESOL
CONMCHjCOOM
6
HIPPURIC ACID
GLYCINE
COOH
BENZOlC AGIO
GLUCURONIC ACID
BEN20YL GLUCURONIDE
GLUCURONIDE AND
SULFATE CONJUGATES
Figure 13-1. Metabolism of Toluene In Humans *nd Animals
(Adapted from Lahaia, 1970)
13-15
-------
1979; Pfaffli et al., 1979; Hansen, 1982). The concentration of _o-cresol in
urine collected at the end of exposure was directly proportional to the time-
weighted average exposure of the workers (Pfaffli et al., 1979). Angerer (1979)
estimated that approximately 0.05% of the retained toluene had been metabolized
to ci-cresol. £-Cresol also may have been a metabolite of toluene, as its concen-
tration was higher in the urine of workers exposed to toluene than in the urine
of unexposed workers (Angerer, 1979). The difference, however, was not
significant. Wiowode reported finding jn-cresoi in addition to _o- cresol and
£-crescl in the urine of workers exposed to 280 ppm toluene (Woiwode et al.,
1979.) and male subjects who were experimentally exposed to 200 ppm toluene for
4 hours (Woiwode and Drysch, 1981). No ni- cresol was detected in the urine of
unexposed workers or the subjects before the experimental exposure. No other
studies of ^r, vivo human or animal metabolism or _in vitro microsooal metabolism
reviewed for this document have detected _m-cresoj. as a metabolite of toluene.
The concentration of pnenol has been reported to be slightly elevated in the
urine of exposed workers as compared to controls (Angerer, 1979; Szadkowski
et al., 1973/- The origin of the increased phenol excretion was thought to be
the sTsall amount of benzene present in industrially-used toluene (Angerer,
1^79).
The metabolism of toluene has been more fully studied in animals than in
h'jma.-is. T*"'e initial .itep in the metabolism of toluene to benzoic acid appears to
be sice-chajn hydroxyLation of toluene to benzyl alcohol by the microsorual mixed-
function oxidase system. Toluene has been shown to produce a type I binding
spectrum v«ith cytochrome P45Q from rat? and hamsters, indicating that it is
probably a substrate for the mixed-function oxidase system (Canady et al., 1974;
Ai-Goilany eL al., 1978). When incubated with rabbit hepatic microsomes, toluene
was metabolized primarily to benzyl alcohol (Daly et al., 1968) and small amounts
of benzyl alcohol have been detected in the urine of rats given toluene orally
(Bakke and Sneline, 1970).
Additional evidence that toluene is metabolized by mixed-function oxidases
has been obtained by Jkeda and Ohtsuji (1971) who demonstrated that the induction
of hepatic mixed-function oxidases by pretreatment of adult female rats for
1 days witn phenobarbital increased the metabolism of toluene. When given
1. IB ing toluene/kg body weight intraperitoneally, phenobarbital-pretreated
(induced) rats had greatly elevated urinary excretions of hippuric acid and
decreased concentrations of toluene in the blood compared to non-induced rats
13-16
-------
given the same dose of toluene. Induced i^ats had high levels of benzoic acid in
the blood; non-induced rats had none (blood was obtained at decapitation).
The increased metabolism of toluene by induced rats appeared to reflect an
increase in side-chain hydroxylation of toluene, because the activity of hepatic
sides-chain hydroxylase, assayed, in vitro with the model substrate p-nitro
i ~~~~~~~
toluene, was significantly increased per gram of liver. The i_n vitro oxidation
of the resultant alcohol (p-nitrobenzyl alconol) to the acid vp-nitrobenzoic
acid) was not affected. The conjugation of benzoic acid with glycine, measured
in vivo as the total amount of hippuric acid excreted after benzoic acid adminis-
tration, was also unaffected (Ikeda and Ohtsuji, 1971).
It has been assumed (Ikeda and Ohtsuji, 1971; Nomiyama and Nomiyama, 1978;
NRC, 1980), by analogy with the metabolism of the model substrate p-nitrotoluene
(Gillette, 1959), that benzyl alcohol is metabolized to benzaldehyde by alcohol
dehydrogenase and that benzaldehyde in turn is oxidized to benzoic acid by
aldehyde dehydrogenase. These enzymes both are.found in the soluble fraction
from liver. Benzaldehyde itself has not been detected in the urine or expired
air of animals given toluene orally (Smith et al., 1951*; EUkke and Sheiine,
1970). Metabolism of toluene probably occurs primarily in the liver. This
assumption is based on the previously discussed tissue distribution of metabo-
lites, the demonscrated metabolism of toluene by liver microsomal preparations,
and by analogy with the metabolism of other xenobiotics.
Rabbits intubated with 300 mg toluene/kg body weight eliminated approxi-
mately 18$ of the dose in the expired air (Smith et al., 195*0 and, in another
study from the same laboratory, excreted about 7*t? of the dose as hippuric acid
in the urine (El Masri et al., 1956). These results are similar to those
obtained with humans who inhaled toluene. None of the toluene appeared to be
converted to benzoyl glucuronide (Smith et al., 195*0, although about T4J of an
oral dose of benzoic acid was excreted by rabbits as the glucuronide conjugate
(Bray et al., 1951).
Toluene metabolism appears to be rapid in animals, as shown by the
appearance of metabolites in the livers, kidneys, and blood of mice within
minutes of exposure to toluene (Bergman, 1979; Koga, 1978) (discussed in
Section 13.2.) and by the increase.' Tinary excretion of hippuric acid in rabbits
within 0.5 hour of the initiation of inhalation exposure (Nomiyama and Noraiyama,
1978). As was previously mentioned for humans, the rate of conjugation of
benzoic acid with glycine may be limited in animals by the availability of
13-17
-------
glycine. Administration of glycine to dogs exposed by inhalation to 200, 100, or
600 ppm toluene enhanced the rate 01 hippuric acid excretion (Von Oettingen,
19H2b). At tne end of 8 hours of exposure to 600 ppm toluene, the concentrations
of toluene in peripheral venous blood from glycine-treated dogs were lower than
the concentrations in dogs that had not been treated with glycine. No such
difference was observed at the two lower exposure levels. This result suggests
that conjugation of benzoic acid with glycine may have limited metabolic
elimination at the highest level of exposure. The level of exposure at which
glycine treatment produced a difference in venous blood levels of toluene is
similar to that (780 ppm) calculated by Riihimaki (1979) for saturation of the
glycine conjugation capacity of humans.
A minor pathway for the metabolism of toluene is ring hydroxylation by
mixed-function oxidases. Incubation of toluene with rat or rabbit liver micro-
somes resulted in the production of small amounts of ^-cresol and _p_-cresol (Daly
et al., 1968; Kaubisch et al., 1972). The migration of deuterium when toluene
was labeled in the ^-position and a comparison of the rearrangement products of
arene oxides of toluene with the cresols obtained by microsomal metabolism of
toluene indicated that arere oxides are intermediates in the metabolism of
toluene to o- and £-cresols (Daly et al., 1968; Kaubisch et al., 1972).
Because phenols, including cresols, are eliminated in the urine as sulfate
conjugates, thereby increasing the excretion of organic sulfates and decreasing
the excretion of inorganic sulfate, investigators have used urinary sulfate
excretion after toluene administration as an indicator of cresol formation. Oral
doses of 350 mg toluene/kg body weight produced no increase in organic sulfate
excretion in rabbits (Smith et al., 195*1). In rats, high doses (2.2 and
-------
macromolecules. Very little toluene is metabolized via this pathway, however,
and the studies already discussed in the distribution section indicate that
binding of toluene metabolites to proteins and nucleic acids does not occur to
any significant extent.
Van Doorn and coworkers (I960) have reported detecting small amounts of a
mercapturic acid, tentatively identified as benzylmercapturic acid (N-acetyl-S-
benzyl-L-cysteine), in the urine of male rats treated with toluene. Approxi-
mately O.i; to 0.7$ of a dose of 370 mg/kg toluene body weight, administered
intraperitoneally, was recovered as the mercapturic acid. The concentration of
glutathione in the liver was decreased slightly by administration of toluene.
Benzylmercapturic acid would arise from conjugation with glutathione of an
electrophilic product of side-chain oxidation of toluene.
The metabolism of toluene appears to result in its detoxification. The
length of the sleeping time produced by high doses of toluene (1.18 to 1.45 g/kg
intraperitoneally) was decreased in phenobarbital-induced female rats to 50? or
less of the sleeping time of controls (Ikeda and Ohtsuji, 1971). Similar results
were obtained with male mice (Koga and Ohmiya, 1978). Phenobarbital-induced
animals, however, did not have significantly different mortality rates than
controls when given high doses of toluene (Ikeda and Ohtsuji, 1971; Koga and
Ohmiya, 1978). Male mice given various inhibitors of drug metabolism (SKF 525A ,
cyanamide, and pyrazole) 30 minutes before the injection of toluene had sleeping
times that were significantly longer than those of control mice and had higher
mortality rates than did control mice (Koga and Ohmiya, 1978).
13.1. EXCRETION
In both humans and animals, toluene is rapidly excreted as the unchanged
compound in expired 'air and as a metabolite, hippuric acid, in the urine. Most
of the absorbed toluene is excreted within 12 hours of the end of exposure.
The concentrations of toluene in exhaled air and in arterial and venous
blood of human subjects declined very rapidly as soon as inhalation exposure was
terminated (Astrand et al., 1972; Carlsson and Lindquist, 1977; Ovrum et al.,
1978; Sato et al., 1974b; Veulemans and Masschelein, 1978a, 1973b). Sato et al.
(197^b) reported that semilogarithmic plots of toluene concentrations in
alveolar air and in peripheral venous blood versus time after the end of exposure
suggested that desaturation occurred in three exponential phases: an initial
rapid phase, followed by an intermediate phase, and then a slow phase. The data
were obtained from 3 male subjects who inhaled 100 pptn toluene for 2 hours (Sato
13-19
-------
et al., 1974b; clarified in Sato and Nakajima, 1979b). The desaturation curves
were resolved graphically into three components, and constants were determined
by the least squares method. The rate coefficients and corresponding half-lives
(t.,?) for the decay of toluene in peripheral venous b? ood were 0.355 min ^1/2
= 1.95,.'minutes), 0,0197 min~1 (t..,- = 35.2 minutes), and 0,00339 min" (t1/2
204 minutes). Rate coefficients and half-lives for the decay of toluene in
alveolar air were 0.437 min"1 (t,/2 - 1-5^ minutes), 0,0262 min" (t-i/o
-26.5 minutes), and 0.00313 min'1 (t1/2 221 minutes).
Because the rate coefficient for the rapid phase was derived from only two
points (at-C and 5 minuces), the second of which belonged with the intermediate
phase, Sato et al. (1974b) noted that the coefficient for the rapid phase
invol%'ed some error. The data of Sato et al. (1974b) indicate that the decay of
toluene concentrations in peripheral venous blood was more gradual than that in
expired air. Similar conclusions have been reported by Astrand et al. (1972),
and Veulemans and Masschelein (1978b). Astrand et al. (1972) have reported that
peripheral venous concentrations declined more gradually than did arterial
concentrations .
Veulemans end Masschelein (1978a) and Nomiyama and Nomiyama (1974b) found
the excretion curves for toluene in expired air to be adequately described as the
smr, of 2 exponential terms rather than 3- Subjects for these studies were
exposed to ^0, 100, or 1^0 pptn toluene for about 4 hours. The sampling regimens
differed from that of Sato et al. (1974b), in that Veulemans and Masschelein
(19?&a) did not begin monitoring expired air as soon after exposure ended, and
Nomiyama and Noitiyama (1974b) sampled expired air infrequently during the period
used by Sato et al. (1974b) to determine the first two exponential phases. Rate
coefficients for the rapid and slow phases were calculated by Veulemans and
Maaschelein (19783) to be 0.340 min and 0.00608 min , respectively, using a
curve-fitting computer program. These rate coefficients corresponded to half-
lives of 2.04 and 114 minutes. Nomiyama and Nomiyama (1974b) reported rate
coefficients for the rapid phase of 5.10 h~ (** - 8.16 minutes) for men and
_ 1
3-22 h (t - 12.9 minutes) for women; the rate coefficient for ti e slow phase
was 0.335 h~1 U - 124 minutes) for both sexes.
In the desaturation period, men and women expired 17.6 and 9-4?, respec-
tively, of the total amount of toluene' calculated to have been absorbed during
exposure (Nomiyama and Nomiyama, 1974b). These values are close to what had been
reported previously (i.e., 16J) by Srbova and Teisinger (1952, 1953) in abstracts
13-20
-------
from the foreign literature. .Veulemans and Masschelein (1978a) estimated that
about 4$ of the toluene absorbed during exposure was subsequently excreted in the
expired air. Unlike the continuous exposures employed in the other pertinent
investigations, however, the exposure regimen employed by Veulemans and
Masschelein (19?8a) was discontinuous (i.e., four 50-minute periods of exposure
separated by 10-minute intervals of nonexposure).
According to Veulemans and Masschelein (1978a) a much greater variability
was observed for the excretion of toluene in expired air during the first 4 hours
after the end of exposure than had been observed for the related lung clearances
during exposure. This variability could be explained partially by differences in
respiratory minute volume during the post-exposure period; the percent of
absorbed toluene iroreted in the expired air during the first 4 hours after
2
exposure correlated positively with respiratory minute volume (r - 0.7D.
Another factor that appeared to affect excretion was the amount of body fat,
because there was a significant (p < 0.025) negative correlation between fat
content as measured by the index of Broca and the percent excretion in expired
I 2
air after exposure at rest (r = 0.2134). This indicates that less of the
absorbed toluene would be excreted in the expired air of an obese person than in
the expired air of a thin person during the first 4 hours of desaturation.
Additionally, subjects who had been exposed to toluene while exercising expired
less of the absorbed amount during the first 4 hours of desaturation than did
subjects who had been exposed while resting (Veulemans and Masschelein, 1978a).
As previously described, 60 to 70? of the toluene absorbed by humans during
inhalation can be accounted for as hippuric acid in the urine (Veulemans and
Masschelein, 1979; Ogata et al., 1970). The excretion rate of hippuric acid in
the urine of subjects inhaling 50, 100, or 150 ppm toluene increased during the
first 2 hours, leveling off at about the third hour after initiation of exposure
(Veulemans and Masschelein, 1979; Nomiyama and Nomiyama, 'i978). Hippuric acid
excretion (mg/hr) declined fairly rapidly after cessation of about k hours of
exposure. Nomiyama and Nomiyama (1978), treating this decline as a
monoexponential process, determined a half-life for hippuric acid in urine of
117 minutes for men and 74 minutes for women. Veulemans and Masschelein (1979)
reported an initial, fairly rapid decrease with a half-life between 2.0 and
2.3 hours, followed by a more gradual return to baseline excretion levels by
about 24 hours after the start of exposure.
13-21
-------
The excretion rate of hippuric acid, measured at the end of about 4 hours of
experimental exposure or 8 hours of occupational exposure, correlated reasonably
well with the uptake rates (Veulemans and Masschelein, 1979) or total uptake
(Wilczok and Bieniek, 1978) during exposure. At a given level of physical
activity and exposure concentration, the intra- and interindividual variability
in hippuric acid excretion was greater than that noted for uptake rates and was
attributed to the variable baseline excretion of this compound because it was not
explained by other factors (body weight, body fat, cardiorespiratory parameters)
.(Veulemans and Masschelein, 1979). Exercise during exposure increased the rate
of excretion of hippuric•acid (Veulemans and Masschelein, 1979) in acccrdance
with the increase in uptake rate.
Hippuric acid is a normal constituent of urine derived from benzoic acid and
precursors of benzoic acid in the diet (Quick, 1931). Concentrations of hippuric
acid in thfe urine of 101 workers not exposed to toluene ranged from 0.052 to
1.271 mg/mJl (corrected to urine specific gravity of 1.02^) and rates of excretion
of 'hippuric acid ranged from 18.47 to 23-00 mg/hr for diuresis of greater than
30 mSYhr (Wilczok and Bieniek, 1978). Others .have also reported great varia-
bility in the physiological concentrations of urinary hippuric acid (Ikeda and
Ohtsuji, 1969; Ir.amura and Ikeda, 1973; Engstrom, 1976; Kira, 1977; Ogata and
Suglhara, 1977; Angerer, 1979).
Volunteers exposed in a chamber to 200 ppm toluene for 3 hours followed by a
1 hour break and an additional 4 hours of exposure excreted hippuric acid as
shown in Figure 13-2 (Ogata et al., 1970). This exposure regimen was chosen to
simulate exposure in the workplace. After leveling off after approximately
3 hours of exposure, excretion increased again during the afternoon exposure.
The rate of hippuric acid excretion remained elevated for about 2 hours after
exposure was terminated and then declined almost to baseline levels by 18 hours
after the end of exposure. The total quantity of hippuric acid excreted during
the period lasting 26 hours from the initiation of exposure was directly
proportional to the degree of exposure (ppm x time) up through the highest
toluene concentration of 200 ppm and could be used to calculate exposure with a
fairly high degree of accuracy. Less accurate for this purpose were excretion
rates during exposure (i.e., total hippuric acid excreted during exposure +
time) and concentrations in urine, corrected for specific gravity.
Concentrations of hippuric acid in urine collected during the entire exposure
period and corrected to a specific gravity of 1.021) were 0.30 + 0.10, 2.55 +
13-22
-------
-« CONCENTRATION (mg/mi)
u>
I
ro
u>
~ 12-,
z
o
cc
I-
z
a) c j
o 6-
z
Q 4-|
o
u
E 2H
D
. o RATE (mg/minute)
6 8 10 12 14 16 18 20 22 24 26
HOURS
Z _
2 g
U H
< D
-4 E I
-2 £
i L0
Figure 13-2. Urinary Concentrations and Excretion Fates of Hippuric Acid in
Volunteers Exposed to Toluene (Volunteers were exposed to 196 ppm
toluene for 3 hours in the morning and for A hours in the after-
noon with one hour's break in between. Points are means + SEH.)
(Ogata et aj.. , 1970)
-------
0.55, and 5.99 ± 1.20nig/niS, (mean + standard deviation) for control, 100 ppro,
and 200 ppm exposed subjects, respectively. Values for controls were lower and
more uniform than those reported by others, as described previously^
Spot urine samples collected from workers after at least 3 hours of exposure
to toluene (and from nonexposed workers at the sarqe time) have not given as good
a distinction between unexposed and exposed workers. Imamura and Ikeda (1973)
have pointed out tnat the upper fiducial limit (P ^ 0.10) of' normal hippuric acid
concentrations, whether or not corrected for specific gravity, is so close to the
lower, fiducial limit of workers exposed to 100 ppm toluene (the Threshold Limit
Value) that such a measurement would not be reliable in screening for
overexposure. This conclusion was based on data reported jy Ikeda and Ohtsuji
(1969). The correlations between concentrations of toluene in workplace air and
the•concentration of hippuric acid in urine of individual workers have been
i
relatively poor (Veulemans et al., 1979; Szadkowski, 1973; Ogata et al., 1971).
The correlation between exposure concentration and excretion rate during
o
exposure, although slightly better, was also poor: r1" - '">.096 for the
correlation with hippuric acid concentration (corrected for specific gravity)
and r^ 0.116 for the correlation with rate of excretion of hippuric acid
(Veulemans et al., 1979). Some of the variance in excretion rates was accounted
for by differences in lung clearance, and, hence, uptake among workers (Veulemans
et al., 1979).
Ill
Mice exposed to a very high initial concentration of methyl- C-toiuene in a
closed chaaber for 10 ciinutes excreted about 10? of the absorbed dose as volatile
material in the exnaled air and about 68J as unidentified compounds in the urine
within 8 hours (Bergman, '.979). Details of exposure were discussed in
Section 13.1. In these experiments, volatile expired radioactivity (thought to
represent the parent compound) was collected continuously in a trapping device.
The total volatile radioactivity expired during each time interval was converted
to the roear, percent dose excreted per minute during that interval and plotted at
the end cf the interval. The resultant semilogarithmic plot of mean percent dose
exhaled per minute versuj time was a curve. Computerized non-linear regression
analysis of the data according to the method of least squares yielded 3
exponential components with rate coefficients of 0,0659, 0.0236, and
0.0014 min~ corresponding to apparent half-lives of 10.5, 29.^, and
158.7 minutes, respectively.
-------
The respiratory rates of the mice were, according to Bergman (1979)f
"remarkably reduced" during exposure, and. nence probab.ly were reduced during at
least part, of the post-exposure period. If respiratory minute volumes were also
.decreased, thJLs. would, on the basis of the observations of Veulemans and
Masschelein (1978a), be expected to reduce the pulmonary excretion of toluene.
TheWsults of Bergman (1979) nay therefore not be relevant to exposures at lower
concentrations of toluene.
After inhalation exposure of rats or mice to toluene, the disappearance of
toluene and its metabolites from blood and from most tissues, including brain,
was rapid (Peterson and Bruckner, 1978; Benignus et al., 1981; Carlsson and
Lindquist, Pyykkc et al., 1977; Bergman, 1979) as described in Section 13.2. The
exceptions were white adipo.se tissue, for whicn both accumulation and
elimination were slow, a_'id bone rr.irrow, for which elimination was very slow
(Carlsson and Lindquist, 19''?; Pyykko et al ., 1977). By 2U hours after exposure
to radioactively-labeled toluene, the concentration of radioactivity remaining
in most tissues was less than 1. and that regaining in adipose tissue was about
5J of the initial whole-body concentration (Pyykko et al., 1977).
Rabbits exposed to toluene- vapor at 55U ppm for 100 minutes or 4500 ppm for
10 minutes had increased rate? of urinary hippuric acid excretion that reached
maximum values l.h hours after* exposure (Nomiyana and Nomiyaaa, 1978).
Excretion rates returned to baseline levels at 7 hours after the initiation of
exposure to 350 ppzi for 100 minutes and at about 3 hours after the initiation of
exposure to 4500 ppm for 10 tLinutes.
Dermal exposure of human subjects to toluene liquid or vapor resulted in the
appearance of toluene in the expired air (Guilleraan et.al., 197**; Riihircaki and
Pfaffli, 1978) as discussed in Section- 13.1. The excretion of toluene in the
expired air of subjects exposed to 600 ppm toluene for 3 hours appeared to
consist of at least 2 exponential phases (ffiihimaki and Pfaffli, 1978). The mean
amount of toluene expired during the "quantitatively significant" portion of the
excretion curve was calculated to be 45.9 umole (4.23 mg) Riihimaki and Pfaffli,
1978). Piotrowski (1967, reviewed in NIOSH, 1973) found that subjects exposed
dennally (with respiratory protection) to 427 ppm (1600 nig/or) toluene for
8 hours had no detectable increase in urinary excretion of benzoic acid
(presumably analyzed after hydrolysis of conjugates).
Oral administration of toluen^ to rabbits resulted in a pattern of excretion
similar to thai observed after inhalation exposure of humans. Rabbits (N = 2)
13-25
-------
intqbated with 350 mg toluene/kg body weight expired 18J of the dose as
parent compound within 1^.5 hours; less than ^% of the dose was eliminated in the
expired air in the period from 1^.5 through 35 hours after dosing (Smith et al.,
1951)). In similar experiments from the same laboratory, rabbits intubated with
274 mg toluene/kg body weight excreted an average of 7'4f of the dose in the urine
as hippuric acid; excretion was complete with 2^ hours of dosing (El Masri
et al., 1956). The elimination of toluene and its metabolites from tissues and
blood of rats given toluene orally (Pyykko et al., 1977) was similar to the
pattern already described after inhalation exposure (Pyykko et al., 1977) except
that elimination after oral administration appeared to be delayed by a slower
rate of absorption than had been observed for inhalation exposure.
'.The excretion of other metabolites of toluene (i.e., cresols, benzyl
alcohol, glucuronide and sulfate conjugates, benzylmercapturic acid) in the
urine of humans and animals has already been described in Section 13-3- With the
possible exception of benzoylglucuronide (Srbova and Teisinger, 1953), none of
these excreted metabolites represented more than about 1? of the total dose of
toluene administered or absorbed (Ar.gerer, 1979; Bakke and Sheline, 1970; Van
Doom et al., 1980; Smith et al., 195^). Trace amounts of toluene were
eliminated in the urine of humans exposed to toluene (Srbova and Teisinger,
1952).
Biliary excretion of toluene or its metabolites appeared to be negiigiole.
ill
Rats given 50 mg C-toluene/kg body weight intraperitoneally excreted less than
2% of the administered radioactivity in the bile within 2*4 hours
(Abou-El-Markarem et al., 1967).
Most of the experimental work on the disposition of toluene in humans and
animals has focused on single exposures. The elimination of toluene is rapid
enough that few investigators have studied its potential accumulation with
repeated daily exposure. Ovrum and coworkers (1978) took samples of capillary
blood daily before work from 8 printers exposed occupationally to 35 to 353 ppm
toluene. No cumulative increase in blood concentrations of toluene was found
during the course of a 5 day work week. Konietzko and ooworkers O9&0) observed,
however, that toluene concentrations in peripheral venous blood tended to
increase during the course of a 5 day work week, although the ranges overlapped
(Table 13-3). Mean exposure concentrations, measured by a personal air sampling
method, did not increase during the week. The blood samples were taken before
work on Monday, Wednesday, and Friday from 8 workers exposed to 18I< to 332 pptn
13-26
-------
TABLE 13-3
Toluene Concentrations in Workplace Air and Peripheral Venous Blood of Exposed Workers
a,b
First week
r
ro
-j
Second week
Toluene in air (ppm)
Toluene in blood
before exposure (jig/ml)
Toluene in blood
after exposure (ng/mi)
Toluene in air (ppm)
Toluene in blood
before exposure (^g/mi.)
Toluene in blood
after exposure (ug/nul)
Monday Tuesday
225 233
(95-303) (153-383)
0.12
(0.09-0.21*)
3.63
(2. 3-1*. 75)
285 304
(145-473) (190-521)
0.27
(0.07-0.57)
11.60
(6.99-17.10)
Wednesday
209
(107-341)
0.51
(0.28-0.82)
6.69
(4.21-10.36)
309
(213-413)
1.00
(0.35-151)
10.49
(3. 24-20. 3D
Thursday Friday
212 203
(92-314) (124-309)
0.77
(0.29-1.
6.70
(3.99-10
232 191
(125-451) (105-432)
1.21
(0.44-2.
5.85
(1-94-9.
67)
.6?)
29)
73)
Source: Konietzko et al., 1980
Means and (range) of eight workers
-------
daily in a plastic processing factory. Concentrations in blood samples taken
after work were highly variable arid did not seem to follow a consistent pattern.
In an analysis of 3155 samples of urine taken in the course cf biological
monitoring from different workers on different days of the week and in different
workplaces, Lenhert et al. (1978) observed that concentrations of hippuric acid
in\ the urine did not vary with the day of the week except on Monday, when the
concentrations were significantly higher than on other days. Tha authors
conjectured that the elevation of hippuric acid concentrations on Mondays was a
result of different: eating habits on the weekend.
In experiments with dogs, exposure to 400 ppm for 7 hours a day for 5
consecutive days did net result in an increase in the total amount of hippuric
acid excreted per day over the period of 5 days or change the time course of
urinary excretion (Von Cettingen et al., 19^2b). Nor did the concentration of
toluene in peripheral venous blood sampled at the end of exposure increase with
dayiof exposure.
13.5. SUMMARY
Toluene is readily absorbed through the respiratory tracts of humans and
expennental animals, as would be expected from its blood/air partition
coefficient of approximately 15 (Sato and Nakajima, 1979a; Sato et al., 197^3,
197^b; Sherwood, 1976). The amount of toluene absorbed (uptake) is proportional
to the concentration in inspired air, length of. exposure, and pulmonary
ventilation (respiratory minute volume) (Astrand et al., 1972; Astrand, 1975;
Veulemans and Masschelein, 1978a).
The uptake of toluene by humans was about 50? of the amount inspired
(Veulemans and Masschelein, 1978a; Carlsson and Lindqui.3t, 1977. Ovrun et al.,
1978). Total uptake (absorption) can be approximated as follows:
Uptake = 0.5 V C. t, where V is the respiratory minute volume in JL/min, C. : s
the inspired concentration in mg/S,, and t is the length of exposure in minutes
(Ovrum et dl., 1978; Veulemans and Masschelein, 1978a). Because of its
dependence on respiratory minute volu-me, the uptake of toluene is affected by the
subjects' l*>vel of physical activity (Astrand et al., 1972; Astrand, 1975;
Veulemans and Masschelein, 1978a; Carlsson and Lindquist, 1977). A subjects'
content of adipose tissue had little or no effect on the uptake of toluene during
exposures lasting M hours or less (Veulemans and Masschelein, 1978a; Astrand et
*!•» 1972) except in the case of extremely obese individuals (Carlsson and
Lindquist, 1977), zvnd even then the increased uptake may have been at least
13-28
-------
partly due to greater pulmonary Ventilation in the obese subjects than in the
thin ones. Under "steady state" conditions, peripheral venous concentrations of
toluene correlated roughly with exposure concentrations. Inter- and intra-
individual variability were high enough to make this an insensitive estimate of
exposure concentration or uptake (Von Oettingen et al., 19*42a, 19*»2b; Veuleaans
and Masschelein, 197db).
Although toluene appears to be absorbed less readily through the skin than
through the respiratory tract, percutaneous absorption of liquid toluene may be
significant. The tnaxitausi toluene concentration in peripheral venous blood of
subjects who imaersed one hand in liquid toluene for 30 minutes was about 26$ of
the concentration in peripheral venous blood of subjects who inhaled TOO pptn
toluene vapor for 30 minutes (Sato and Naxajima, 1978). Absorption of toluene
vapor through the skin in humans, however, probably anounts to less than 5? of
the total uptake through the respiratory tract under the same- conditions of
exposure (Riihimaki and Pfaffli, 1976; Piotrowski, 1967; reviewed in NIOSH,
1973)' Absorption of toluene through the gastrointestinal tract appears to be
fairly complete, based on the amounts of toluene and its metabolites excreted by
experimental animals after administration of toluene (Pyykko et al.. 1977;
El Hasri et al., 1956; Smith et al., 1951).
Toluene appears to be distributed in the body in accordance with the
tissue/blood distribution coefficients and its metabolic and excretory fats.
Thus, toluene itself is found in high concentrations in adipose tissue and bcne
marrow, and toluene and its metabolites are found in moderately high concentra-
tions in liver and kidney (Peterson and Bruckner, 1978; Bruckner and Peterson,
198la; Carlsson and Lindquist, 1977; Pyykko et al., 1977; Bergoan, 1979). The
time course of toluene concentrations in the brain appeared to correlate with
behavioral effects (Petersor and Bruckner, 1976; Bruckner and Peterson, 198la).
The major portion of inhaled or ingested toluene is metabolized by side-
chain oxidation to benzoic acid, conjugated with glycine to form hippuric acid,
and excreted in the urine. Regardless of the route of administration, dose, or
species, 60 to 75J of the absorbed (inhalation) or administered (oral) toluene
could be accounted for as hippuric acid in the urine (Veulemans and Masschelein,
1979; Ogata et al., 1970; F.I Masri et al., 1956). Much of the remaining toluene
(9 to 18J) was exhaled unchanged (Nomiyama and Noraiyama, 19?1b; Srbova and
Tsisinger, 1952, 1953; Smith et al., 195M. Two percent or less appeared in the
urine as cresols and benzylmercapturic acid; these metabolites are of concern
13-29
-------
because they indicate formation of reactive intermediates that potentially could
bind to tissue macromolecules. No evidence of covalent binding to tissue
components has been detected, however, by autoradiography of mice that inhaled
iaC-toluer.e (Bergman, 1979).
Most of the toluene absorbed by humans or animals after inhalation or oral
exposure is excreted within 12 hours of the end of exposure (Ogata et al., 1970;
Veuleaans and Masschelein, 1979; Nomiyama and Nomiyama, 1978; Smith et al., 1951;
Bergman, 1979). In experimental animals, elimination of toluene and its metabo-
lites from most tissues, including brain, was rapid; elimination from fat and
bone qaarrow was slower (Peterson and Bruckner, 1978; Benignus et al., 1981;
Bruckner and Peterson, 198la; Pyykko et al., 1977; Carlsson and Lindquist,
1977).
In humarLS , tr.e time course of desaturation after cessation of inhalation
exposure appeared to consist of 3 exponential phases with half-lives of 1.95,
35.2, and 20^ minutes for toluene concentrations in peripheral venous blood and
1.59, 26.5, and 221 minutes for toluene concentrations in alveolar air (Sato
et ol., i9'ii). Toluene concentrations in expired air or peripheral venous blood
after the encJ of inhalation exposure were not reliable indicators of toluene
•uptake or of exposure concentrations because of the great variability among
individuals (Veulemans and Masschelein, 1978a, 1978b; Astrand et al., 1972).
Sone of *.:u s variability, particularly in expired air concentrations, could be
explained ty Differences in exercise loaa during exposure, in respiratory minute
volumes a: ter exposure, and in adipose tissue content (Veuleraans and Masschelein
'978a, i97b:,;. Siitilariy, although the excretion of hippuric acid ir; the urine
is roughly proportional to the degree of exposure to toluene, inter- and intra-
ini.Viduai variations in tr.e physiological excretion of hippuric acid render
quantitatior. of exposure or uptake n'rom urinary hippuric acid concentration or
excretion rat<=c unreliable (InsEazura and Iksda, 1973; Vetileaians et al., 1979;
Veulemans ar.d Masschelein, 1979; Ogata et al., 1971; Wilczok and Bienick, 1978;
arid otners as reported in Section I^.U.).
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23(4):382-385.
OGATA, M., TOMOKUNI, K., and TAKATSUKA, Y. (1970). Urinary excretion of
hippuric acid and m- or p-methylhippuric acid in the urine of persons exposed to
vapors of toluene and m- or p-xylene as a test of exposure. Brit. ^J. Ind. Med.
27(1):43-50.
OGATA, M., and SUGIHARA, R. (1977). An improved direct colorimetric method for
the quantitative analysis of urinary hippuric acid as an index of toluene expo-
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OVRUM, P., KULTENGREN, M., and LINDQUIST, T. (1978). Exposure to toluene in a
photogravure printing plant. Concentration in ambient air and uptake in the
body. Scand. J_. Work, Environ. Health. H( 3): 2 37-2*45.
PETERSON, R.G., and BRUCKNER, J.V. (1978). Measurement of toluene levels in
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and Carrol, L.T., editors. Rockville, MD: Nat. Inst. Drug Abuse. 2£:33-^2.
PFAFFLI, P., SAVOLAINEN, H., KALLIOMAKI, P.L., and KALLIOKOSKI, P. (1979).
Urinary c-cresol in toluene exposure. Scand. ^J. Work Environ. Health.
5(3):286-289.
13-36
-------
FJOTROWSKI, J. (1967). Quantitative estimate of the absorption of toluene in
people. Med. PraOy. _^8:213-223- (In Pol.) (Cited in NIOSH, 1973).
PYYKKO, K., TAHTI, H., and VAPAATALO, H. (1977). Toluene concentrations ifi
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RIIHIMAKI, V., and PFAFFLI, P. (1978). Percutaneous absorption of solvent
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SATO, A., FUKIWARA, Y., and NAKAJIMA, T. (197^b). Solubility of benzene,
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SATO, A., and NAKAJIMA, T. (1-?79b). Dose- dependent metabolic interaction
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13-37
-------
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SREOVA, J., and TEISl'NGER, J. (1952). Absorption and elimination of toluene in
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3RECVA, J., and TEISINGER, J. (1953). Metabolism of toluene. Pracov. Lek.
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SZADKOWSKI, D., PETT, R. , ANGERER, J., MANZ, A., and LEHNERT, G. (1973).
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VAN DCORN, R., BOS, R.P., and BROUNS, R.M.E. (1980). Effect of toluene and
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VERSCHUEREN, K. (1977). Handbook of Environmental Data or. Organic Chemicals.
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VEULEKANS, H., and MASSCHELEIN, R. (1978a). Experimental human exposure to
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Abst. _90:l8l.040q, 1979-
VEULEMANS, H. and MASSCHELEIN, R. (1978b). Experimental human exposure to
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O^ccup. Environ. Health. 42(2): 105- i7. Taken from: Chem. Abst. 90: I8l040q,
1979.
13-38
-------
VEULEMANS, H., and MASSCHELEIN, R. (1979). Experimental human exposure to
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584. ^.
VON OETTINGEN, W.r., NEAL; P.A.; DONAHUE, D.D,, SVIRBELY, J.L., BAERNSTEIN,
H.D., MONACO, A.R., VALAER, -P.O., and MITCHELL, J.L. (19^2b). The Toxicity and
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WILCZOKv T., and BIENIEK, G. (1978). Urinary hippuric acid concentration after
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i
WINEK, C.L., and COLLOM, W.D. (1971). Benzene and toluene fatalities. J_.
Occup. Med. J^:259-261/
WINEK, C.L., WECHT, C.H., and COLLOM, W.D. (1968). Toluene fatality from glue
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WOIWODE, W., WODARZ, R., DRYSCH, K., and WEICHARDT, H. (1979). Metabolism of
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WOIWODE, W., and DRYSCH, K. (1981). Experimental exposure to toluene. Further
consideration of cresol formation in man. Br. J. Ind. Med. 38: 19^-197.
13-39
-------
T4. CARCINOGENICm, MUTAGENICITY, AND TERATOGENICITY
11). 1. CARCINOGENICITY
CUT (1930) concluded that exposure to toluene at levels of 30, 100, or
300 pppn for 6 hours/day, 5 days/week for 24 months did not produce an increased
incidence cf neoplastic, proliferative, inflammatory or degenerative lesions in
Fischer 3^ male or female rats (see description of study in Section 12.1.2.).
Neoplasms were observed frequently in the lungs and liver, endocrine organs,
lymphoreticular system, mammary gland, integument, testis and uterus, but the
lesions occurred with equal frequency in all control and treatment groups.
Although the CUT (1980) study was comprehensive and is the only chronic
bioassay of toluene presently available, it should be noted that there are
several factors that preclude a definite conclusion of non-carcinogenicity.
First, it should be noted that this study has been considered inadequate for
carcinogenic!ty evaluation (Powers, 1979) because a maximum tolerated dose (MTD)
was not achieved at the highest dose tested in either this 2-year study (300 ppm)
or in a preliminary 90-day study (1000 ppta). Also, the low mortality of rats in
the CUT study (1*4.6%) differs from the mortality rate (up to 25?) normally
associated with maintaining these animals under barrier conditions (NCI, 1979a,
b). If the CUT animals were not raised under barrier conditions (which is not
stated), then still higher mortality rates would be expected in this age group of
Fischer 314*4 rats. A high spontaneous testicular interstitial cell tumor
incidence in aging F3t*14 rats (66 and 85J reported by Coleman et al., 1977 and
Mason et al., 1971, respectively) removes this organ frotc any assessment of
carcinogenicity. Additionally, the high spontaneous incidence (165) of mono-
nuclear ceil leukemia on aging F3^ rats (Coleman et al., 1977) suggests that
this strain may be inappropriate for the study of a chemical that may be myelo-
toxic (Table 12-7). An independent quality assurance audit of the CUT study
indicated that there were no deviations from protocol requirements, and that the
final report accurately reflects (with minor exceptions) the data from the
laboratory records. The errors that were noted in the final report, do not affect
the conclusions drawn frotn the data.
A chronic bioassay of commercial-grade toluene in rats and mice exposed by
inhalation is currently being conducted by the NTP Carcinogenesis Testing
Program. Prechronic testing of commercial toluene in the same species exposed by
gavage has been completed (NTP, 1983).
1U-1
-------
Toluene has been utilized extensively as a solvent for lipophilic chemicals
being tested for their carcinogenic potential when applied topically to the
shaved skin of animals. Results of control experiments with pure toluene have
been uniformly negative. Peel (1963) r f°r example, applied toluene (volume not
stated) to the shaved Interscapular skin 3 times a week throughout the lifetime
of 54 male SWR, C3HeB, and A/He mice and found no carcinogenic response. Coombs
et al. (1973) treated the dorsal skin of 20 randomly bred albino mice with 1 drop
of toluene (6 nt) twice a week for 50-weeks. There was no evidence of squamous
papiilcwas or carcinomas in the mice one year following termination of exposure,
although survival was only 35$ (7 of 20). Doak et al. (1976) applied estimated
toluene volumes cf 0.05 to 0.1 mi/mouse to the backs of CF1, C H, and CbaH mice
(approximately 25 mice of each sex of each strain) twice weekly for 56 weeks, and
failed tc elicit skin tumors or a significantly increased frequency of systemic
tumors over untreated controls. It is unclear in these studies, however, whether
the toluene was applied under an occlusive dressing or allowed to evaporate.
Li'jinsky and Garcia (1972) did report a skin papilloma in 1 mouse and a skin
carcinoma in a second nouse in a group of 30 animals that were subjected to
topical applications of 16 to 20 \ii of toluene twice a week for 72 weeks.
Frei and Kingsley (1968) examined the promoting effect of toluene in Swiss
mice following initiation with 7,12-diraethylbenz[a]anthracene (DMBA). In this
st'irty, the ears cf the mine wer° topically treated once with 0.1 mx, of 1.5? "H3A
in mineral oil ar:d subsequently, beginning a week later, twice a week with the
same volume of 10CX toluene for 20 weeks. Results showed that 11 of 35 mice
developed tumors (6 permanent, 5 regressing) compared witn 8 of 53 negative
controls treated with 100? mineral oil (Table 14-1). In 14 mice painted with
100$ toluene but no DMBA initiator-, 2 developed tumors (1 permanent, 1 regress-
ing). In anotner study with an identical experimental design, Frei and Stephens
(1968) similarly found that 100$ toluene promoted a yield of tumors no different
from that found in the concrols (Table 14-1). In this study, a total of 7 tumors
were found in 35 surviving mice treated with toluene following initiation with
DMBA; th<: negative control group (DMBA followed by biweekly applications of
mineral oil) had 3 sKin tumors in 53 survivors after the 20 weeks.
11.2. MUTAGENICITY
11.2.1. Growth Inhibition Tests in Bacteria. The ability of toluene to induce
DNA damage was evaluated in two studies by comparing its differentia?! toxicity to
wild-type and DNA repair-deficient.bacteria (Fluck et al., 1976; Mortelmans and
1U-2
-------
TABLE 14-1
Epidermal Tumor Yielc! in 20 Week Two-Stage Experiments0
DMBA Promoting Age-it
4- None
* 5% croton oil6
* 100J toluene
4- 100? mineral oil
5J croton oil
100J toluene
f 4- None
LO
4- 51 croton oil
4- 100*
4- 5J croton oil
5J croton oil0
100J toluene
No. Surviving
Mice
33b
35b
53b
25b
146
23d
33e
35d
53e
20d
!4d
Tumor
bearing
sifrvivors
NR
NR
NR
NR
NFi
NR
88?
11$
11?
5*
oj
Number of Tumors
Permanent
0
381
6
8
1
1
NR
NR
NR
NR
NR
0
Regressing
0
70
5
0
2
1
NR
NR
NR
NR
NR
0
Total
0
1)51
11
8
3
2
1
352.
7
8
1
0
Tumors
per
Survivor
0
13-7
0.31
0.15
0.11
0.14
0.04
10.7
0.2
0.15
0.05
0
Regressing
Tumors
(J) Reference
0 Frei and Kingsle^ ,
1968
15.5
45.4
0
66.6
5.0
.NR Frei and Stephens,
1968
NR
NR
NR
NR
0
aEars of Swiss mice treated once with 0.1 mZ of 0.51 DMBA and subsequently, beginning 1 week later, twice a week with the
.promoting agent.
Not specifically staged whether this is the number of surviving mice. Also, the number of mice at the start not stated.
°In mineral oil
30 mice at the star',
e60 mice at the stare.
NR = not reported
-------
Riccio, 1980). Two species were tested with negative results: Escherichia coli
W3110 (jgol A*) ana p3478 (pol A") and Salmonella typhimurium SL^525 (rfa) (ree*)
and SLWO >fa) (reef). In the first study, Fluck e.t al. (1976) applied
toluene (25 ni/plate) without metabolic activation directly to wells in tr.e
center of culture plates containing the E. coli and found no zones of growth
inhibition with either strain. In the Mortelmans and Riccio (1960) study, growth
inhibition was also found to be comparable with both the repair* competent and
deficient strains of the E. coli and S. typhimurium when sterile filter discs
inoculated with O.C01 to 0.01 \i$L toluene were placed in the centers of culture
plates; these assays were performed both with and without metabolic activation.
Mortelmans and Riccio (I960) furtner found that toluene (0.001 to 0.01 ni/plate)
was not differentially toxic to either strain of the E_. coli or S_. typhimuriun. in
quantitative growth inhibition tests. In the quantitative assays, the toluene
was preincubatcd in liquid suspension with the bacteria, with and without S-9
activation, prior to plating; following plate incubation, the numbers of surviv-
ing cells were counted (instead of recording measurements of diameter.'; of zones
of growth inhibition).
T4.2.2. Tests for Gene Mutations
1*4.2.2.1. ASSAYS USING BACTERIA AND YEAST — Toluene has been reported to
be non-mutagenic in the. Ames Salmonella assay when tested with strains TA1535,
TA1537, TA1;.33, TA9S, and TA100 (Litton Bionetics, Inc., 19?8a; Mortelma.is and
Riccio, 1930; Nestmann et al., I960; Bos et al., 1981; Snow et al., 1981), and in
the Z. coli WP2 reversion to trp* prototrophy assay (Mortelmans and Riccio,
1980). The details of these studies are summarized in Table T4-2. All assays
were performed in the presence and in the absence of Aroclor 125^-induced rat
liver hoaogenate (3-9) and employed positive and negative controls. It should be
noted that there may have been significant losses of toluene from tne culture
media during incubation in all but one of the aforementioned studies (Snow
etal., 1981), particularly at the higher doses tested. Snow et al. (1981)
conducted plate incorporation assays in sealed plastic bags and chambers as well
as vapor exposures in desiccators to prevent excessive evaporation. The design
of the Snow et al. (1981) study is also noteworthy, because the toluene was
tested wi'.h toluene-induced rat liver S-9 fraction as well as with Aroclor-
induced S-9.
Toluene, with and without metabolic activation, was also tested in IJ.
for its ability to induce reversions to isoleucine independence in
-------
Typ« of Assay
Reverse Mutation
S. typhlRurlua
S. typhleurluo
S. typhlBurlua
S. typhtsajrluB
S. typhlourlua
S. typhlsurlua
f
Ui £. coll
S. c«revlsiae
Kitotic Can* Conversion
S. csrrvUlaa
S. cerovlsl*<8
Kitotic Crossing-Over
S. C-«.-.iVlsi»»
Metabolic
Strain Activation*
TA 98, 100, yes and no
1535, 1537,
1538
Ta98, 100, yes and no
1535, 1537,
1538
TA98, 100, yes and no
1535. 1537,
1538
TA98, 100, yes and no
1535, 1537,
1538
TA98, 100, yes and no
1535, 1537,
15j8
7*98, TA100 re8 *n(1 n°C
yes and noc
V?2 yes and no
D7 y«a «nd no
J.J yes and rs>
°
yes and x>
07 yss and AO
D7 yes ?nd no
ilose Application Ftrspon^c
0.001 to 5.0(il/
plate
0.001 to O.OJII6
0.01 to I0til/plat«
5 Ml/plate
0.115 to ?,~) tit/
pi He
0.3 (il to 100 t't''
plat*
11 to 3761 ppa
0.01 to 10 (it/
pl»te
0.001 to 0.5Jf
0.001 to 5. Out/
pi»t»
0. 138 to 1. t»°
O.C01 to 5.0Jf
O.OOi to 5.0»f
Plate
Llq ild
Plat.
Plato
Plate
Plate
Vapor
Title
Liquid
Plato
Liquid
Liquid
L 1 iju 1 d
Incorporftt 1 on
suspension
Incorporation
1 ncorpor it Ion
Ircorporrit Ion
Incorporation
exposure*
Incorporation
suspension
Incorporation
suspension
suspension
suspension
Hef«renc-«
l.ltlon Blonetlcs, Inc.,
1978a
Horieli&ana and Rlcolo,
19SO
N«!>teann « toluene «j tea ted with toluene- IniucJ-J S-9 a.i well as irlth »roclor lndur«d S-9.
"Hhe plates w«re Incubited In sealed plaatlc bags or chaisbers for part of a 7?-^r Incut-stlon period; 1n the Arcclor-lnduced
S-9 testa, th* plAtca uvrr rrasovei fron thr bags after Ii8 hr, counlfd, Incubatfd an ad-tlllon .""I hr, rind recounted; In tha
expcrlBCnt^ with tolu«^*-induced 3-9 th? pl^tpa w*re rcaov»«(J after ?** hr to prevsnt aolature anil 31-rpaJlng problffias, and then
Incubated an additional «8 tir Ntfore count Ing.
*Tha aanaya *rrt run in a »»-*lfl(3 Incubation rh.iist.cr with a .ifrv.nd glass (ilate (op*n! which contained the toluene; sftrr
2*1 hr th* ch^iabers were open" j and the platps Inrub.iteJ for an additlon.il $8 hr.
1001 Borlal.ly al 0.11 an<: O.',l
-------
strain D7 (Mortelsnans and .RicciOi 1980). mitotic gene conversion to tryptophar,
independence in strains DU (Litton Bionetic, Inc., 197&a) and D7 (Morte.lmans ana
Riccio, 1980), and mitotic crossing over at the ade2 locus in strain D7
(Mortelmans and Riccio. I960). Toluene did not elicit a positive mutagenic
response in any of these tests (Table 14-2).
iu.2.2.2. TK MUTATION IN L5178Y MOUSE LYMPHDMA CELLS -- Litton Bionetics,
Inc. (19?6a) reported that toluene failed to induce specific locus forward muta-
tior. in the L5178y Thynidine Kinase (TK) mouse lytnphoma cell assay. Toluene was
tested at concentrations of 0.05 to 0.30 n£/m£., with and without mouse liver S-9
activation.
1^.2.3. Tests for Chromosomal Mutation?
HJ.2.3-1 MICRON'JCLEUS TEST IK MICE — It was reported recently by SRI
International (Kirkhart, I960) that the intraperitoneal administration of
toluene to male Swiss sice failed to cause an increase in aicronucleated poly-
chromatophilic erythrocyte^ in the bone marrow. Doses of 250, 500, and
1000 mg/kg were aizinistered to groups of 32 mice at 0 and 2U hours, witn sacri-
fices 30, 18, and 72 hours after the first dose (8 mice/sacrifice). Five hundred
polychromatic erythocytes per animal were evaluated for the presence of micro-
nuclei. The highest dose tested (1000 mg/kg) approximated the LDj-^ for male mice
(Koga and Ohniya, 1978),
1^.2.3.2. XG'J" DOMINANT LETHAL ASSAY — Toluene was reoei/.-ly evaluated for
its ability to induce dominant lethal mutations in sperm cells of CD-I male mice
(Litton Bior.etics, Inc,, 1981). Test mice (12 pen dose) were'exposed via inhala-
tion to targeted exposure levels of 100 ar.d ^00 ppm 6 hours per day, 5 days per
week for 6 weeks. Twelve negative control aice were exposed to filtered air in
an identical exoosore regiaen, and 12 positive control nice were injected intra-
peritoneally with 0.3 mg/kg triethylenemelaniine (TEH; on day *O of the dosing
schedule. Following treatment, the males were mated sequentially to 2 fenales
per week for each of 2 weeks; 1^4 days after the midweek of mating, each female
waa sacrificed using COV and the number of living and dead implantations were
counted. The results of this study showed that tolutne die! not cause ary
significant reduction In the fertility of the treated Bales, and did not cause
increases in either pre- or post-implantation loss of embryos when compared with
the negative controls. A significant induction of dominant le^r.al nutations was
observed in the positive control mice.
-------
14.2,3.3- CHROMOSOME ABERRATION STUDIES -•* Two reports from the Russian
literature concluded that toluene induced chromosomal aberrations in rat bone
marrow cells following subcutaneous injection (Dobrokhotov, 1972; Lyapkalo;
1973). In an analysis of 720 metaphases from the bone marrow of 5 rats th?t had
been subcutaneously injeoted with 0.8 g/kg/day toluene Tor 12 days, Dobrokhotov
(1972) fouqd that 78 (13$) showed aberrations. .Sixty-six percent of the aberra-
tions were chromatic breaks, 24$ were chromatid "fractures", 1% were chromosome
"fractures", and 3$ involved multiple aberrations. The frequency of spontaneous
aberrations in 600 marrow metaphases from 5 control rats injected with vegetable
oil averaged 4.16$ (65.8$ were breaks and 32.4$ were chromatid aberrations; no
"fractures" or multiple injuries were recorded.). It was further found that
similar administration of 0.2 g/kg/day of benzene induced a frequency of chromo-
somal damage (13.6$) comparable to that of 0.8 g/kg/day of toluene, and that when
a mixture of 0.2 g/kg benzene and 0.8 g/kg toluene was injected daily for
12 days, the damage was approximately additive (33-33$ aberrations). The
significance of the positive clastogenic effects attributed to toluene is dif-
ficult to assess, however, because the purity of the sample employed was not
stated, and because the distinction between chromatid breaks and fractures is
unclear.
Lyapkalo (1973) administered 1 g/kg/day toluene to 6 rats and 1 g/kg/day
benzene to 8 rats by subcutaneous injection for 12 days. Treatment with toluene
reportedly resulted in chromosome aberrations in 11.6$ of the bone marrow cells
examined (84 aberrant metaphases/724 cells) compared with 3.87$ (40/1033) in
olive oil injected controls. The types of aberrations that were observed con-
sisted of "gaps" (60.47$), chromatid breaks (38.37$) and isocromatid breaks
(1.16$). Benzene caused a greater degree of chromosome damage than the toluene
(57.2$ of the cells examined had aberrant chromosomes (573/1002)), and the dis-
tribution of aberration types was different (44.72$ "gaps", 50.94$ chromatid
breaks^ 4.34$ isochromatid breaks). The purity of the toluene used in this study
also was not stated.
In a third Russian study, Dobrokhotov and Enikeev (1975) reported that rats
exposed to 80 ppm (610 mg/m ) toluene via inhalation, 4 hours daily for
4 months, showed damaged metaphase chromosomes in 21.6$ of the bone marrow cells
analyzed* The percentage of metaphases with damaged chromosomes in bone marrow
cells from air-exposed control rats was 4.02$. Inhalation of 162 ppm benzene
caused damage to chromosomes in 21.56$ of the marrow cells, and a mixture of the
-------
toluene and benzene (80 and 162 ppm, respectively) damaged chromosomes in ar,
additive manner (41.21$ of the cells were involved). Chromosome damage was also
observed in all of tne groups 1 and 2.5 months after the initial exposure, and 1
lionth after the end of exposure, the frequency of chromosome damage was still
elevated. A total of 96 rats were used in this study, but the number of rats in
each group was not stated; it should also be emphasized that the number of cells
scored .and the purity of the toluene used were not reported.
In contrast to the aforementioned Russian cytogenetics studies, Litton
Bionetics, Inc. (197.8b) found that intraperitoneal injection of pure toluene
into Charles River rats did not induce bone marrow chromosomal aberrations.
Toluene was injected at dose levels of 22, 71, and 214 mg/kg in 2 different
experiments. In 1 study, 5 rats were sacrificed at 6, 24, and 48 hours following
injection of each dose; in a second study, 5 rats were dosed daily at each level
for 5 days, and the rats were sacrificed 6 hours after injection of the last
dose. Approximately 50 cells per animal were scored for danage. Dimethyl
sulphoxide (DMSC; the solvent vehicle) administered intraperitoneally at
0.65 m£,/rat was used as a negative control, and triethylenemelamine (TEM) in
saline at 0.3 mg/kg was used as a positive control. The results of the tone
marrow cytogenetic analyses following sacrifice are summarized in Table 14-3-
It was also noted that none of the observed aberrations differed significantly in
frequency or type from either concurrent or historical spontaneous values.
Gerner-Smidt and Friedrich (1978) reported that toluene at concentrations
of 1.52, 152, and 1520 ^g/an£ did not influence the number of structural chromo-
somal aberrations in cultured human lymphocytes. Benzene and xylene at the sane
concentrations also 'had negative clastogenic effects hut toluene (152 and
1520 ug/mZ) and xylene (1520 tig/mil) caused a significant cell growth inhibition
that was not observed with benzene. The data from this study cannot be ade-
quately evaluated, however, because the source and purity of the toluene were not
Stated, no positive control experiments were performed, no metabolic activation
system was employed, an^ the type of chromosome damage scored was not specified.
Peripheral blood lymphocytes of toluene-exposed rotogravure workers have
also been examined for chromosome aberrations with negative results. In one
study, Forni and cowotkers (1971) examined the lymphocyte chromosomes from 34
workers from a single plant and 34 controls from outside the plant matched for
age and sex. Ten of the workers were exposed daily to minimum concentrations of
131 to 532 ppm benzene for 2 to 7 years and subsequently to toluene in the
-------
TABLE 11-3
Rat Bone Marrow Cell Aberrations Following Intraperitoneal Injection of Toluene
Treatment Dose
DHSO 0.65 ml/rat
(Solvent)
Triethylene 0.3ng/kg
Malaolna
Toluene 22 mg/kg
Toluene 71 ag/kjj
Toluene 211 Bg/kg
Tlae of
Sacrifice
6 h
21 h
18 h
6 h (SA)°
21 h
6 h
21 h
18 h
6 h
6 f
21 h
18 h
6 H
6 h
21 h
16 h
6 h (SA)d
No. of
Animals
5
5
5
5
5
5
5
5
5
5
5
3
5
5
5
5
5
Total No.
of Cells
225
250
250
227
250
250
242
250
238
239
227
150
212
250
250
250
250
Type and Frequency
of Aberrations
Structural
2f,1td
n,b,if
Hd
11tb,23b,5af
26t ,1r,10td.
Ipu, 1qr, 2ac,
—
3f
ltd
2td,1af,1f
—
—
1f
—
1tb,1td
1td,3af
N'Jraerlcal
__
—
._
--
,l5f, 2pp
12>,
3tr
_.
—
—
--
IPP
—
_-
—
2PP-
1pp
—
--
No. of Cells
With One or More
Aberrations
3 (1.3*)
0 (O.OJ)
2 (0.8*)
1 (0.1J)
72 (28.8*)
0 (0.0*)
0 (O.OJ)
0 (O.OJ)
2 (0.8*)
2 (0.8J)
1 (1.8*)
0 (0.0*)
0 (O.OJ)
3 (1.2J)
1 (0.1*)
2 (0.8*)
2 (0.8*)
No. of Animals
Without
Aterratlons
3
5
1
1
0
5
5
5
3
1
3
3
5
3
1
3
3
Mitotlo
Index8
3.8
6.0
6.1
5.0
1.1
3.1
5.9
7.0
6.3
2.5
1.3
5.7
3.3
1.5
3.6
5.1
5.1
Source: Litton Blonetics, Inc., 1978a
The toluene used was 99.96 wt. J pure (ethylbenzene, 0.03*; £-xylene, <0.01*; m-xylens, <0.01*; sulfur, 0.1 ppis) (Fowle, 1981).
°SA s subaoute study; rats were dosed dally for 5 days, with sacrifice '6 hours after the last dose
af = acentric fragment (2 tld); f = fragaents; pp = polyplold; pu = pulverized chroousoite; qr = quadrlradlal; r = ring; sb = chromosoBis break;
t j translocstion; tb = chromatid break; td = chrcaatld deletion; tr = trlradlal; > = greater than 10 aberrations
*Basad on a couit of at least 500 cells per animal
-------
general range of 200 to ^00 ppm for 14 years; 24 of the workers were exposed only
o toluene for 7 t9 15 years, (the ink solvent used in this plant was changed
from benzene to toluene, which contained some xylene, but reportedly no benzene,
after an outbreak of benzene poisoning in 1954.) No significant differences were
found between the toluene and control groups in frequencies of stable and
unstable chromosome aberrations or in chromosome counts (Table 14-4). Approxi-
mately IOC metaphases from each subject or control were scored. The proportion
of chromosome changes was significantly higher statistically in the
benzene/toluene group compared with controls, and in the! benzene/toluene group
relative to the toluene grcup.
Maki-Paakkanen et al. (1980) found no evidence of clastogenicity in
cultured peripheral blood lymphocytes from 32 printers and assistants from 2
different rotoprinting factories who had a history of exposure to pure toluene
(benzene concentration, £0.05?; average benzene concentration, 0.006?) at
8-hour, time-weighted average (TWA) concentrations of 7 to 112 ppm. The average
age of the workers was 34.2 years and the average length of employment was
•14.6 years. Results of analyses showed that when frequencies of chromosome
aberrations were compared with those of 15 unexposed research institute workers,
there were no significant differences (Table 14-5). Similarly, no significant
deviation? were observed in the frequencies of - aberrations in relation to
duration of exposure.
Bauchinger et al. (1982) performed cytogenetic analyses on peripheral
lymphocytes from 20 male rotogravure plant workers who were exposed for _>16 years
to toluene that contained
-------
TABLE 14-4
Frequency of Unstable and Stable Chromosome Changes and Chromosome
Counts in Subjects Exposed to Benzene or Toluene or Both
Expsoure
Benzene
Toluene
Control
Subjects
( + toluene)
subjects
No. of
Cases
10
24
34
Age
Range
36-54
29-60
25-60
Total
Cells
Counted
964
2,400
3,262
C
u
1.66(1
0.80(0
0.61(0
% Cells
b
<87)d,e,f
.83)d
.67)
C
s
0.
0.
0.
% Cells
Q
62e'f 13.1
08 14.3
09 10.2
With Chromosome Number
46
86
85
89
.0
.4
.5
>U6
(Polyploid)
0.9(0.52>
0.3(0.29)
0.3(0.3)
Source: Forni et al., 1971
Cells with "unstable" chromosome aberrations (fragments, dicentrics, ring chromosomes). The presence of each
fragment was considered as one break, the presence of a dicentric or ring chromosome as two breaks.
Cells with "stable" chromosome changes (abnormal monocentric chromosomes due to deletions, translocations. etc.,
trisoraies)
j
Numbers in parentheses show percentage of calculated breaks.
Difference from toluene group was significant (P < 0.05)
f
Difference from control was significant (P < 0.01)
-------
TABLk. 11-5
EfCecl. of Occupational Toluere Exposure £.nd Smoking on Ci.romoaomal Aberrations and Slater Chromatld Exchanges
Cells with Chromosomal Aberrations (1)
— •
t
r\>
Occupational
Toluene Exposure
(yr)
Total Worker
(11.6 yr average
Total Cortrol
C (controls)
Nonsmokers
Smokers
Total
1-10 Voean, 8.0)
Nonauoker;)
Snokera
Total
>10 Joean, 19.3)
Norafflokers
Sookers
lotal
No. of
Subjects
32
exposure)
15
M
11
15
3
to
13
1 *
8
19
Mean
Age
(yr)
31. 2e
31. 2e
31.0
3<; _ 5
31.3
27.7
28.2
28.1
38.5
35.9
37.5
Cells
Analyzed
,._
—
800
1100
1900
300
1000
1JOO
1100
800
1900
Chroma t Id
Type
1.0
0.7
0.5
0.9
0.7
0.7
0.7
0.7
0,8
1.8
1.2
Gaj,).° Excluded
Chromosome
Type
0.5
0.9
0.8
1.0
0.9
0.3
0.3
0.3
0.5
0.8
0.6
Sister ChromatM Exchanges (SCEs)
Total
1.5
1.6
1.3
1.8
1.6
1.0
1.0
1.0
1.1
2.5
1.8
Gaps Included
Total
2.5
2.7
2.3
3.1
2.7
2.3
1.9
2.0
2.5
3-1
2.8
Cells
Analyzed
—
231
318
552
79
295
371
330
205
535
Hear per Sub
per Cell
8.5
8.9
8.0
9.7"
9.2
7.9
9.1"
6.8
7.5
9.6»*
8.3
iect
9
•
Source: Makl-Paakkanen et al., 1980
100 cells analyzed per Individual
°30 cells analyzed per individual
Calculated fron Individual roeana
hean value
f.-- , r
OX'OJ Mci'o ^Uj f oU
yr i year
*"F '. 0.0' and •*• P '. C.001 ~:-parci tc norajiokcrs In the group, one-tPlleJ Student's t-test
-------
TABLE 11-6
Mean Frequency of Chromosome Abnormalities * S.E. a'id SCEs + S.E. In L
of Toluene- Exposed Rotogravure Workers and Unexposed Controls'^
ytnphocyte
No. of
Subjects
Toluene-Exposed 20°
Unexposed Controls 21
.
Age
(years)
Caps
S Cells6
I.S.D. per cell (J)
'f'4.2 » 0
7.0 ~ 0
12.1 * 0
10.5 0
.0218 +
.0021
.019 t
.003
0.90 t
0.13s"
0.51 +
0.06
Aberrations per Cell
Chromatld
breaks
0.0036 +
O.OOIO6"
0.0019 +
0.0005
Chromatid
exchanges
0.
0.
0.
0.
0015-+
0005
OOOU +
0002
Acentric
fragments
0
0
0
0
.0035 +
.0008
.0023 +
.OOOll
Dicentrlca
0,
0.
0.
0.
.0005 +
,0003
.0005 +
.0002
SCE
per cell
9.62 +
0.37^
6.18 +
0.25
"source: Bauchlnger et •!., 1982
300 cells and 500 cells were analyzed for structural chronoscmal cbangea In each exposed and control subject, respectively. Fifty cells/subject were
scored for SCEs.
C11 heavy snokerj (>10 clfiarettes/day), 1 moderate snoker, and 8 non-snokers
8 heavy smokers, 1 moderate aooker, and 15 f^on-smokers
cells with structural chromosome changes (S-oells)
Difference f. as the unaxposed control group was significant (P<0.05-)
Siffwenos free the unexposed control group was significant (F<_0.0!)
The subjects of either group were subdivided Into smokers and non-saokers for statistical evaluation. Non-smoking workers had significantly higher
(P=0.02) SCE values (8.55 * 0.27) than non-smoiclng controls (7.75 + 0.25), fi)id smoking workers lad significantly higher (P=0.020) SCE values (10.33
t O.t9) than aaoking controls (8,85 + O.'JI).
-------
cantly higher. Although the workers examined in this study were exposed to
.levels of toluene that, are similar to those reported by Forni et al, (1971) and
Maki-Paakkanen et al . (I960), it .should be noted that a,-greater number of
cells/individual we^e scored for aberrations ("300 or vDQ versua 100).
J'R- a report or, chromosome aberrations or" women i-n laboratory work,
Funes-rCravicta et ai. C197Y) «*lsj presented datH'.on T< workers who were exposed
to toluene in a rotogravure factory. Exposures ranged from 1.5 to 26 years and
air measurements of toluene show-ed TWA values of 100 to 200 ppm, with occasional
rises up tc 500 to 700 ppa; tr,t exposures were sufficient in cnotst cases to elicit
frequent he'acjacr.^s ar:d fatigue, and occasional vertigo, nausea, and feelings of
drunkenness. T.-.e workers had teen exposed to toluene since approximately 1950;
before 195i, ir- way at,at-;d t.'r.ai. toe toluene was probaoly contaminated by a "low"
percentage of ber.:".:r.i. Hesults of lymphocyte analysis showed an excess of
chromosome aierrati^r.s (ahr,jr~ui chromosomes and breaks) in the 14 toluene-
exposed workt?rs relative to a control group of 1(2 adults. It should be noted,
i
however, that only a saiiii; r.umber or' subjects were examined in this study and the
exposure badure re toluene at concentrations Of 15.2, 152, and
1520 ug/nii. hac r;c <=-rffcct oi; '.se number of sist^r-chromatid exchanges (SCEs) in
culturea hur-an 1-,-Trspn...', ytes, but no positive control experiments were performed
.and no- meta^ii^' activati.'.". syot.em was eraployed. Twenty-six cel.\s/dose were
scored fcr iCJ^r and cyt^toxi': i ty was observed at the highest dose. Evans and
Mitchell {'i9 112 ppm
pure toluene, Maki-1-aakkanen et al. (1980) found no increase in SCEs relative to
a group of "5 unexposed control subjects. The average age of the worksrs was
31.2 years and their average length of employment was 1^.6 years. The SCE
-------
TABLE 11-7
Chromosome Aberrations in Rotoprinting Factory Workers
No. of Subjects
Age (year)
Ra.'.ge
Mean
No. of Cells Analyzed
Total
Aononnal
Total
Frequency range (J)
Mean frequency ($)
No. of Chroaosomes Analyzed
Total
Breaks
Total
Range (per 100 cells)'
Mean (per 100 cells)
Control
H9
0.16 to 63
21. 1
5000
217
0 to 20
1.3
230,000
233
0 to 22
5.1
Group
Toluene
11
23 to 51
37.2
1,100
108
2 to 15
7.7
61,100
121
2 to 17
8.9
Benzene/Toluene
8
51 to
61.3
800
76
1 to
9.5
36,800
95
6 to
11.9
65
17
17
Source: Funes-Craviota et al., 1977
Exposure details provided in accompanying text.
11-15
-------
analysis was part of a study examining chromosomal aberrations in these workers;
the exposure history of the subjects is described in more detail with the summary
of the aberration findings (Section 11.2.1.1.), and the.results of the SCE
analyses are included in Table 11-5.
Bauchinger et al. (1982) reported a significantly increased number of SCEs
per peripheral lymphocyte in a group of 20 male rotogravure workers who had been
exposed to 200-300 ppm pure (<0.3?) toluene for >l6 years (Table 11-6). As
described in the more detailed Section 11.2.1.1 sumn00 to 700 ppm), but benzene concentrations were riot
measured. The technicians also had a history of exposure to toluene, but the
exposures were poorly characterized (duration and concentrations not stated) and
each had considerable concurrent exposure to other solvents as well, particu-
larly benzene and chloroform. Results of peripheral lymphocyte analysis
(20 cells/individual scored) showed a statistically significant increase in SCEs
in the laboratory technicians and the children of female technicians, but not in
the exposed printers; however, due to the nature of the exposure, the increases
noted cannot be exclusively attributed to toluene.
11.3- TERATOGENICITY
11.3.1. Animal Studies. Toluene was reported in a recent abstract to be
teratogenic to CD-1 mice following oral exposure (Nawrot and Staples, 1979).
Toluene was administered by gavage from days 6-15 of gestation at levels of 0.3,
0.5, and 1.0 m£/kg/day (approximately 0.26, 0.13, and 0.87 g/kg/day, respec-
tively) and from days 12 to 15 at 1.0 mil/kg/day. The vehicle used was cottonseed
oil (0.5$ of maternal body weight per dose). A significant increase in embryonic
lethality occurred at all dose levels when administered on days 6 to 15, and a
significant reduction in fetal weight was measured in the 0,5 and 1.0 mi/kg
groups. Exposure to 1.0 mJZ./kg toluene on days 6 to 15 also significantly
increased the incidence of cleft palate; this effect reportedly did not appear to
be due merely to a general retardation in growth rate. When toluene was adminis-
tered at 1.0 ra£/kg on days 12 to 15, however, decreased maternal weignt gain was
11-16
-------
the only effect observed. Maternal toxicity was not noted after exposure to
toluene on days 6 to 15 at any dose level. It should be emphasized that the
numbers of mice exposed and the numbers of fetuses examined were not stated in
the available abstract of this study; a complete copy of this report is not
available for review but has been submitted for publication.
Hudak and Ungvary (1978) recently concluded that toluene was not terato-
gen\ic to CFLP mice or CFY rats when administered via inhalation according to the
following schedule:
Dose
CFPL .nice
133 ppm (500 rag/m3)
399 pps (1500 mg/in3)
CFY rats 266 ppc (1000 ag/m3)
399 ppm ( 1500 mg/nr )
399 ppm (1500 mg/m3)
Days of Pregnancy
6-13
6-13
1-21
1-8
9-1M
Duration
2k hours/day
2*1 hours/day
6 hours/day
2^4 hours/day
2*4 hours/day
It was found that the entire group of mice exposed to 399 ppm toluene died within
2*4 hours. Toluene administered to rats at 399 ppm also had an effect on maternal
survival, but none of the exposures adversely affected the incidence of external
or visceral malformations, in either species relative to air-exposed controls
(Table 14-8). An increased incidence of skeletal anomalies (fused ste^nebrae,
extra ribs) was observed, however, in the rats exposed continuously to 399 ppm
tcluwie on days 9 to 1*4. and signs of retarded skeletal development (including
poorly ossified s'cernebrae, bipartite vertebra centra, and shortened 13th ribs)
were found in the rats exposed on days 1 to 8 (399 ppm) and during the entire
period of pregnancy (days 1 to 21) at 266 ppm for 8 hours/day. An erobryotoxic
effect of toluene was further indicated by low fetal weights in the mice, and in
the rats exposed on days 1 to 8 of pregnancy. Fetal loss (percent of total
implants), mean litter size, mean placental weight, and maternal weight gain were
unaffected by exposure in either species.
In a more recent teratogenicity study, groups of 20 CFY rats were exposed to
266 ppm (1000 mg/m ) toluene, 125 ppm WO mg/nr) benzene, or a combination of
these concentrations of toluene and benzene vapor for 2*4 hours/day on days 7 to
H of gestation (Tatrai et al., 1979). A group of 22 rats inhaling pure air
-------
TABLE 11-8
Toralogenlclty Fvaluallr/n of Toluene in Cfl Rats and CP1P Mice*
No. pregnant anloals exaalned
No. pregnant an! Mia died
Maternal weight g*lnb (J)
No. live fetuses
No. resortxd fetuses
c: No. dead fetuses
— Fetal loss (J)
Mean litter site
Mean fetal velght (g)
Mean placantal weight (g)
Weight retarded fetuses0 (J)
External oal format lorj
No. fetuses dissected
Internal ealforaatjona
Anophthalaia
Hydrocephalua
Hydronephoroa 1 -.
No. of Alizarin-stained
frtuses
Skeletal retardation signs'
Air Inhalation
Days 1 to ?1 t
8 h/d
10
0
16.6
111
8
0
6.7
11.1
3.8
0.5
7.2
0
51
0
--
1
57
0
?M> ppa
JllfS 1 tO
8 h/d
10
0
11.1
133
3
0
2.2
13-3
3-6
0.5
16
0
61
0
..
6
69
17"
Toluene
399 ppo
21 flay.i 1 13
21 h/d
9
5
11.0
95
6
0
5.9
10.6
3.3"
0.5
16"
0
19
0
1
H
12
7"
Flats
Air Inhalation
B Days 9 to 11
21 h/d
?6
0
16.9
318
15
0
1.1
13-1
3.6
0.5
6.9
0
;79
1
--
16
169
11
Toi uene
399 ppo
Days 9 to 11
21 h/d
19
?
11.8
213
1B
0
7.8
11.2
3.8
0.5
17.3
0
110
0
—
4
102
21"
Kir Inhalation
Days 6 to 13
?1 h/d
11
0
—
121
6
1
6.1
9.0
1.1
--
6.5
0
6!)
0
—
1
60
3
Mice
Toluene
133 ppo
Days 6 to '3
21 h/d
11
0
—
112
10
0
8.2
10.2
1.0»
--
27.6"
0
58
0
--
3
51
1
399 ppa
Days 6 to 13
21 h/d
0
15
0
0
0
0
--
~
—
—
__
0
—
—
«
—
-_
-------
TABLE 14-8 (cont. )
_,
tr
1
Skele'.al anomalies
Fused stsrnebrae
Extra ribs
SkeH-lal malformations'1
Missing vertebrae
Brachizella
Air Jnl a! at lor,
Daya 1 to 21
8 h/d
3
0
0
0
Toluene
2bt ppns 399 ppn
lays 1 to ?' Day« ! tr
8 h/d 2!i l./d
0 .0
0 0
0 0
0 0
Rats
Mr Inhibition Tolunne
39') ppffi
B rays 'i to 14 Days 9 to
tJU h/J 21 h/d
2 ?••
0 2?'*«
0 2
- 0 0
Mice
Air Inhul stlon Toluene
133 ppra 399 Ppo
11 Dnys 6 to 13 Daya 6 to 13 Days 6 to 13
24 h/d 24 h/d 24 h/fi
0 0
0 0 —
0 0 —
1 0
a
Source: Hudsk and Ungvary, 1978
Percent of starting body weight
°Porcent of living fstuaea weighing <3.3 g (rats) or 0.9 g (sice)
Agnathla, brachloclla, tlaalng ti.ll
The rats were sacrificed on day ;;l of pregnancy, the nice on day 18
Thynus hypolasla alao looked for
Including poorly ossified stsrnebrae, bipartite vertebra centra, and rmortened Ijih ribs
rissura aternl and agnathla alsd looked for
•P < 0.01 (t-test); •« P < 0.05 :Hann Whitney U Test); ••• P < 0.01 (K»nn Whitney U Teal)
t, i hour; d = day
-------
served as controls, and trw fefj.-s^s were exa.tin*.",! t^ri ciay .^ * of pregnancy. The
results of the toluene exposures ir,-Mus study are consistent wit.r: those ot l-udak
.and Ungvary's continuous TV-* p.;'" t.Jje-ie ex^csjre^ with rats • or -Jays 9 to lit of
gestation. ?atr*i et a!. '^"'.S c-j:.cl'j-.i';J -tn-:it : or.li r.uc.ia' t-xpiiurt to 266 ppa
toluene was not teratoger.se (no • exterr.ai , internal, or: skelct ji aalforaaticns
.were reported), aithougn the e.<;osu: es were dssiciatea with »/i.-:er.ce of skeletal
retardation (not detailed) ar;: ar: increased insidenvt of extra ribs
(Table 1^-9) • It was additionally- fcunc tnat tr.e incidence of extra ribs was
higher in the group exposed f; toluene in ?oa;tir.4t:-jn with teiz^rit* than ir. the
groups exposed to toluene alor.e. Mat^r.'.ui less, m;»t^rr.al weight gau., n-icber of
litters, aear. ispla.ntatiori'aaa, plaoer.tal we^^rit, fetal loss, arid fetal -eight
less were r.c-t s..5r.i!':".a:* y >: r--..-ted by t: e toluene exposures. Exposure to
125 PPfB bentene -JAd cause jecrre liies in aaterr.-j; weight pain, placer;tal weigr.t and
fetal weight, but these effects app-ear-d *- ce :r.n:bited by concurrent exposure
to 266 'pps toluene. Further, it war. reported tr.at po'st-iapiar.tation fetal loss
(the nucber of dead and resort;: f^t-jses relative to the nuaber wf total implan-
tation sites in percent' wa? sigr.iiic2~.tiy increased in the; grsup exposed to
ber.zer.e in -v.^Dinatior. w: tn tolu»T:r; feta. loss ua.s r.ct, as indicated earlier,.
affected by exposure to tne t^l_ehe (or b-rri-.i.-ie; alone.
In a -third .inhalati'jr study, "jitt-:, £:or.-:tlca. Inc. (1972C-J rtpcrted no
evidence cf teratogeni .: u/ in tr.*- :•)-,^y-.'-c f?--. :3ti of Cnarles Piver rats that
were exposed to 'Cj or w >'.• pps: toluene ;apr,»- for r; :;ojr3/day on day^ c to 15 of
gestation. Histologi.;al rx:: .rS r.acior.a revea^e..; uo unusual incidence of visceral
or skeletal ahr.r -rs.al ities ;7atle " • - ' f - ; oinu.ijal skeletal variation;, were
observed in' a scall out cotipar^oie .-,-._;o>-:r -if !etu.?^i from both the exposed ana
control groups, but tr.^ae c-! .t.i^es «-re iri -ost c^es attributed to retarded bone
ossification arid were r.ot cc/.-.^idL-T-'.-'i t>, fc-t U3^fonr.a';ior
-------
TABLE 14-9
Teratc-^enic Effects of Exposure to Toluene, Benzene^
arid a ^cunbir.ation of Toluene and Benzene in CFY Rats"
Inhalation or. days
7 to 14 of pregnancy
2-K h/d
Hunter of females
treated
dies
r.or. pregnant
total rescrption
Nusbtr cf liters
Hear, ixplantation/caa
Maternal weight gair.
in i of starting body
weigh'.
Re'.itive liver weight
U}'
Hear, placenta! weight
(f,'>
i
Naaber of fe-tuses
live
dead
resarbed
Mean fetal weignt CgJ
Weight retarded
fetuses in i of .living
fetuses
External malformations
Fetal loss/ total
Implantation sites (%}
-------
TABLE 14-9 (cont.)
Inhalation on days
1 to 1A of pregnancy
24 h/d
Skeletal anomalies
sternua m-isal igned
asyaaietric vertebra
extra ribs
Air Toluene
266 ppm
h h
1
1 7*
Benzene
125 ppc
5
3
1
Toluene/Benzene
266 ppm •* 125 ppo
1
1
19*"
oigrdf icance
of
Interaction
Skeletal malformations
No. fetuses dissected
Internal nalformations
poiycystic lungs
pyeiectasia
dystopia renic
vesica giganta
nicrophthalmia
ar.opjithalaia
•hyflrocephalus
ir.ternus
133
118
116
"Source: Tatrai et al., 1980
+ -- p < 0.1; * = p < 0.05; •• - p
-------
TABLE 14-10
Teratogenicity and Reproductive Performance
Evaluation in Rats Exposed to Toluene
v. .
Pregnancy ratio
(Pregnant/Bred)
No. pregnant rats that- died
Live litters
Implantation sites
(Left Horn/Right Horn)
Resorptions
Litters with resorptions
Dead fetuses
Litters 'with dead fetuses
Live fetuses/implantation site
Mean live litter size (fetuses)
Average fetal weight (g)
Number of fetuses examine for soft
tissue (visceral) changes^
Nuaber of fetuses examined for
skeletal changes
Number of fetuses with normal
skeletal examinations
Fetuses with commonly encountered
e f
skeletal changes '
Fetuses wij,h unusual skeletal
variations' 'g
0
26/27
0
26
152/194
26
13
0
0
320/3^6
12
3-6
108(51/57)
212
139
67(20)
6(4)
Dose (ppm)
100
27/27
0
27
181/177
28
20
1
1
329/358
12
3-5
105(47/58)
221
150
62(20)
9(4)
400
27/27
0
26
179/190
4lb
17
0
0
328/369-
12
3-8
104(51/53)
224
158
58(20)
8(6)
Source: Litton Bionetics, Inc., 1978b
The increase in total resorptions at this dose was attributed to the total
resorption of the litter of one particular female.
Cumbers of male/females examined in parentheses.
Tour specimens froa one litter were not examined (missing).
A qualitative examination of the observations recorded for the fetuses indicates
that bilateral ribs, unilateral ribs, and reduced ossification of various bones
j.were the most frequently encountered changes.
Number of litters in parenthesis.
T'hese were generally cases of more severe and extensive retarded ossification.
-------
incubation. Survival incidence after 14 days of incubation appeared to be
influenced only after injection of toluene on day 6 at 100 umol/egg; the "approx-
imate LE> " for toluene was judged to be in excess of 100 umcl/egg. Macroscopic
examination on day 14 indicated that only 3 of 46 of the chick embryos treated
with 5 to 100 |imol/egg of toluene were malformed; 1 displayed profound edema and
3 had skeletal abnormalities (musculoskeletal defects of the lower extremities,
but not wings).
Mclaughlin et al. (1964) injected toluene at dose levels of 4.3, 8.7, and
17.'4 mg into the yolk sac of fresh fertile chicken eggs before incubation.
Following incubation, the percentages of hatch at the 3 doses were, respectively,
&5%, 25?, and 0%. Teratogenic effects were not observed in either the eggs that
failed to hatch or in the chicks that, did hatch.
14,3-2. Human Reports. Holmberg (1979) gathered information on exposure to
noxious agents during the pregnancies of 120 mothers of children with congenital
CMS defects and tneir matched-pair controls. The matched-control mother is the
mother whose delivery immediately preceded that of the case mother in the same
Finnish maternity welfare district. Results showed that 14 of the 120 case
mothers had been exposed more often than control mothers (3/120) to organic
solvents during the first trimester of pregnancy. Among the 14 exposed mothers,
2 had been exposed to toluene. One of thf toluent-exposed mothers (age 18) had
reportedly been exposed in the metal products manufacturing industry (no other
details of exposure given), and gave birth to a child that died after 2 hours and
showed internal congenital hydrocephaly and agenesis of the corpus callosum upon
autopsy; other findings included pulmonary hypoplasia and a diaphragmatic
hernia. The other mother was exposed to toluene concomitantly with other sol-
vents (xylene, white spirit, methyl ethyl ketone) during rubber products manu-
facturing; her child was hydranencephalic and died 24 days after birth, it was
noted that in this case parental age (maternal, 42 years; paternal, 44 years) and
a previous child with brain injury (born 20 years previously, died at age 4) were
more likely than the recent exposure to have predisposed the more recent child to
the defect.
Toutant and Lippman (1979) described the birth of a child with "nearly
classic" fetal alcohol syndrome to a 20-year-old primigravida whose major addic-
tion was to solvents (reportedly, primarily toluene). This woman had a 14-year
history of daily heavy solvent abuse (no details provided) and a 3-year history
of alcohol intake of about a six-pack of beer weekly. On admission, she
14-24
-------
exhibited signs compatible with severe solvent and/or alcohol abuse (ataxia,
resting and intention tremors, mild diffuse sensory deficits, short-term memory
loss, and poor intellectual functioning). The child was born at term, was small
(10th percentile in weight, 5th percentile in head size), and exhibited abnormal
features that included microcephaly, a flat nasal bridge,, hypoplastic mandible,
short palpebral fissures, mildly low-set ears, pronounced sacral dimple, sloping
forehead, and uncoordinated arm movements. It was noted that although solvent
abbse rather than alcohol predominated in this mother's addiction pattern, the
case seemed no different from reports of fetal alcohol syndrome.
14.1. SUMMARY
CUT (1980) concluded that exposure to 30, 100, or 300 ppm toluene for
24 months did not produce an increased incidence of neoplastic, proliferatiye,
inflammatory, or degenerative lesions in rats relative to unexposed controls;
the highest dose tested was not, however, a maximum tolerated dose. Other
studies indicate that toluene is not carcinogenic when applied topically to the
shaved skin of mice (Pohl, 1973; Lijinsky and Garcia, 1972; Coombs et al., 1973;
Doak et al., 1976), and that it does not promote the development of epidermal
tumors following initiation with PMBA (Frei and Kingsley, 1968; .Frei and
Stephens, 1968).
Toluene has yielded negative results in a battery of microbial, mammalian
cell, and whole organism test systems. The microbial assays conducted include
differential toxicity testing with wild-type and DNA repair-deficient strains of
E.- coli- and f3. typhimurium (Fluck et al., 1976; Mortelmans and Riccio, 1980),
reverse mutation testing with various strains of S. typhimurium, E. coli WP2, and
S. cerevisiae D7 (Litton Bionetics, Inc., 1978a; Mortelmans and Riccio, 1980;
Nestman et al., 1980), and mitotic gene conversion and crossing-over evaluation
in 5, cerevisiae D4 and D? (Litton Bionetics, Inc., 1978a; Mortelmans and Riccio,
1980). Toluene also failed to induce specific locus forward mutation in the
L5178Y Thymidine Kinase mouse lymphoma cell assay (Litton Bionetics, Inc.,
1978a), was negative in the micronucleus test in mice (Kirkhart, 1980), and was
negative in the mouse dominant lethal assay (Litton Bionetics, Inc., 1981).
Sister-chromatid exchange (SCE) frequencies were not altered in Chinese hamster
ovary cells (Evans and Mitchell, 1980) or in human lymphocytes (Gerner-Smidt and
Friedrich, 1978) cultured with toluene _in vitro. The frequency of SCEs in
peripheral lymphocytes from workers that had a history of chronic exposure to
similar levels of toluene has been reported to be increased (Bauchinger et al.,
14-25
-------
1982) as well as uncharged (Funes-Craviota et al., 1977; Maki-Paakkanen et al.,
1980).
In the Russian literature, chromosome aberrations were reported in the bone
marrow cells of rats exposed subcutaneously (Dobrokhoto'f, 1972; Lyapkalo, 1973)
2nd via inhalation (Dobrokhotov and Enikeev, 197f ) to toluene. These findings
were not corroborated, however, in a Litton Bionetics, Inc. (1978b) study in rats
following intraperitoneal injection or in cultured human .lymphocytes exposed to
toluene in vitro (Gerner-Smidt and Friedrich, 1978). An excess of chromosome
aberrations in lymphocytes free workers who were chronically exposed to similar
levels of toluene has been reported by Bauchinger et al., 19£0 and Funes-Craviota
et al., 1977, but not by Forni et al.. '971 or Maki-Paakanen et al., 1980; it is
probable, however, thai part of the exposure in the Tunes-Craviola et al. (1977)
study was to benzene-contaminated toluene.
Toluene was reported in a recent abstract from NIEHS to induce cleft palates
at a level of 1.0 mJl/kg (0.87 g/kg) following oral exposure to mice on days 6 to
15 of gestation (Nawrot and Staples, 1979); significant increases in embryo-
lethality and decreases in fetal weight were noted as well at doses as low as
0.3 m/kg/day and 0.5 m/kg/day, respectively. The teratogenjc effect reportedly
did not appear to be due merely to the general retardation in growt'i rate. Three
other studies concluded that toluene is not tpratogenic in mice (Hudak and
Ungvary, 1978) or rats (Hudak and Ungvary, 1978; Litton B:onetics, Inc., 1978b;
Tatrai et al., 1980) following inhalation exposure. Embryotoxic effects
(increased incidence of skeletal anomalies and signs of retarded skeletal
development, low fetal weights) and increased maternal mortality wer« noted,
however, in some of the rats and mice exposed via inhalation. Injection o*"
toluene into the yolk sac (McLaughlin et al., 1964) or air space (Elovaara
et al., 19795) of chicken eggs before incubation or during development, respec-
tively, did not result in teratogenic effects.
14.5 REFERENCES
BAUCHINGER, M., SCHMID, E., DRESP, J., KOLIN-GERRESHEIM, J.; HAUF, R. and
SUHR, E. (1982). Chromosome changes in lymphocytes after occupational exposure
to toluene. Mutat. Res. 102(4):
14-26
-------
BOS, R.P.; BROUNS, R.H.E.; VAN DOORN, R.; THEUWS, J.L.G.; and HENDERSON, P.T.
(1981). Non-mutagehicity of toluene, p-, m-. and p-xylene> o-methylbenzyl
alcohol and ^-methylbenzyl sulfate in the Ames assay. Hutat. Res.
88^0:273-279.
CHEMICAL INDUSTRY INSTITUTE OF TOXICOLOGY (CUT). (I960). A twenty-four month
inhalation toxicology study in Fischer-S'J1! rats exposed to atmospheric toluene.
Executive Summary and Data Tables. Conducted by IndustriaJ Bio-Test
Laboratories, Inc., Decatur, IL, and Experimental Pathology Laboratories, Inc.,
Raleigh, NC, for CUT, Research Triangle Park, NC. October 15, 1980.
COLEMAN, G.L., BARTHOLD, S.W., OSBALDISTON, G.W., FOSTER, S.J. and JONES, A.M.
(1977). Pathological changes during aging in barrier-reared Fischer 3^ male
rats. ±. Gerontology. 32: 258-278.
I
COOMBS, M.M.; SHATT, T.S.; and CROFT, C.J. (1973). Correlation between carcino-
genicity and chemical structure in cyclopenta[a]phenanthrenes. Cancer Research.
33:832-837.
DOBROKHOTOV, V.B., and ENIKEEV, M.I. (1975). Mutagenic effect of benzene,
toluene, and a mixture of these hydrocarbons in a chronic experiment. Gig.
Sanit. J_:32-3^. (In Russian with English summary; evaluation based on an
English translation provided by the U.S. EPA.)
DOBROKHOTOV, V.B. (1972). The mutagenic influence of benzene and toluene under
experimental conditions. Gig. Sanit. ^7_:36-39. (In Russian; evaluation based
on an English translation provided by the U.S. EPA.)
DOAK, S.M.A. et al. (1976). The carcinogenic response in mice to the topical
application of propane sultone to the skin. Toxicology. 6^:139.
1U-27
-------
ELOVAARA, c). et al. (1979). Effects of methylene chloride, trichloroethane,
trichloroethylene, tetrachloroethylene and toluene on the development of chick
embryos. Toxicology. 12(2):111.
EVANS, E.L., and-MITCHELL, A.D. (1980). An Evaluation of the Effect of Toluene
on Sister Chromatid Exchange Frequencies in Cultured Chinese Hamster Ovary
Cells. Prepared by SRI International, Menlo Park, CA, under Contract No.
68-02-29^7 for the U.S. Environmental Protection Agency, Research Triangle Park,
NC,
FORNI, A.; PACIFICO, E.; and.LIMONTA, A. (197'). Chromosome studies in workers
exposed to benzene or toluene or both. Arch. Environ. Health. 22(3):373-378.
FLUCK, E.R. et al. (1976). Evaluation of a DNA polyraerase-deficient mutant of
E. coli for the rapid detection of carcinogens. Chem. Biol. Inter. 15:219.
FREI, ,J.V., and KINGSLEY, W.F. (1968). Observations on chemically induced
regressing tumors of mouse epidermis. J_. Natl. Cancer. Inst. J4J: 1307-1313.
FREI, J.V., and STEPHENS, P. (1966). The correlation of promotion of tumor
growth and of induction of hyperplasia in epidermal two-stage carcnogenesis.
BrU. ,;. Cancer. 22:63-92.
FUNES-CRAVIOTA, F. et al. (1977). Chromosome aberrations and sister-chromatid
exchange in workers in chemical laboratories and a rotoprinting factory and in
children of women laboratory workers. Lancet. 2:322.
GiRNER-SMIDT, P., and FRIEDHICH, U. (1978). The mutagenic effect of benzene,
toluene and xylene studied by the SCE technique. Mutat. Res. 58(2-3):313»
HOLMBERG, P.C. (1979). Central-nervous-system defects in children born to
mothers exposed to organic solvents during pregnancy. Lancet. 2:177-179.
HODAK, A., and UNGVARY, G. (1978). Embryotoxic effects of benzene and its
methyl derivatives: Toluene and xylene. Toxicology. 11:55.
11-28
-------
KIRKHART, B. (1980). Micronucleus Test on Toluene. Prepared by SRI Intkrna-
ticnal, Menlo Park, CA, urder Contract No. 68-02-2917 for the U.S. Environmental
Protection Agency, Research Triangle Park, NC.
KOGA, K., and OHMIYA, Y. (1978). Potentiation of toluene toxicity by hepatic
enzyme inhibition in mice. .J. Toxicol. Sci. 3(1) :25-29.
LIJINSKY, W., and GARCIA, H. (1972). Skin carcinogenesis tests of hydrogenated
derivatives of anthracene and other polynuclear hydrocarbons. Z.- Krebstorseh.
Klin. Onkcl. .77:226. (Cited in U.S. EPA, 1980).
LITTON BIONETICS, INC. (1981). Mutagenicity Evaluation of Toluene—Mouse
Dominant Lethal Assay. Final Report. Submitted to the American Petroleum
Institute, Washington, D.C. in January 1981. LBI Project No. 21111-05. Licton
Bionetics, Inc., Kensington, MD. 15 pp.
LITTON BIONETICS, INC. (1978a). Mutagenicity Evaluation of Toluene. Final
Report. Submitted to the American Petroleum Institute, Washington, D.C. in Kay
1978. LBI Project No. 20847. Litton Bionetics, Inc., Kensington, MD. 150 pp.
LITTON BIONETICS, INC. (1978b). Teratology Study in Rats. Toluene. Final
Report. Submitted to the American Petroluem Institute, Washington, D.C. in
January 1978. LBI Project No. 20698-1. Litton Bionetics, Inc., Kensington, MD.
17 pp.
LYAPKALO, A.A. (1973). Genetic activity of benzene and toluene. Gig. Tr. Prof.
Azbol. VJ_: 2^-28. (In Russian with Engligh summary; evaluation based on an
English translation provided by the U.S. EPA.)
MAKI-PAAKKANEN, J. et al. (1980). Toluene exposed workers and chromosome aber-
rations. J. Toxicol. Environ. Health. j6:775.
MASON, M.M., GATE, C.C. and BAKER, J. (1970. Toxicology and csrcirogenesis of
various chemicals used in the preparations of vaccines. Clinical Toxicology.
Hi 185-201.
11-29
-------
MCLAUGHLIN, J. et al. (196*0. Toxicity of fourteen volatile chemical as measured
by the chick embryo method. Am. Ind. H%£. Assoc. J_. 25:282.
MORTELMANS, K.E., and RICCIO, E.S. (1980). In vitro Microbiological Gentoxicity
Assays of Toluene. Prepared by SRI International, Menlo Park, CA, Under Contract
No. 68-02-29^7 for the U.S. Environmental Protection Agency, Research Triangle
Park, NC.
NAWROT, P.S., and STAPLES, R.E. (1979). Embryo-fetal toxicity and teratc-
genicity of benzene and toluene in the mouse. Teratology. J9:41A. (abstract).
NCI (NATIONAL CANCER INSTITUTE). (1979a). Bioassay of 2,5-Dithiobiurea for
Possible Carcinogenicity. National Institute of Health, DHEW Publ. No. (NIH)
79-1387.
NCI (NATIONAL CANCER INSTITUTE). (1979b). Bioassay of 3-Nitrc-p-acetophenetide
for Possible Carcinogenicity. -National Institute of Health, DHEW Publ. No. (NIH)
79-1388.
NESTMANN, E.R.; LEE, G.G.-H*; MATULA, T.I.; DOUGLAS, G.R.; and MUELLER, J.C.
(1980). Mutagenicity of constituents identified in pulp and paper mill effluent
using the Salmonella/mammalian-microsotne assay. Mutat. Res . 79:203-212.
NTP (NATIONAL TOXICOLOGY PROGRAM). (1983). Chemicals on Standard Protocol
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POWERS, M.B; (1979). Memorandum for the Record from the NTP Chemical Selection
Group, Toxicology Branch, CGT, DCCP, National Institute, Washington, D.C., May
25, 1979-
14-30
-------
ROCHE, S,M., and MINE, C.H. (1968). The teratogenicity of some industrial
chemicals. Toxicol. Appl. Pharmacol. 12:327.
SNOW, L.; KACNAIR, P.; and CASTO, B.C. (198O. Mutagenesis testing of toluene
in Salmonella strains TAlOO and TA98, Report prepared for the U.S. EPA by
Northrup Services, Inc., P.O. Box 12313, Research Triangle Park, NC 27709.
TATRAI, E.; HUDAK, A.; and UNGVARY, G. (1979). Simultaneous effect on the rat-
liver of benzene, toluene, zylene and CCL'J. Acta. Physiol. Acaci. Sci. Hung.
53(2):261.
TOUTANT, C., and LIPPMANN, S. (1979). Fetal solvents syndrome (letter).
Lancet. 1(8130):1356.
.TRACOR JITCO, INC. (1982). Report of Audit-IBT Study No. 8S62-08810, 2^-Month
.Chronic Inhalation Toxicity and Carcinogenicity Study with Toluene in Albino
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Institute of Toxicology, Resaarch Triangle Park, NC. January 15, 1982.
-------
15. SYNERGISKS AND ANTAGONISMS AT THE PHYSIOLOGICAL LEVEL
15.1. BENZENE AND TOLUENE
Arunai studies have shown that benzene and toluene may be metabolized by
similar enzyme ays tens in the parer.chymal cells of the liver. Pawar et al.
(1976) found that the activities of hepatic aninopyrine N-detsethylase,
NADPK-linked peroxidation, and ascorbate-induced lipid peroxidation were
reduced, while acetar.il ide hydrcxylast- was increased, by either benzene
pretreata;ent or toluene pretreatment in male rats. Induction of aminopyrine
N-denethylase ar.d components of the electron transport system was seen when the
anisals were giver, p.ner.obarbital (Fawar et al., 197c; Mungikar and Pawar, 1976).
When phencbarDital was coacxir.istered with benzene or toluene, the changes in the
activity of these enzymes produced by single administration of the xenobiotios
were attenuated (Pawar et al., 1976). That induction of hepatic enzymes by
phenobarbitai affects metabolism of toluene is indicated by the reduction of
toluene toxicity (decreasea narcosis) in f stale rats or male itice given
phenobarbitai prior to intraperitoneal injection of toluene (Ikeda and Ohtsuji,
1971; Koga ana Ohaiya, 197c), and the accelerates excretion of toluene
metabolites froe female rats as described in Sections 12-3- and 12.U. (Ikeda and
Ohtsuji, 1971).
The following studies indicate that toluene has the potential for altering
the fcioactivity of benzene wr.en Riven in sufficiently large quantities. When
benzene was given in combination with toluene, the conversion of benzene to its
metabolites (phenols) was suppressed in rats (Ikeda. et al., 1972) and in mice
(Andrews et al., 1977;. Ikeda et al. (1972) administered a mixture of benzene
arid toluene (equivalent to 110 oig benzene/kg and iJ30 mg toluene/kg) intraperi-
toneal ly to female rats and observed a reduced excretion of total phenols. When
a mixture of toluene and benzene (110 mg toluene/kg and 4*10 mg benzene/kg) was
administered, hippuric acid excretion was reduced up to k hours after injection.
Induction of hepatic microsoraal enzymes by phenobarbitai prior to administration
of the mixture alleviated the suppression.
Andrews et al. (1977) co-administered ^40 or 880 mg/kg benzene and
1720 mg/kg toluene intraperitoneally to mice and found a significant reduction
in urinary excretion of benzene metabolites and a compensatory increase of pul-
monary excretion of unmetabolized benzene. When toluene and benzene were coad-
15-1
-------
ministered by subcutaneous injection, toluene did not significantly change the
total amount of benzene found in fat, liver, spleen, blood, or bone marrow, but
it did reduce significantly the accumulation of metabolites in these tissues.
Coadrainistratior. of toluene and benzene also counteracted benzene-induced reduc-
cq
tion of red eel] J'Fe uptake in developing erythrocytes, suggesting that the
myelotoxicity of benzene might be attenuated by toluene-inhibition of benzene
metabolism in the bone marrow. In an ir\ vitro study with a liver microsorae
preparation, Andrews and coworkers (1977) determined that toluene is a competi-
tive Inhibitor of benzene metabolism.
In the studies of Ikeda et si. (1972) and Andrews et al. (1977">, benzene and
toluene were administered intraperitoneally in large amounts. Sato and Nakajima
(1979), however, used doses in the range of 2*4.2 to 390.6 mg/kg of benzene and
23.6 to U6G.8 rag/kg of toluene tc assess the effects of concentrations that Eight
be found in the workplace. They found that when benzene was given to rats in the
range of 24.2 to 97=7 mg/kg, there was no significant difference in the rate of
disappearance of benzene from the blood whether the benzene was administered
singly or in coraDination with an equimolar amount of toluene. At a dose of
390.6 mg/kg benzene, an equimolar dose of toluene delayed the disappearance of
benzene from blood, and the excretion of phenol was reduced. A dose-dependent
inhibition of the metabolism of benzene by toluene was found. In a study of
human exposure, inhalation of a mixture of 25 ppm benzene and 100 r?10 toiuene for
2 hours did not exert any influence on the disappearance rate of benzene and
tcluene in either blood or end-tidal (alveolar) air when compared to inhalation
of either solvent singly. Desaturation curves (concentration versus time) for
blood or en^-tidal air for each solvent after inhalation of the specified mixture
were virtually identical to desaturation curves obtained after inhalation of the
same solvent (25 ppm benzene or 100 ppm toluene) by itself. These results
indicate that in the range of threshold limit value "the pharmacokinetic
processes ... of absorption, distribution, excretion, and metabolism ef either
benzene or toluene are not influenced by simultaneous exposure to the other"
(Sato and Nakajima, 1979). The data for the single-solvent exposures had been
published previously (Sato et al., 1974); details of the experiment with toluene
were discussed in Section 12.4.
15.2. XYLENES AND TOLUENE
When 0.1 m£/kg cr 0.2 mJL/kg toluene was co-administered with similar doses
of m-xylene intraperitoneally into male rats, the amounts of hippurjc and
15-2
-------
o-methylhippuric acid excreted in urine over a period of 21 hours were not
different from the amount of metabolites formed by single injections of toluene
or m-xylene. The velocity of excretion of metabolites in the simultaneously
injected group was slightly slower than that in the singly injected groups.
Thus, simultaneous administration of the compounds does not significantly inter-
fere with the metabolism of either compound (Ogat.a and Fujii, 1979).
To study the excretion kinetic interactions between toluene and xylene,
Riihimaki (1979) determined the conjugation and urinary excretion of metabolites
of toluene m-xylene, benzoic acid and methylbenzoic acid in vivo in one adult
human male. Forty-one mmol benzoic acid or 7-4 mmol methylbenzoic acid was
ingested singly or in combination by the subject. Urine was collected for 25 to
30 hours after ingestion; the total recovery of the ingested compounds with the
exception of one sample (84$ of the dose excreted in that case) indicated that
all elimination took place via the kidneys. Combined intake of methylbenzoic
acid and benzoic acid did not significantly affect conjugation or excretion of
either'metabolite. This study indicates that during simultaneous exposures to
toluene and JB-xylene, even at relatively high occupational exposure levels,
conjugation and excretion of metabolites are not likely to be rate-limiting steps
except under conditions of lirrxted availability of glycine.
15.3- TOLUENE AND OTHER SOLVENTS
Simultaneous intraperitoneal injection of 1.18 g/kg toluene and 0.91 g/kg
n-hexane into female rats did not affect the concentrations of _n-hexane in the
blood nor excretion of hippuric acid (Suzuki et al., 197*O .
Impaired peripheral (ta;l) nerve function (as indicated by'decreased motor
nerve conduction velocity and mixed nerve conduction velocity, and increased
distal latency) was observed in rats after 8, 12, and 16 weeks' exposure to 1000
ppm ji-hexane for 12 houru/day (Takeuchi et al., 1981). Similar exposure to a
mixture of 1000 ppm n-hexane plus 1000 ppm toluene resulted in only slight
impairment, and exposure to 1000 ppm toluene alone had a negligible effect on the
above indices. Clinical signs of neuropathy were not observed in any of the
groups throughout the experiment.
Coadministracion of ethanol by ingestion and toluene by inhalation
(1060 ppm, 6 hours daily, 5 days a week for *4 weeks) to rats did not change the
electrocardiogram, hematocrit values, or histological and histochemical struc-
ture of the heart. Toluene increased vascular resistance of the myocardium and
reduced cerebral blood flow, while alcohol ingestion reduced arterial blood
15-3
-------
pressure, the cardiac index, and blood flow to the myocardium, kidney, skin, and
carcass. Myocardial and cutaneous vascular resistance, as well as cerebral blood
flow, increased after alcohol ingestion. li was concluded that combined exposure
to the two substances produced additive effects on myocardial vascular resis-
tance (Morvai and Ungvary, 1979). During subchronic exposure of rats to toluene
and ethanol, there is a potentiation of microsomal and mitochondrial changes in
the liver (Hudak et al., 1978). Ethanol administered to rats in single oral
doses of 4 g/kg enhanced the _in vitro metabolism of toluene without causing an
increase in the microsomal protein and cytochrome P-<450 contents (Sato et al.,
1981). The enhancement was greatest (about twofold) at the time when ethanol was
disappearing from the body, i.e., 16 to 18 hours after ethanol administration.
Smyth et al. (1969) suggested in a study of joint toxic action that
perchloroethylene is capable of enhancing the toxicity of orally administered
toluene in rats. Withey and Hall (1975) observed that intubation administration
of trichloroethylene and toluene to rats, in combinations of mixtures at five
different dcse levels, revealed a departure from an additive model. They
concluded that the effect of co-administration of the solvents could not be
described in terms of synergism or potentiation until further studies were made.
Ikeda (197^) found that coadministration of trichloroethylene and toluene
(730 mg/kg and J430 mg/kg, respectively) to rats by the intraperitoneal route
reduced the amounts' of metabolites of both solvents compared with amounts
excreted after administration of either solvent alone.
15.4 REFERENCES
ANDREWS, L.S.; LEE, E.W.; WITHER, C.M.; KOCSIS, J .J.; and SNYDER, R. (1977).
Effects of toluene on the metabolism, disposition and hemopoietic toxicity of
(SH)benzene. Biochem. Pharmacol. 77(4):293-300.
HUDAK, A.; SZEBERENYI, S.; MOLNAR, J.; CSEH, I.; SUVEGES, M.; FOLLY, G.; MANYAI,
S.; and UNGVARY, G. (1978). Effect on liver of chronic exposure to toluene and
ethanol in rat. Acta Physiol. Acad. Sc i. Hung. 5U1-2): 128.
IKEDA, M. (1974). Reciprocal metabolic inhibition of toluene and trichloro-
ethylene in vivo and in vitro. Int. Arch. Arbeitsmed. 33(2):125-130.
15-1
-------
IKEDA, M.; OHTSUJI, H-; and IMAMURA, T. (1972). In vivo supression of benzene
and styrene oxidation by coadjninisterred toluene in rats and effects of4 phenobar-
bital. Xenobiotica. 2(2): 101-106.
IKEDA, M., and OHTSUJI „ H. (1971). Phenobarbital-induced protection against
tbxicity of toluene and benzene in the rat. Toxicol. A£p_l_. Pharmacol .
20 rO: 30- '13.
KOGA, K,, and OHMIYA, Y. (1978). Potentiation of toluene toxicity by hepatic
enzyme inhibition in mice. J_. Toxicol. Sci. 3( 1 ): 25-29.
MORVAI, V., and UNGVARY, G. (1979). Effects of simultaneous alcohol and toluene
poisoning on the cardiovascular system of rats. Toxicol. Appl. Pharmacol .
50(3J.: 38 1-389.
MUNGIKAR, A.M., and PAWAR, S.S. (1976). The effect of toluene, phenObarbital
and 3-nethylcholanthrene on hepatic microsomal lipid peroxidation. Curr. Sci .
OGATA, M., and FUJII, T. (1979). Urinary excretion of hippuric acid and m-
methylhippuric acid after administration rf toluene and m-xylene mixture to
rats. Int. Arch. Occup. Environ. Health. ^3( 1): 1*5-51.
PAWAR, S.S.; MUNGIKAR, A.M.; and MAKHIJA, S.J. (1976). Phenobarbii:al induced
effect on pulmonary and hepatic microsomal ethylmorphine N-dPScthylase and lipid
peroxidation during oral intoxication of organic solvents in rats. Bull .
Environ. Contam. Toxicol . 15(5) : 357-365.
RIIHIMAKI, V.. (1979). Conjugation and urinary excretion of toluene and m-xylene
metabolites in a aan. Scand. J_, Work Environ. Health. 5(2): 135-1*42.
SATO, A.; NAKAJIMA, T.; FUJIWARA, Y.; and HIROSAWA , K. (1974). Pharmacokinetics
of benzene and toluene. Int. Arch. Arbeitsmed. 33(3) : 169-182.
15-5
-------
\
SATO, A., and NAKAJIMA, T. (1979). Dose-dependent metabolic interaction between
benzene and toluene ^n vivo and ^n vitro. Toxicol. Appj.. Pharmacol.
US(2):2^9-256.
SATO, A., NAKAJIMA, T. and KOYAMA, Y. 1981. Dose-related effects of single dose
of ethanol on the metabolism in rat liver of some aromatic and chlorinated
hydrocarbons. Toxicol. Appl. Pharmacol; 60: 8-15.
SMYTH, H.F., Jr.; WEIL, C.S.; WEST, J.S.; and CARPENTER, C.P. (1969). Explora-
tion of joint toxic -action: Twenty-seven industrial chemicals intubated in rats
in all possible pairs. Toxicol. Appl. Pharmacol. 11(2):340-3^7.
SUZUKI, T,; SHIMBO, S.; and NISHITANI, H. (WO. Muscular atrophy due to glue
sniffing. Int. Arch. Arbeitsmed. 33(2):115-123.
TAKEUCHI, Y.; ONON, Y.; and HISANAGA, N. (1981). An experimental study on the
I
combined effects of n-hexane and toluene on the peripheral nerve of the. rat.
Brit. Jour Indus. Med. _3_8: 14-19.
WITHEY, R.J., and HALL, J.W. (1975). Joint toxic action of perchloroethylene
with benzene or toluene in rats. Toxicology. M(1):5-15.
15-6
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16. ECOSYSTEM CONSIDERATIONS
16.1. EFFECTS ON VEGETATION
16.1.1. Introduction. Toluene volatilizes rapidly from solutions (Mackay and
Wolkoff, 1973)« Most studies investigating the phototoxicity of toluene have
been with algae. Of thsse studie's, only one (Dunstan et al., 1975) was done
under conditions that maintained a nearly constant concentration of toluene in
the culture medium throughout the experiment. Other studies were done with
culture vessels capped with metal caps or with cotton plugs, allowing the toluene
to volatilize and escape from the exposure solutions. Even though steady-state
concentrations are lacking, these studies do approximate situations in the
environment where a point source of toluene exists to a body of water. The
discussion of these studies will, therefore, be under the headings of "closed"
and "open" experimental systems.
16.1.2. Effects of Toluene on Plants.
16.1.2.1. ALGAE
16.1.2.1.1. Closed .System Studies — Dunstan et al. (1975) exposed *4
marine algal species to toluene concentrations ranging from 1 to 10
Axenic algal cultures were inoculated at 18=C and grown with a 12-hour light/dark
cycle under cool-white fluorescent light C4000 nW/cm , 380 to 700 nm) in
filtered enriched seawater. To minimize loss of toluene by vaporization, thj
125 m£, Erlenmeyer flasks were made airtight with rubber stoppers. Experiments
were never run beyond a cell density at which C0? limitations might limit growth.
The four species used were the diatom, Skeletonema costatum; the dinoflagellate,
Amphidinium carterae; the cocolithophorid, Cricosphaera carterae; and the green
flagellate, Dunaliella tertiolecta.
To illustrate the difficulty of establishing absolute concentration when
working with toluene, Dunstan et al. (1975) observed the toluene concentrations
at three intervals in stoppered flasks (Table 16-1). Eighty-four percent of the
theoretical initial concentration was lost at the beginning of the experiment
during the handling and dispensing of the toluene into culture flasks, even when
the toluene was rapidly dispensed under sterile conditions.
Figure 16-1 shows how toluene can both stimulate and inhibit algal growth
depending on the species and the concentration of toluene. The dinoflagellate,
Amohidinium carterae. was inhibited at all concentrations of toluene (1 to
16-1
-------
TABLE 16-1
Concentrations of Toluene in Stoppered FJasks
Time of Measurement Percent of Theoretical
Concentration
Theoretical initial concentration 1C?
Measured initial concentration 16
Concentration after 3 days of growth
Stoppered flask 14
Cotton-plugged flask 1
Source: Dunstan et al., 1975
16-2
-------
150-,
UJ Z
UJ
K
I
O
cc
o
UJ
a.
100-
50-
0-fv\A
1
150-,
150-,
Amphidmium cartorM
UJ Z
P °
3£
Q.
UJ
' I O
100-
50-
10
103
10*
10
CONCENTRATION
Ul Z
-> o.
UJ —
CC -I
l§
§1
100-
50-
Skeleton»ma costatum
102 103 104
CONCENTRATION (jif /8)
uj z
^ ec 100-
-J Q.
UJ —
EC _l
§5 50
c
°
105
Dunsliefla tertk>l»cU
^Qi 'O3
CONCENTRATION
10*
10a
Cricotphaoru cwtaro
10Z 10J
CONCENTRATION
TO4
FIGURE 16-1
Phytoplankton Growth in Various Concentrations of Toluene (Organisms were grown
in stoppered flasks. Growth, cieasured by cell numbers and in vivo chlorophyll,
was determined on the 2nd and 3rd days of logarithmic growth. Concentrations of
low molecular weight hydrocarbons are In theoretical values.)
Source: Dunstan et al., 1975
16-3
-------
10 ng/X.) from 20 to 50%. The other three species, however, were stimulated by 1
li
to 10 ng/H, but- higher concentrations of toiuene either had no effect
(Dunaliella tertiolecta) or became inhibitory (Skeletonema costatum and
Cricosphaera carterae). This work indicated that one of the most significant
environmental effects was in the short-term selection of certain phytoplanktonic
species by the growth stimulation brought about by low levels of toluene.
Dunstan et al. (1975) concluded that the differential growth of phytoplanktonic
species within the phytoplankton population ultimately determines the community
structure, its succession, and its trophic relationship.
Potera (1975) evaluated the effect of toluene on saltwater phytoplankton
dominated by Chlorella sp. using Warburg manometry. Toluene inhibited photo-
synthesis 29% at 3^ mg/4, and 35$ at 342 mg/2. (at 20=C). Respiration (at 20=C)
wan inhibited 62% at 34 mg/JL and 16J at 342 mg/fc.
16.1.2.1.?. Open Studies — Illustrative of the "open" type of experiment
is that of Kauss and Hutchinson (1975). The freshwater alga, Chlorella vulgaris,
was exposed to toluene for 10 days in 125 m2, cotton-plugged Erlenmeyer flasks.
Each flask was agitated to resuspend the cells daily. The concentrations listed
in Figure 16-2 are nominal initial concentrations. In this open experiment,
toluene was less toxic to the alga because the toluene concentration diminished
by volatilization during the experiments. Comparison with controls revealed
that a lag phase that lasted for 1 day existed between inoculation and
commencement of growth for 50 and 100 mg/J,. Recover;, was less rapid with
250 mg/i. At concentrations approaching toluene saturation (i.e., 505 mg/£),
toluene was lethal to the cells.
Table 16-2 summarizes the toxic effects of toluene on algae. In assessing
the toxicity of toluene to algae, both the inherent toxicity of toluene and the
exposure time need to be considered. The no-effect concentration for sost algal
species studied appears to be at the 1C mg/£, level. The evaporation rate from
solution (fresh or saltwater), however, rapidly diminishes the exposure concen-
tration of toluene (Dunstan et al . , 1975). The toxicity of toiuene is more
closely approximated by levels of 100 mg/i. in "open" systems, as ?hown by Kauss
and Hutchinson (1975).
16.1.2.2. EFFECTS ON HIGHER PLANTS — Currier (1951) exposed barley,
tomatoes, and carrots to toluene vapor. Air at a flow rate of 11.5 K./min passed
through a small vaporizing chamber containing the toluene and into the top of a
bell jar containing the plants. The concentration of toluene in ~he vapor
16-4
-------
3
CM
. O——O lOOppm
A • * ZSOppro
468
T!ME(DAYS)
FIGURE 16-2
Growth of Chlorella vulgaris in Medium Containing Toluene (Data plotted are
the average of three replicates. Lines of best fit were determined using
regression coefficients. Numbers represent initial hydrocarbon concentration
on a parts per million basis. The arrow on the ordinate indicates starting
cell concentration.)
Source: Kauss and Hutchinson, 1975
16-5
-------
TABLE 16-2
Toxic Effects of Toluene to Algae
Species
Concentration
Effect
Reference
FRESHWATER
Chi or el la vulgaris 245 mg/J.
Chlorella vulgaris 250 mg/X.
Microcystis aeruginosa 105 mg/i,
Scenedesiaus quadricauda >400 mg/£
2H h ECCO
(cell number)
96 h no-effect cone.
(cell number)
8 d no-effect cone.
(chlorophyll _a)
8 d no-effect cone.
(chlorophyll a)
Kauss and Hutchinson,
1975
Kauss and Hutchinson,
1975
Bringmann and Kuhn,
1978
Bringniann and Kuhn,
1978
SALTWATER
Amphidinium carterae <0.001 Eg/2,
Dunaliella tertiolecta 10 mg/i
Skeletonena costatura
Ectocarpus sp.
Enteromorpha sp.
10 mg/S,
Cricosphaera carterae 10 mg/i.
1730 mg/S.
1730 mg/«.
2 to 3 d no-effect
cone, (cell number
and chlorophyll)
2 to 3 d no-effect
cone, (cell nuinber
and chlorophyll)
2 to 3 d no-effect
cone, (cell number
and chlorophyll)
2 to 3 d no-effect
cone (cell nuinber
and chlorophyll)
inhibits asexual
spore germination
inhibits asexual
spore germination
Duns tan et al.,
1975
Duns tan et al.,
1975
Dunstan et al.,
1975
Duns tan et al.,
1975
Skinner, 1972
Skinner, 1972
h s hour; cone. = concentration; d = day.
16-6
-------
chamber was varied by changingithe temperature of the toluene. The concentration
of vapor in the air was determined by measuring the amount of toluene evaporated
per unit of time. Three tomatoes, 20 carrots, and 12 barley seedlings were
tested 32, 32, and T< days respectively after planting. Plants were exposed in
the gas chamber for 1M, 1/2, 1, and 2 hours. Ths type and extent of injury were
recorded after 'i month to allow for a recovery period. Temperature of the plants
was held at 25°C.
Results showed that toxic effects of toluene vapor were influenced by expo-
sure period and dosage (Table 16-3). Toluene was observed to be toxic at
concentrations of 6.4 to 12.0 mg/JL after 15 minutes of exposure (Currier, 1951).
Fifteen minutes of exposure at 12 mg/i. toluene produced a 50. 0, a:>J 60J injury
to tomato, carrot, and barley, respectively. The effects of ^he exposures on
flower and fruit development were not determined. For lethality to occur at
12.0 mg/i, barley required 1 hour, tomato 2 hours, and carrot over- 2 hours. The
toxicity appeared to vary markedly within a narrow limit. By lowering the
concentration of toluene from 12.0 to 6.4 mg/S,, the percentage of injury to
barley after a 2-hour exposure was reduced from 100$ (lethal) to 15J. At
24.1 mg/£, toluene was only twice as toxic to barley seedlings as at 12.0 mg/S,
after a 30-minute exposure.
Toluene entered the plant rapidly through the cuticle and stomata. Symptoms
of injury included a darkening of the tips of the youngest leaves, presumably as
a result of leakage of sap into the cellular spaces (Currier, 1951). This
darkening spread to the older leaves. There was a loss of turgor, with draping
stems and leaves. In bright sunlight, the chlorophyll was destroyed.
Toluene is classified as a contact poison that quickly kills the plant
tissue with which it comes in contact (Currier, 1951). This material is not
accumulated in plants nor is it translocated. The nech.anj.sm of toxicity involves
disorganization of the outer membrane cf the cell due to solvent action on the
lipoid constituents, resulting in disruption of photosynthesis, respiration, and
turgor pressure.
16.2. B10CONCENTRATION, BIOACCUMULATION, AND BIOMAGNIFICATION POTENTIAL
Limited information is available concerning toluene's potential for accumu-
lating in aquatic organisms and aquatic food chains. Possible pathways of
toluene uptake *"••? dirtily rrom water (bioconcentratlon) and from both water and
food (bioaccumulation). Biomagnification occurs if the concentration of a com-
16-7
-------
TABLE 16-3
Toxic Effects of Toluene Vapor pn Carrots, Tomatoes, .and Barley
Percent Injury
Material
Tomato
Carrot
Barley
Barley
Barley
Concentration
12.0 mg/JZ.
12.0 ffig/ I
12.0 mg/i
6.H mg/£.
2U.1 mg/J.
Exposure Time (h)
1/4
50
0
60
0
ND
1/2
60
50
50
25
100
1
75
75
98
15
100
2
100
75
100
15
ND
Source: Currier, 1951
0? = no effect; 100} = lethal 1 month after exposure.
h = hour; ND = not determined.
16-8
-------
pound in an organism increases with its trophic level as a result of passage
through rood chains.
Nunes and Benville (1979) studied the uptake and depuration of toluene and
other monocyclic aromatic components of the water-soluble fraction (WSF) of
Alaskan Cook Inlet crude oil in Manila clams (Tapes aemidecussata). Claina were
exposed for 8 days to a constant WSF concentration under continuous-flow exposure
conditions. The toluene concentration in water was measured daily. The toluene
concentration in a pooled sample of 10 clams was measured at 2, 4, 6, and 8 days.
At the end of the exposure period, remaining clams were transferred to
clean-flowing seawater and pooled tissue samples were analyzed for toluene after
1, 7, and 12 days of depuration. The data are provided in the following tabula-
tion:
Toluene Concentration (ppm)
Exposure
Depuration
Davs
1
2
3
14
5
6
7
8
1
7
Water
1.2
1.3
1.7
1.14
1.2
0.9
1.0
1.1
Tissue
2.3
2.2
0.87
2.0
3.30
0.80
1.10
The mean water concentration during the uptake period was 1.2 ppm toluene.
Tissue concentrations reached a maximum by 2 days of exposure and remained
relatively constant except for a temporary decline on day six. The average
tissue concentration during the exposure period was 1.5 ppm. The calculated
bioconcentration factor (BCF) is 1.25 (which is equivalent to 1.5 ppm in tissue
and 1.2 ppm in water). The depuration study showed that to_luene was lost rapidly
during the first week of depuration, but that a significant concentration of
toluene remained in the clams by 2 weeks after beginning depuration.
iij
Hansen et al. (1978) investigated the uptake and depuration of C-toluene
by blue mussels (Mytilus edulis). Groups of mussels were exposed under static
conditions to four concentrations of C-toluene for up to 8 hours, followed by
16-9
-------
exposure to clean, recirculating seawater for up to 192 hours. The C-toluene
concentration in water and tissue (pooled sample from four mussels) was measured
by liquid scintillation counting at 1, 2, *», and 8 hours after beginning the
uptake phase and periodically in tissue during the depuration phase.
The C-toluene concentration in tissue exceeded the water concentration by
1 hour at all exposure concentrations except the highest (^0 pi/kg = ppm), which
was toxic as shown by closure of the missels at this concentration (Hansen
et al . , 1978). Equilibrium was reached by 1 hours in all groups. The BCF values
at 8 hours, expressed as the tissue concentration divided by the mean water
concentration, were as follows:
Water concentration
BCF
0.05 3-8
O.H 5.7
4.0 3.6
U.O 3.6
The BCF values, which averaged U.2, seemed to be independent of the exposure
concentration, indicating that accumulation was proportional to the level in
water (Hansen et al., 1978). More than half of the accumulated C-toluene was
eliminated by 1 hour after the depuration phase began at all exposure concen-
i ii
trations. The depuration time by which no C-tbluene was detectable in tissue
1 4
was 1 hour in the mussels exposed to 0.05 ui C-toluene/kg, 4 hours for those
exposed to O.U uA/kg, 120 hours for those exposed to 4 jiJl/kg, and 192 hours for
the animals exposed to UO ufc/kg.
Lee et al . (1972) reported that the same species of mussel (Mytilus edulis)
took up 3 to 10 ng of C-toluene per mussel (average dry weight tissue r 0.3 g)
during static exposure for an unspecified period of time to 0.1 to 0.5 mg/Jl.
Using tissue toluene concentrations of 10 to 33 ug/g, the BCF is calculated to
have been, between 66 and 100. Because these values are based on dry tissue
weights rather than wet weight, they are considerably higher than those reported
by Nunes and Benville (1979) and Hansen et al. (1978).
Berry (1980) investigated the uptake of l4C-toluene by bluegill sunfish
(Lepomis macrochirus) and crayfish (Orconectes rustlcus). The exposure solu-
1ii
tions were prepared by adding 1 mJl of C-toluene to 100 I of water for the fish
16-10
-------
experiment and by adding 1 mS, C-toluene to 10 I of water for the crayfish
experiment. A group of 1*0 animals was added after thorough mixing of the solu-
tions. Duplicate water samples and 2 to 4 animals were taken at 0, 0.5, 1, 2, 4,
8, 12, 16, 20, 2^, and 48 hours after beginning exposure. The C-toluene
concentration, expressed as nanograms per milligram ( = ppm), was determined in
water and in 7 (crayfish) or 9 (fish) tissues or organs by liquid scintillation
counting. The BCF for each tissue was also calculated. Analysis of water
samples showed that the toluene concentration in water decreased at a much
greater rate in the crayfish experiment than in the bluegill experiment (89J
versus 51? loss by 48 hours). The maximum BCF of bluegill tissues ranged from
about 3 for brain to 45 for spleen. Fish muscle tissue was not analyzed. The
maximum BCF for most fish tissues was reached by 8 hours. The maximum BCF of
crayfish tissues ranged from about 8 for muscle to 140 for hepatopancreas. The
B.CF values increased throughout the 48-hour exposure period for all tissues
except testes and muscle. These results indicate that toluene is accumulated
above the water concentration by many tissues in these two species. The BCF of
eight in the edible portion (muscle) of crayfish is considered to be a minimum
' value bf .ause of the rapidly decreasing toluene exposure concentration during
this experiment.
Berry et al. (1978) also measured the uptake of ^K-toluene by fed and unfed
mosquito (Aedes aegypti) larvae and the uptake of H-toluene by fed larvae in the
presence or absence of benzene. The larvae were exposed to an initial concentra-
tion of 0.5 m£ ^H-toluene/Jt, water. Duplicate water samples and 2 to 5 larvae
were taken at 1, 2, 4, 8, 12, 15, 20, and 24 hours and counted individually by
liquid scintillation counting. Maximum ^H-toluene counts per minute (cpm) were
equal in fed and unfed larvae, but were reached more quickly (1 hour versus
4 hours) by the fed animals. The K-toluene counts per minute values in larvae,
expressed as the percentage of initial water counts, were greater during the
first 4 hours in the benzene and toluene mixture than in the solution containing
toluene alone. BCF values cannot be calculated because the authors expresssed
H-toluene uptake as counts per minute per larvae rather than counts per minute
per gram. The weight of the larvae was not provided. Interpretation was also
complicated by rapid loss of ^H-tbluene (half-time about four hours) during the
uptake period. It is likely, however, that uptake by ingestion of toluene
adsorbed to food particles can be a significant route of accumulation in aquatic
organisms.
16-11
-------
Ogata and Miyake (1973) identified toluene as the cause of offensive odor in
the flesh of grey mullet (Hugil Japanicus) taken from a harbor receiving efflu-
ents from refineries and petrochemical industries. Toluene was identified in
seawater and fish tissue by gas chromatography, infrared (IR) and ultraviolet
(UV) absorption, cind mass spectrotnetry. The toluene concentration in most fish
was not quantified; however, the flesh of one mullet with an offensive odor con-
tained 5 pp« toluene. Additional exparioNentj showed that toluene was accumu-
lated by caged eels kept for 10 days in several locations in the harbor to an
average of 2.** times the water concentration-. These eels had the same offensive
odor as mullet collected from the harbor. In another experiment, four eels were
exposed in seawater to which a mixed solution of benzene, toluene, and xylenes
was added daily for 5 days. The concentration of each chemical was then measured
in seawater, muscle, and liver. The results with toluene were as follows:
Toluene Concentration
Fish No. (ppm) BCF
Muscle 1 11.2 0.70
2 2.6 0.16
3 5.1 0.32
U 30.8 1.91
Mean 12.4 0.77
Liver 1 9.0 0.56
2 2.5 0.1C
3 5.2 0.32
U 2.5 0.16
Mean U.8 0.30
Water — 16.1
The results indicate that BCF in muscle was equal to or greater than the BCF in
liver and that tissue concentrations rarely exceeded the water concentration.
In later experiments, Ogata and Miyake (1978) found that eels (Anguilla
Japonica) accumulated toluene to whole-body concentrations greater than the
water concentration in freshwater. For this study, the authors studied the
uptake and elimination of toluene by eels exposed in freshwater to crude oil.
The animals were exposed for 10 days to a recirculating oil suspension (50 ppm,
w/v), yhich was renewed every day. During this period, the toluene concentration
was meadured in pooled groups of 5 eels taken on 1, 5, and 10 days after
beginning exposure. The concentration of toluene in water was measured each day
16-12
-------
at 1, 3, 6, 9, 1J4.5, and 24 hour? after preparing the crude oil suspensions. The
regaining eels were then transferred to clean seawater and sampled after 3> 5,
and 10 days of depuration. The average toluene concentration in Water during the
uptake period was 0.130 ppm. The concentration in eels was 0..641 ppm after
1 day, 1.547 ppm after 5 days, and 1.718 ppm after 10 days. The respective BCF
values were 4.9, 11.9, and 13.2. A semilogarithmic plot of the logarithm of
tissue concentration versus time indicated that equilibrium had not quite been
reached by 10 days. The depuration phase of the experiment showed that tissue
concentration decreased rapidly from 1.718 ppra at the beginning of depuration to
0.31b ppm after 3 days, 0.121 ppra after 5 days, and 0.035 ppm after 10 days. A
sem'ilog plot showed that toluene was eliminated in 2 phases. The elimination
half-time during the first phase, lasting from 0 to 5 days, was 1.4 days. About
93J of the accumulated toluene was eliminated by the end of this period. The
remaining toluene was eliminated at a somewhat slower rate, with about 2% of the
accumulated toluene remaining after 10 days of depuration.
The only information found concerning fo.od-chain transfer of toluene is
provided by Berry and Fisher (1979). who exposed mosquito larvae (Aedes aegypti)
• ji
to C-toluene for 3 hours and then fed them to bluegill sunr'ish (Lepomis
macrochirus). In duplicate experiments, e,;ch of 25 fish in separate containers
were fed with 10 contaminated larvae. The mean level of radioactivity in 10
larvae was 736 cpm in the first experiment and 3196 cpm in the second experiment.
Internal organs (spleen, gall bladder, liver, stomach, intestine, and kidney)
from 5 fish, sampled at each interval of 1, 4, 8, 24, and 48 hours after feeding,
were analyzed for radioactivity by liquid scintillation counting. Radioactivity
was expressed as counts per minute per organ rather than or. a weight basis. The
only organ that had counts per minute values significantly greater than back-
ground levels was the stomach at 1, 4, and 8 hours after feeding. The authors
concluded that an insignificant amount of toluene, if any, leaves the digestive
tract to be accumulated in other organs of sunfish. The validity of this
conclusion is unknown because the dose was so low that absorption, if it had
occurred, could not have been differentiated from background counts and because
the counts were not expressed on a tissue weight ^asis, even in the stomach.
In summary, the available information indicates that the primary path of
toluene uptake in aquatic organisms is direct absorption from water. The
reported or calculated BCF values for the edible portion or the whole organism
ranged from <1 to about 14, indicating that toluene has a low bioconcentration
16-13
-------
potential. These BCF values are lower than the value predicted on the basis of
the relationship established between octanol-water partition coefficient (P) of
lipophilic compounds and .steady-state BCF (Veith et al., 1979). This relation-
ship, expressed by the equation I:log BCF 5 (0,85 log P) - 0.70," would predict a
BCF of 39, using a log P value of 2.69 for toluene (see Subsection 3.4.2.).
Low bioconcentraton potential, rapid depuration, and the ability of fish to
metabolize toluene all indicate that toluene is unlikely to biomagnify through
aquatic food chains. Aquatic organisms do accumulate toluene, however, and con-
centrations in edible species from polluted areas have reached levels that cause
organoleptlc effects'in humans (Ogata and Miyake, 1973).
16.3. EFFECTS ON MICROORGANISMS
Toluene has been used for quite some time as an antimicrobial agent.
Sabalitschka and Preuss (1954) sterilized a urine sample containing Escherichia
coli and Pseudomonas fluorescens within 24 hours with 4000 mg/S, toluene.
Threshold concentrations for toluene have been established by Bringmann and Kuhn
(1959., 1976, I960) and Bringmann et al. (1977) for various microorganisms.
These investigators reported values of 29 mg/JL for P_. putida, 200 mg/Jl for IE.
coli, and greater than 450 mg/2, for the ciliated protozoan Uronema parduczi.
Partial sterilization of soil was achieved by adding toluene to the soil (Pochon
and Lajudie, 1948).
The effects of toluene on bacterial activity and growth have also been
studied. As measured by methane evolution rates, 20 mg/£, toluene increased the
growth rate of bacteria in sewage sludge deposits, while 200 mg/S, produced a
toxic effect (Barash, 1957). Similarly low levels of toluene allowed good growth
o' jp. putida and Nocardia sp., while saturation levels (515 mg/& at 20°C) were
toxic (Gibson, 1975). Depending on the concentration (173 to 17,300 mg/X,), a
rotifer (Dicranophorus forcipatus) was unaffected, or temporarily inhibited, or
permanently inhibited by toluene (Erben, 1978). Death and disintegration of
rumen ciliates occurred between 460 and 645 mg/2, of toluene (Eadie et al., 1956).
At sublethal concentrations (1000 and 6000 mg/£,), toluene caused a negative
chemotactic response or totally inhibited the chemotatic response of all marine
bacteria tested (Mitchell et al., 1972; Ycung and Mitchell, 1973). Although the
effects were reversible, the authors of the 1972 paper expressed concern that the
inhibition could seriously undermine the capacity of the marine microflora to
control the self-purification processes in the sea. Beck and Poschenrieder
(1963) found that high concentrations of toluene (50 to 100,000 mg/g of soil)
16-14
-------
suppressed soil microflora activity. In addition, they found that gram-positive
bacilli sporeformers, streptomycetes, and cocci were especially resistant, while
gram-negative bactrr-ia were sensitive.
Toluene has been shown to affect the integrity of the inicrobial cell wall
and cytoplasmic membrane (Dean, 1978). Thompson and Macleod (1974) reported that
marine pseudomonad cells washed and suspended in 0.5 M Nad were lysed by treat-
ment with 20,000 mg/Ji toluene and released 95? of the cells' alkaline phos-
phatase. Because the cells remained intact with 0.05 M MgSO. and 20,000 mg/S.
toluene, the authors concluded that Mg ions prevented cellular disruption by
strengthening the integrity of the cell wall. Woldringh (1973) established that
a 2500 mg/2, solution of toluene partially dissolved the inner cytoplasmic
memorane of E). coli and displaced nuclear material to the periphery of the cell.
DeSmet et al. (1978) reported that at 100,000 mg/2, toluene, the cytoplasmic
membrane was completely disorganized. The presence of Mg ions at lower toluene
concentrations (up to 10,000 mg/2.), however, prevented extensive damage to the
cytoplasmic membrane and loss of intracellular material; thus, permeability
depended on the integrity of the outer membrane (DeSmet et al., 1978). Deutscher
(197^) found that the effects of tolrene treatment were dependent on various
cultural conditions including pH, temperature, Mg ion concentration, and age of
the culture. Temperature-dependent effects of toluene treatment were also
reported by Jackson and DeMoss (1965). Toluene changed the asymmetric unit
membrane profile to a symmetric profile in vegetative cells of Bacillus subtil is
and caused gaps in the membrane to appear (Silva et al., 1978). Fan and
Gardner-Eckstrom (1975) found that toluene-treated Bacillus megaterium cells
liberated a membrane protein essential for- peptidoglyca synthesis and that this
protein could be added back to the membrane to reconstitute peptidoglycan syn-
thesis. Toluene at 86,000 mg/H induced the autolysij of Saccharomyces
cerevisiae, the release of UV absorbing substances from the cells, and the
deacylation of phosphoplipids (Ishida-Ichimasa, 1978). At saturation
concentrations of toluene, however, no cytolysis of yeast occurred (Lindenberg
et al., 1957). Scholz et al. (1959) noted that toluene-treated yeast cells
accumulated hexosephosphates. Bucksteeg (19^2) found that the concentration of
toluene and time of exposure determined its effect on Cytophaga sp. and
time needed to produce lethal effects. Azotobacter was more resistant than the
Cytophaga sp. Bucksteeg theorized that toluene affected the physical and
16-15
-------
i chemic?! constitution of the cell. An alteration in plaque morphology in two
coliphages (Tgrt and Tj occurred with 1% toluene (Brown, 1957).
The ability of toluene to disrupt cell membranes led to the use of this
compound as an unmasking agent in microbial research to assay a variety of
enzymes (Herzenberg.. 1959; Dobrogosz and DeMoss, 1963; Levinthal et al., 1962).
The _in vitro assays using toluene have been used to make enzymes within a cell
accessible to exogenous substrates (Jackson and DeMoss, 1965; DeSmet et al.,
1978). Generally, toluene treatment makes the cells permeable to low molecular
\ weight compounds (such as -deoxynucleoside triphosphate dNTP) and several macro-
molecules while remaining impermeable to proteins larger than ^pnroximately
50,000 daltons (Deutscher, 1974; DeSmet et al., 1978). Several investigators
have used these findings to study DNA replication in bacteria (E. c?li, B.
subtilis), bacteriophage (E. coli, Tj,), and diatoms (Cylindrotheca fusiformis)
after treating the organisms with 0.1 to 1? toluene in solution (Miller et al.,
1973; McNicol and Miller, 1975; Moses and Richardson, 1970; Matsushita et al.,
1971; Winstun and Matsushita, 1975; Sullivan and Valcani, 1976). Other uses of
toluene treated cells are in studying the synthesis of heteroribonucleotides,
' RNA, and peptidoglycan and the repair synthesis of DNA (DeSmet et al., 1978;
Moses and Richardson, 1970; Segev et al., 1973; Winston and Matsushita, 1975).
Burger (1971) showed that toluene-treated E_. coli cells continued DNA replica-
tion, but only in that chromosomal region that was about to be replicated'
iri vitro. Toluene-treated cells can also be used to study the effects of various
antibiotics in cell growth and DNA replication (Hein, 195^; Burger and Glaser,
1973).
Although the exact mechanisms of toluene-induced disaggregation of cell
membranes are not known, Jackson and DeMoss (19&5) state that the mechanisms fall
into two classes: (1) a disaggregating (autolytic) enzyme(s), perhaps syn-
thesized in the presence of toluene, or (2) a direct denaturation of cell
membrane constituents such as phospholipids; a condition inhibited by
stabilizing factors such as divalsnt cations (e.g., Mg).
16-16
-------
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DOBROGOSZ, W.J. and DeMOSS, R.D. (1963). Induction and repression of
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HERZENBERG, L.A. (1959)- Studies on the induction of beta-galactosidase in the
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ISHIDA-ICHIMASA , M. (1978). Degradation of lipids in yeast (Saccharomyce
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LINDENBERG, B.A., MASSIN, M. and GAUCHAT, G. (1957). Cytolysis of yeast caused
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MACKAY, D. and WOLKOFF , A.Q. (1973). Rate of evaporation of low-solubility
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MATSUSHITA, T., WHITE, K.P. and SNECKA. (1971). Chromosome replication in
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Winston and Matsushita, 1975).
McNICHCL, A.L. and MILLER, R.C. (1975). Biological activity of Ty DNA synthe-
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MILLER, R.C., TAYLOR, D.M., McKAY, K, and SMITH, H.W. (1973). Replication of Ty
DNA in Escherichja coli treated with toluene. J. Virol. 12: 1195-1203.
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MITCHELL, R., FOCEL, S. and CHET, I. (1972). Bacterial chemoreception. Impor-
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MOSES, R.D. and RICHARDSON, C.C. (1970). Replication and repair of DNA in cells
of Escherichia coli treated with toluene. Proc. Nat. Acad. Sci. 6j: 67^-681.
NUNES, P. and BENVILLE, P. (1979). Uptake and depuration of petroleum in the
manila clam, Tapes semidecussath Reeve. Bull. Environ. Contain. Toxicol.
21(6); 716-726.
OGATA, M. and MIYAKE, Y. (1978). Disappearance of aromatic hydrocarbons and
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16-22
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17. EFFECTS ON AQUATIC SPECIES
17.1. GUIDELINES FOR EVALUATION
Evaluation of the available information concerning the effects of toluene
on aquatic organisms must take into account several factors. A primary con-
sideration for evaluation of toxicity test results is toluene's high volatility.
The half-life for volatilization of toluene from a water column 1 m deep has been
reported to be between approximately 30 minutes (Mackay and Wolkoff, 1973) and
5 hours (Mackay and Leinonen, 1975). Benville and Korn (1977) analyzed the
toluene concentration in test containers during a 96-hour static toxicity test
and showed that the percentage of toluene lost was 48$ by 24 hours, 53% by
48 hours, and greater than 99$ by 72 hours. Korr. et al. (1979) reported that
toluene was lost at a greater rate from bioassay containers at 12°C (99$ loss by
72 hours) than at 8°C (>99$ loss by 96 hours) or at 4°C (75$ loss by 96 hours).
Potera (1975) found that the observed half-life of toluene in bioassay containers
was 16.5 jf 1.13 hours. The rate of volatilization of toluene from water varies
with the amount of mixing, temperature, surface area to volume ratio, and other
factors. Adsorption to sediments and suspended particles may decrease evapora-
tive loss and result in greater persistence of toluene. Although adsorption may
lower the concentration of dissolved toluene in the water column, binding to
sediment and suspended matter may increase the effective exposure concentration
to benthic. and filter-feeding organisms.
Most of the reported aquatic toxicity studies with toluene have used a
static exposure technique. In most cases, the LCCQ has been calculated on the
basis of initial nominal (unmeasured) or initial measured concentrations. The
test organisms in these static experiments, however, are exposed to rapidly
decreasing toluene concentrations. Most of the reported acute static toxicity
studies show little or no change in the LC5Q value between 24 and 96 hours. This
lack of change indicates that most, if not all, of the mortalities in these tests
occurred during the first 24 hours when toluene concentrations were highest. In
contrast, those flow-through studies that reported acute LC™ values at more than
one exposure period showed that LCrQ values decreased significantly with time.
Numerous other factors may affect the results of toxicity tests with
toluene. It has been shown that the acute toxicity of toluene is affected in
some cases by temperature and salinity (Section 17.3.). These effects on
17-1
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toxiclty may be due to effects o'n the test organisms (metabolism, uptake, stress,
etc.), effects on the physicochemical behavior of toluene (solubility, volatili-
zation, etc.), or interactive effects of both. For example, toluene is less
soluble in saltwater than in freshwater and is both more soluble and more vola-
tile at higher temperatures. Laboratory results may also bs influenced by t-he
loading ratio (gram organism per liter water); dissolved oxygen concentration;
age, health, and species of test organisms; and other exposure conditions, all of
which may interact to affect the results in an unpredictable manner.
Prediction of environmental effects from laboratory results must consider
the influence of the variables associated with laboratory tests and with the
natural variability intrinsic .to the aquatic environment. Results of static
acute toxicity tests with volatile compounds such as toluene may approximate the
acute toxic effects that may occar in nature to the same species during acci-
dental spills, because toluene concentrations rapidly Decrease in both situa-
tions. Flow-through acute toxicity tests may provide some insight into the
expected effects of a short-term but constant release of toluene into the aquatic
environment, as might occur in areas receiving refinery or petrochemical
effluents. Neither static nor flow-through acute toxicity tests can predict the
chronic effects of low level toluene pollution. In addition, acute toxicity
tests usually determine the concentration of toxicant that kills or affects 50%
of the test population. LC™ or EC,-n values, therefore, represent concentrations
that are toxic to half the population, and provide no information concerning the
concentration that will have no adverse effects during acute or chronic exposure.
17.2. EFFECTS OF ACCIDENTAL SPILLS'
No information was found concerning the effects of accidental spills of
toluene per se on aquatic organisms; however, toluene is one of the major aroma-
tic components of crude oil and such refined petroleum products as diesel fuel,
gasoline, anc1 jet fuel, all of which have been released in large amounts to thn
aquatic environment during spills.
The long term ecological impact of accidental spills of toluene is unknown.
In spill situations, most of the toluene would probably evaporate rapidly. For
instance, McAuliffe (1976) reported that toluene, benzene, and xylene could be
found in the water under crude oil slicks only during the first 30 minutes after
spillage. In contrast, spills in areas of shallow water and restricted water
floW, auch as in certain portions of estuaries, lakes, and streams, have a
17-2
-------
greater potential for causing acute mortalities because the toluene may reach
higher dissolved concentrations and may persist longer through adsorption to
sediments. Toluene is acutely toxic to many aquatic species at concentrations
well below its water solubility, and lethal exposure may occur during spills in
shallow water.
Although chronic, low-level pollution by toluene has been reported in a
Japanese river (Funasaka et al., 1975) and a harbor (Ogata and Miyake, 1973) that
received refinery and petrochemical effluents, the effects of such low level
chronic pollution in natural aquatic habitats are unknown.
17.3. LABORATORY STUDIES OF TOXICITY
17-3.1. Lethal Effects. The lethal effects of toluene have been reported for
numerous species of freshwater and marine fish and invertebrates. The acute LCc-0
for 22 species of freshwater and marine animals ranged between 3 ana 1130 ppm
(Table 17-1). All but six of the LC5Q values were determined in static tests. Of
the six flow-through LC tests, four utilized measured toluene concentrations.
No information was found concerning the effects of toluene on amphibians.
17.3.1.1. FRESHWATER FISH — The earliest investigation of toluene
toxicity to freshwater fish was conducted by Shelford et al. (1917), who reported
that 1 hour of exposure to 61 to 65 mg/Ji toluene was lethal to orange spotted
sunfish (Lepomis humilis). This test was conducted under static conditions at
20°C in freshwater of unspecified temperature and composition.
Degani (19^3) conducted static toxicity tests with 15-day-old lake trout
(Salvelinus namaycush) fry and 1.5 g mosquitofish (Gambusia affinis) in dechlor-
inated tapwater at 17 to 18°C using 3 to 5 fish per container (2 S, volume). The
time to death at a nominal exposure concentration of 90 ppm toluene was
390 minutes for trout and 47 minutes for mosquitofish. The time to death of
trout fry exposed to 50 ppm toluene was 258 minutes.
Wallen et al. (1957) also conducted static acute toluene toxicity tests
with female mosquitofish (Gambusia affinis) of unspecified size in turbid pond
water (150 ppm turbidity as measured by Jackson turbidimeter, pH 7.5 to 8.5,
methyl orange alkalinity < 100 ppm, temperature 17 to 22°C). For these toxicity
tests, ten fish per concentration were added immediately after addition of
different amounts of toluene to the bioassay containers (15 liter volume). The
test solutions were constantly aerated and mortalities were recorded daily for
96 hours. The 24, 18, and 96 hour LC™ values were 13HO, 1260, and "180 ppm,
respectively. These values were estimated on the basis of the initial nominal
17-3
-------
TABLE 17-1
Acute Toielclty of Toluene to fish and Aquatic Invertebrates
Species
FISH
Freshwater
Ide
(Leuciscus Idus
aelanotus)
Hosqultof lah
(Gaobusla afflnls)
Goldfish
(Carasslus auratus)
Goldfish
— • (Carasslus auratus)
-j
Jr
Goldfish
(Carasslua auratus)
Fathead ralnncv
( Pioephales proeaelas)
LC50
Terap. Type 21 h 18 h 72 h
( °C) Test
20*1 SU 70
2Cj-1 SU — - 1?2
17 to SU 13110 1260
22
20^1 SM 56
25 SU 57.7 57.7
(18.9 (18-9
to to
68.8) 68.6)
17 to FM 11.6 J7.6 25.3
19 (32.0 (21.6 (20.1
to to to
71-7) 36.0) 3V. 9)
25 FM —
No Effect Reported
96 h Concentration Concentration Comments
Units
52 mg/t Lab 1, icoj kill at
BB.ng/l.
365 Lab 2, 1001 kill at
170 n«/L.
Teats were supposedly
conducted under
Identical conditions.
1180 560 ppn Tests were conducted
in afrated turbid
pond water.
Bg/t Test was conducted
in tap water ( pH
7.6)
57.7 — - ng/l Test was conducted
(18.9 in soft water.
to
68.8)
22.80 — - ppa Teats were conducted
(17.1 under flow-through
to to conditions in soft
30.0) dechlorinated tap
water. The test was
continued to 720 h
( 30 d) at which
time the LC (and
951 confidence Intar-
val) was ID. 6 ( 10.7
to 20.0) ppa.
18-7? ng/l Eobryas were »ore
resistant than lartae
Reference
Juhnke and
Ludenann, 197B
Wall en et ml.,
1957
Bridle et •!.,
1979
"ickerlng »nd
Henderson, 1966
Brennisan et •!.,
1976
Devlin at el.,
(982
Fathead oinnow 25 SU
(Pimephales proaetas)
Fathead Blnnov 25 SU
(Plmephales proaelas)
16.3
(37.0
to
59-1)
56.0
(11.7
to
67.1)
16.3
( 37.0
to
59.1)
la
67.D
31.3
(3?.8
to
15.9)
u?.3
(33.5
to
5 J.',)
Tests were conducted
In soft water.
Teits were conducted
in hfird wAler.
Pickering and
Henderson, 1966
-------
TABLE 17-1 (cont.)
Species
Blueglll aunflsh
(Lepoaia nacrochirus)
Blueglll sunfiah
(Lepogia siacrochlrua)
Guppies
(Poecilia retlculata)
Zebrafiah
(Brachydanlo rerio)
>
)
i
Hedaka
(Oryziaa latlpea)
Heoaka
(Oryzlaa latlpes)
Coho salaion fry
(Cncorhynchus klsutch)
MA H INK
Coho sal non
(Onoorhynchus kiauteh)
Pink salmon fry
(Oncoriiynchug klsutch)
Tenp. Type 24 h
(«C) Test
25 SU 24.0
(18.9
to
30.5)
NR SU 16.6
(15.0
to
19.1)
25 SU 62.8
(55.0
to
73.7)
20+1 FU —
25+2 SU 80
(mean:
80)
25^2 SU 4-4
FH
FM
8 SU
12 SM 5.4
(4.4
to
6.5)
48 h 5072 h
24.0 —
(18.9
to
30.5)
13.3 12.7
(11.6 (11.5
to to
14.8) 14.5)
61.0
(52.8
to
71.9)
25 to
27
20 to 135
(oean=
63)
36
...
—
22.4 22.4
No Effect
96 I Concentration
24.0
(18.9
to
30.5)
12.7 10.0
(11.5
to
14.5)
59.3
(50.9
to
70.3)
—
23 to 110 O6
(Beans
54)
32
9.36
3.08
22.4 10
Reported
Concentration
Units
• mg/i
ppm
mg/l
tag/ 1
Bg/Jt
Eg/i
\ll/l
Hi/1
ppa
Pfxn
Conn en ta
Tests wcre-conduot-ed
in hard water.
Only these data
cited in U.S. EPA,
1980.
Tssts were conducted
in hard water.
Tests were conductsd
in closed aquaria
with dechlorlnated hard
tap water at a flow
rate of 6 i/h.
Range and oean of
LC values for dif-
ferent stage esbryoa
LC values for fry.
Th3Ul68 h. LC was
23og/l. 5°
Unparasitlzed
Parasitized
Tests were conducted
in artificial salt-
water (pH 8.1, 30°/oo
salinity).
Testa were conducted
according to methods
of Korn et al., 1979.
Reference
Pickering an
-------
TABLE 17-1 (cont.)
Species Tenp. Typ« 2« h <18 h 5°72 h
( *C) Test
Pink saloon l| SM
(Oreorhynchus Iclsutch)
8 SM
12 SM
Striped bass 16 SM 7.3 —
(Morone saxattlls?
She«pshead Blr.,iow HR SU >277 >277
(Cyprinodon varlegatus) <«85 277
<«85
13
(5.0
to
35)
...
—
No Effect Reported
Concrntrallon .Concentration Cotraents Beferenne
Units
ul/l Tests were conducted Korn et al., 1979
with saloon fry
acclloated to 28°/oo
seawater at dlf-
ferent temperatures.
— ul/t Tests were conducted Benvllle «nd
In 25°/oo salinity Kom, 1977
seawater with Juvenll*
fish.
J77 PPB Data only cited In U.S. EP», T978
U.S. EPA, 1980.
mg/l Tests were conducted Bard et al. ,
In 15J sallnaty sea- 1981
water win Jutenlle
fish.
28 ng/l Test was conducted teBlanc, 1980
with reconstituted
wel! water (hardness
72+b ag/l as CaCO ,
pH 7.0+0.2) in 3
containers sealed with
plastic wrap.
mg/l Test was conducted Brlngsiann and Kuhn,
In natural water { pH 1959
7.5, hardness ?1ll Eg/I).
9. .95 ppm Test was conducted Berry and
with distil' d uramraer, T977
to
21.63)
Harln«
Brine shrimp nauplli
(Srtemla sal Ina)
«f<:.5 SU 33
water.
Test was conducted
with artificial sea-
water.
Price et al., 1971
-------
TH8L8 17-1 (con'...)
Species
Bay shrimp
.(Crogo franclscorua)
Shrlap
(Eualua spp.)
Or»«» snrlrsp
(Peeaeaonetas pugic')
Crass shrltrcp
(Pacnemoneles puglo)
Teisp. Type
(*C) Test
16 SH
« SM
8 SH
12 SM
20 SM
20 SM
10 SM
10 SM
20 SH
20 SH
2» h
12
CO
to
13)
...
...
20.2
(16.3
to
22,5)
17.2
(16,9
to
19.1)
37.6
(35.0
to
50.3)
38.1
(36.1
to
39-6)
30.6
(21.3
to
6H.5)
25. «
(te.8
to
tc«;o
•8 h '72 h 96 h
«.3
(3.1
to
5.8)
21.*
(19.5
to
23.5)
20.2
(17.9
to
22.8)
11.7
(13-1
to
16.6)
... — - ...
__. .„_
... ...
___
— — —
.__ ... ...
Ho Effect Reported
Concentration Concnntratlon
Units
lA/t
vtn
\ilfl
nt/i
•*/l
•g/l
VR/l
«R/t
Bg/l
Of/I
Coraewnts
Tests w«r« conduetad
with 25°/oo
salinity aeavater.
»dtilts st 15°/roo
salinity.
Mults at 25°/oo
salinity.
Adults at 15°/oo
salinity.
Kdults at 25°/oo
anllnlty.
Lsrrae at 15°/oo
salinity.
Lanrse at 25 /oo
salinity.
Reference
B*n»llle and
Kopn, 1977
(Corn et al..
(Corn et *!.,
Korn et at,,
Fotera, 1975
Potera, 1975
Potera, 1975
Potem, 1975
Poters, 1975
Potera, 1975
1979
1979
1979
-------
TABLE 17-1 (oont.)
Species
Cras.i shrimp
(Palacwistcs puglo)
Mysld shrlpip
(Hysldopala bahla)
Dungsnos? crab
(Cancr. ea^lster)
Co -
-------
0
20
80
80
100
100
0
30
80
90
100
100
0
40
100
100
100
100
toluene concentrations. Because the test containers were vigorously aerated, it
is probable that the actual toluene concentrations decreased rapidly during the
exposure period. It was also observed that the turbidity of the toluene
solutions decreased from 150 to 100 ppra over the 96-hour axposwre period. At
concentrations of 560 ppm and below, all fish appeared to be unaffected. The
remainder of the test results are presented below:
Concentration Percent Mortality
(ppm) 21 h 18_h
< 560
1,000
1,600
3,200
5,600
10,000
Pickering and Henderson (1966) investigated the acute toxicity of toluene
to fathead minnows (Pimephales promelas), bluegill sunfish (Lepomis
tcacrochirus), goldfish (Carassius auratus), and guppies (Lebistes reticulatus
- Poecilia reticulata). The length and weight of the fish used for testing were
3.8 to 6.U cm and 1 to 2 g for the first 3 species and 1.9 to 2.5 cm and 0.1 to
0.2 g for guppies. Each test utilized 10 fish per concentration or control in
either 10 S, (minnows, sunfish, goldfish) or 2 I (guppies) of soft water (pH 7.5,
alkalinity 18 mg/JL, EDTA hardness 20 mg/JZ,) made by mixing 5 parts of hard natural
spring water with 95 parts of distilled demineralised water. In addition,
fathead minnows were tested (10 fish/concentration) in the hard spring water (pH
8.2, alkalinity 300 mg/£, EDTA hardness 360 mg/£.) to investigate the effect of
these water characteristics on toluene toxicity. All tests were conducted at
25°C. The test solutions were not aerated, and dissolved oxygen concentrations
were measured but not reported. The 24, 48, and 96-hour LC value? and their
95% confidence limits, as calculated by the moving average-angle method of Harris
(1959) using initial nominal toluene concentrations, are presented in
Table 17-1. The 96-hour LC,-n values increased in the order of bluegill sunfish
(21.0 mg/£), fathead minnow (34.3 mg/£ in soft water, 12.3 mg/j(, in hard water).
goldfish (57.7 tng/H), and guppies (59-3 mg/Jl). The 96-hour LC5Q for fatt-ead
minnows in soft water was not significantly different from the 96-hour LC5Q for
the same species in hard water. Comparison of the 95% confidence limits of the
96-hour LC n values in soft water for the 4 species indicated that the LC_0
values were not significantly different between father! minnows and bluegill
17-9
-------
aunfish or between goldfish and guppies. Both fathead minnows and bluegill
sunfish had 96-hour LC values significantly lower than goldfish and guppies*
The 96-hour LC^g was not significantly different from the 24-hour LC5Q for any of
the species tested in soft water.
Replicate flow-through acute toxicity tests were also conducted with
fathead minnow embryos, 1-day-old protolarvae, and 30-day-old larvae by Devlin
et al. (1982). The 96-hour LC ranged between 18 and 31 mg/K, for 30-day-old
fish,, between 25 and 36 mg/S, for protolarvae,and between 55 and 72 mg/X, for
embryos. Embryos were significantly more resistant that the other life stages.
Static acute LC values for bluegill sunfish have also been reported by the
U.S. EPA (1980). The 24, 48, 12, and 96-hour LC5Q values were 16.6, 13-3, 12.7,
and 12.7 ppm, respectively. No effects were observed at or below 10 ppm.
Additional information concerning these tests was not available.
Berry (1980) mentioned that the upper non-lethal toluene concentration for
bluegill sunfish (Lepomis macrochirus) was 8.7 mg/!l. The duration of exposure
and lowest lethal concentration.were not specified.
Bridie et al. (1979) and Brenniman et al. (1976) also investigated the
acute toxicity of toluene to goldfish. Bridie et al. (1979) used goldfish of
slightly greater weight (mean 3.3 g, range 2.3 to '1.3 g) than Pickering and
Henderson (1966) to determine the static 24-hour LC^. In this test, 6 fish per
concentration were exposed without aeration to a toluene series in 25 I of
tapwater that had a pH of 7-8 and contained (in milligrams per liter): Cl~ = 65;
N02"= 0; N03" = 4; SC^2' = 35; P0^3~ = 0.15; HC03~ = 25; Si02 = 25; NH^ = 0; Fe =
0.05; Mn = r ^a2* = 100; Mg2"1" = 8; and alkali as Na4" = 30. The toluene
concentration was measured at the beginning and end of the test. The 2^-hour
LC,-,,, obtained by interpolation from a graph of the logarithm of concentration
versus percent mortality, was..58 mg/Jt, which is the same as the 24-hour LC for
goldfish reported by Pickering and Henderson (1966).
Much larger goldfish (length, 13 to 20 cm; weight, 20 to 60 g) were used by
Brenniman et al. (1976) to determine the acute toxicity of toluene under flow-
through exposure conditions. The LC_0 values were determined by exposing 6 fish
per 38 i aquarium to three toluene concentrations (and a control) in dechlorin-
ated soft tapwater (methyl orange alkalinity = 34 ppm as CaCO_; phenolphthaline
alkalinity = 37 ppm as CaCCK; total harness = 80 ppm as CaCO^; calcium -
21.6 ppm; magnesium = 5.3 ppm; SiO- = 8 ppm; chromium - <0.002 ppm; pH 7.0 + 0.3;
17-10
-------
temperature 17 to 19°C) at a flow rate calibrateJ to renew the test chamber
volumes every 1.5 hours. This flow rate was sufficient to maintain dissolved
oxygen concentrations at _>7 ppm and to maintain constant toluene concentrations,
as measured by continuous monitoring at 210 ntn by spectrophotometer. The 24, 48,
72, and 96-hour LC™ values, calculated by probit analysis., were 41.6, 27.6,
25.3, and 22.8 ppra, respectively- 'Ithough most of the fi ;h died during the
first 24 hours, the 96-hour LCr^ wag significantly lower than the 24-hour LC,-0«
These LC,_0 values are somewhat lower than those reported by Pickering and
Henderson (1966) and Bridie et al. (1979) for goldfish tested under static condi-
tions. In addition, the LC _ values reported by Pickering and Henderson (1966)
did not decrease significantly from 24 to 96 hours. These differences are
j
probably due to a rapid decline in the toluene concentration through evaporation
in the static tests in contrast to constant toluene concentrations in the flow-
through test. Brenniman et ai. (1976) continued their flow-through exposure
test for 30 days, at which time the LC(-0 had decreased to 14.6 ppm. These
results emphasize the fact that static acute toxicity testa may seriously under-
estimate the acute toxicity of toluene and that chronic effects may occur at
concentrations that are considerably lower than those that cause acute effects.
Juhnke and Ludemann (1978) investigated the static acute toxicity of
toluene to the ide (Leuciscus ijdus melanotus) using comparable procedures in two
different laboratories. The toxicity tests were conducted according to the
methods of Mann (1975, 1976), i.e. 48 hours of exposure with 10 fish (1.5 +
0.3 g, 5 to 7 cm) per concentration in tapwater (pH 7-8, hardness 268 + 54 mg/J!.)
at 20 + 1°C. The 48 hour LC (Q% mortality). LC__, and LC.00 (100% mortality)
values determined at each laboratory were as follows:
48 Hour Lethal Concentration Values (mg/i.)
T r- ip f ^
"°0 50 ""100
Laboratory i 72 70 88
Laboratory 2 365 422 470
Although it was stated that those tests were conducted under comparable
conditions, the results were clearly different. The concentration that caus«d no
deaths of fish in laboratory 2 (365 mg/2,) was about 4 times higher than the
concentration that killed all fish in laboratory 1 (88 mg/i). The authors did
not discuss the reasons for the difference in results.
17-11
-------
Sloof (1978, 1979) reported that the 48-hour LCcn of toluene to zebrafish
50
(Brachydariio rerio) waa 25 to 27 mg/l. This test was conducted under flow-
through (6 &/hr) exposure conditions using 10 fish per concentration in 10 £
sealed aquaria and dechlorir.ated tapwater (20 ^ 1°C; pH 8.0 + 0.2; hardness 180 +
1.8 mg/K. as CaCO ).
The acute effects of toluene on parasitized and unparasitized coho salmon
(Oncorhynchus kisutch) fry were studied by Moles (1980). The parasitized fry
were artificially infected before toluene exposure with glochidial larvae of the
freshwater mussel, Anodont? oregonensis. Toluene exposure waa conducted under
flow-through conditions, using five measured concentrations and 20 fisn per
concentration. The temperature and characteristics of the water used were not
specified. The 96 hour LC as calculated by probit analysis, was
9.36 \iSL/i, (ppm) for unparasitized fish and 3.08 \ii/i for fish parasitized with a
mean number of 69 glochidia per fish. The LC values were significantly dif-
ferent, indicating that parasitized fish were less resistant to the effects of
toluene.
Stoss and Haines (1978) investigated the effects of static exposure to
toluene on tht survival of fertilized eggs and newly natched fry of the meclaka,
Cryzias la*ipes. Groups of ten eggs or fry were exposed in loosely capped vials
'.sricaining 20 m£ of the exposure medium (synthetic rearing medium: pH 7.6;
akalinity 99 mg/£, as CaCO ) at 23 + 2°C. Toluene concentrations were prepared by
j>
diluting a water-soluble extract of 10 tat toluene/2, mec'ium. In order to deter-
mine the sensitivity of different stages of embryo development, tests were begun
with eggs of various ages after fertilization. Tests with fry were all begun
within 24 hours after hatching., Nominal initial toluene concentrations were
used for calculation of LC5Q valjes. The LC5Q values for embryos varied with
length of exposure and the age at time of introduction. The mean 24, 48, ar.d
96-hour LCc/- values for all ages of embryos were 80, 63, and 54 mg/£. The range
of LC values was 20 to 135 mg/fc at 48 hours and 23 to 110 mg/fc at 96 hours
(Stoss, personal communication). Karly (£3.5 hours old) and late (^192 hours
old) embryos had significantly lower LC^n values at each exposure period than
embryos of Intermediate age at time of introduction. The 24, 48, 96, and
168-hour LC.-, values for fry were 44, 36, 32, and 23 mg/Jl, respectively (Stoss,
ylj
personal communication). These values were lower than the maan embryo LC,-Q
values for the same exposure period; however, fry LC values were greater than
ths LCf-n values for the susceptible early and late stage embryos and lower than
17-12
-------
most of the LC^Q values for intermediate stage embryos. Stoas and Haines (1978)
also investigated the sublethal effects of toluene on hatching time and induction
of developmental abnormalities. These sublethal effects are discussed in
Section 17.3-2.1.
17.3.1.2. MARINE FISH — Morrow et al. (1975) studied the effects of
toluene on young coho salmon (Oncorhynchus kisutch) that had been acclimated to
artificial seawater (30 °/oo (parts per thousand) salinity; 8°C; pH 8.1) for up
to 2 weeks. A static exposure technique was used in which toluene was added
directly to exposure aquaria containing fish and 73 £, of seawater (
-------
conducted with 1C to 15 fry per concentration (<1 g fish/A water). Fish were
added to the test containers after addition of an appropriate amount of toluene
in water stock solution. The containers were not aerated until after the first
48 hours of exposure to minimize' evaporative loss. Even so, analysis showed that
toluene decreased to nondetectable levels by 72 hours at 12°C and by 96 hours at
8°c"and to 25% of the initial concentration by 96 hours at 4°C. The 96-hour LC
values, estimated by probit analysis using initial measured concentrations ex-
pressed as \ii/i toluene (= ppm), were 6.4 at 4«C, 7.6 at 8°C, and 8.1 at 12°C.
The 95% confidence intervals of the 4°C and 12°C LC,-n values did not overlap,
indicating that temperature affected the toxicity of toluene. There was no
significant difference between 24 and 96-hour LCj-fs values because almost all
deaths occurred within the first 24 hours of exposure. The effect of temperature
may have been caused by greater sensitivity of the fish at the lower temperature
and/or by the longer persistence of toluene at the lower temperature.
Thomas and Rice (1979) used the previously described techniques of Korn
et al. (1979) to determine the static 24~hour LC-. of toluene with somewhat
larger (1 to 2 g, 4.5 to 5.5 cm) pink salmon fry at 12°C in seawattr. The 24-hour
LC (and 95J confidence interval) was 5.4 (4.4 to 6.5) ppm, which is signifi-
cantly different from the 96-hour LC^ value of 8.1 ppm (7.5 to 8.8) obtained
with younger fry at 12eC by Korn et al. (1979). The reasons for this difference
cannot be determined from the information provided.
A similar static exposure technique was used by Benville -and Korn (1977) in
their study of the acute toxicity of toluene to juvenile striped bass (Morone
saxatilis) in aeawater (25 °/oo salinity, 16CC). The test was initiated by
adding different amounts of saturated toluene in water stock solution to the test
aquaria, each containing 10 fish. Toluene concentrations were measured at the
beginning of the test and every 24 hours thereafter to the end of the test. The
24 and 96-hour LC5Q values were both 7-3 \ii/i (ppm). Almost all mortalities
occurred within 6 hours. The average percent loss of toluene was 40$ by
24 hours, 53J by 48 hours, and >99? by 72 hours.
The only flow-through toxicity test with marine fish was conducted by Ward
et al. (1981). The flow-through 96-hour LC^, based on measured concentrations,
was 13 rng/4 for Juvenile sheepshead minnows (Cyprinodon variegatus). This value
was aauch lower than that obtained with static tests. The static 96-hour LC for
similar fish was reported to be >277 <485 ppm in an unpublished U.S. EPA study
(1978, cited in U.S. EPA, 1980) and in Ward et al. (1981). Although toluene
17-11
-------
concentrations were not measured in the static test, the difference in LC,-0
values is almost certainly due to rapid loss of toluene from the static test
containers.
17.3.1-3. FRESHWATER INVERTEBRATES — Berry and Brammer (1977) investi-
gated the acute static toxicity of toluene to fourth-instar larvae of the
mosquito, Aedes aegypti. The larvae were reared fron eggs and tested in
distilled water at 25 + 1°C. For each of four replicate tests, duplicate groups
of 20 larvae each were exposed to 14 toluene concentrations. The mortality data
were pooled (160 larvae/concentration) to calculate the 24-hour LCt-0 by probit
analysis. Initial exposure concentrations were determined by gas-liquid chroma-
tography. The 21-hour LC,-0 (± standard error) was 21.52 + 0.16 ppm. The highest
concentration (+ standard error) that caused no mortality over the 24-hour
exposure period was 9-95 + 1.30 ppm.
Berry (1980) mentioned that the upper non-lethal toluene concentration for
crayfish (Orconetes rusticus) was 104.4 mg/d. The duration of exposure and
lowest lethal concentration were not specified.
The acute toxicity of toluene has also been determined with the cladoceran,
Daphnia magna, by Bringmann and Kuhn (1959) and by LeBlanc (1980). Bringmann and
Kuhn (1959) reported a 48-hour LCj-. of 60 mg/Jl. This static test was conducted
with first instar (<24 hours old) Daphnia magna in natural freshwater (pH 7.5;
hardness 214 mg/£.) at 23°C.
LeBlanc (1980) conducted static tests with first instar (<24 hours old)
animals in deionized well water reconstituted to a total hardness of 72 j- 6 mg/R.
as CaCO, and a pH of 7.0 + 0.2 at 22 + 1°C. Three groups of 5 daphnids each were
j
exposed to each of at least five toluene concentrations and uncontaminated water
in covered 250 mi beakers containing 150 mS, of test solution. The 24 and 48-hour
LCj... values (and 95$ confidence intervals), based on initial nominal concentra-
tions, were both 310 (240 to 420) mg/Jl. The "no discernible effect concentra-
tion" was 28 mg/S,. This LC^ value is considerably higher than that reported by
Bringmann and Kuhn (1959). The reasons for this difference cannot be determined
from the data provided.
W.3.1.4. MARINE INVERTEBRATES -- Price et al. (1974) determined the
static 24-hour LC,-,, of toluene to brine shrimp nauplii (Artemia salina) in
;>U
artificial seawater (27.87 g/i, Nad; 1.36 g/S, CaSO^; 3.T g/£, MgS04«7H20;
8.42 g/i MgCl2; 0.79 g/fc KC1; 0.16 g/S, MgBr2«6H20) at 24.5'C. Groups of 30 to 50
newly hatched brine shrimp were exposed to 5 toluene concentrations in 100 mi
17-15
-------
seawater- The estimated 24-hour LC50, based on initial nominal concentrations,
was 33 mg/fc.
Bay shrimp (Crago francisoorum) were shown by Benville and Korn (1977) to be
somewhat more sensitive to toluene. The 24-hour static LC,-ni determined in
natural seawater (25 °/oo salinity) at 16°C, was 12 \i!L/l (ppm). The 96-hour LC__
50
for this species (4.3 uJl/Jl) was significa.itly lower than the 24-hour LC5Q (non-
overlapping T5/t confidence limits). These values were calculated from initial
measured toluene concentrations.
Korn et al. (1979) investigated the effects of temperature on the acute
toxicity of toluene to another genus of shrimp (Eualus spp.). Shrimp (0.8 g;
6 cm long) were acclimated to the test temoeratures in natural 26 to 28 °/oo
salinity seawater for 4 days and then exposed in groups of 10 to 15 animals to a
series of toluene concentrations, prepared by dilution of a saturated water
solution. The tissue loading in the test containers was less than 1 g/i. Mea-
surement by UV spectrophotometry showed that toluene concentrations decreased to
nondetectable levels by 72 hours at 12°C and by 96 hours at 8°C, and to 25$ of
the initial concentration by 96 hours at 4°C. The 96-hour LC,-n values, calcu-
lated from initial measured toluene concentrations, were 21.4 \ii/i at 4°C,
20.2 \ii/SL at 8°C, and 14.7 jii/fc at 12°C. The 96-hour LC Q values at 4°C and 8°C
were not significantly different (overlapping 95$ fiducial limits) from each
other, but both were significantly higher than the 96-hour LC at 12°C. This
trend of greater toxicity at higher temperatures was opposite to the relationship
found by these authors for pink salmon fry (Section 17.3.1.2.) and by Potera
(1975) for grass shrimp (see below). The reasons for this difference could not
be established but may have been due to some combination of effects of tempera-
ture on persistence of toluene in water, altered toluene uptake and metabolic
rates, and possible interaction of toluene toxicity and temperature stress. The
authors concluded that temperature affected the toxicity of toluene to these
species of shrimp and salmon but that it would be impossible to predict the
effects of temperature change on the toxicity of toluene to other species.
Potera (1975) investigated the effects of temperature (10 and 20°C),
salinity (15 and 25 °/oo), and life stage (larvae and adults) on the static 24-
hour LCj. of toluene to the grass shrimp, Palaemonetca pugio. The 24-hour LCj-g
values, based on measured initial concentrations, ranged from 17.2 to 38.1 ing/S,.
17-16
-------
As shown by overlapping 95? confidence intervals (Table 12-1), there was no
significant difference in LC(-n values between adults and larvae at the same
salinity and temperature, or between adults tested at the same temperature but at
different salinities. The LC5Q was significantly lower at 20°C, however, than
at ip"DC for adults tested at either 15 °/oo or 25 °/oo salinity. The time to
produce narcosis in at least 50? of adult shrimp at 20°C was less than 30 minutes
at initial exposure concentrations of 19.8 mg/JZ, and greater. Recovery of more
than 90$ of exposed shrimp could occur if shrimp were transferred to clean water
after exposure to up to 30 mg/2, for 30 minutes.
Potera (1975) also determined the 24-hour LC™ for the copepod, Nitocra
spinipes, at a temperature of 20°C and at salinities of either 15 °/oo or
25 °/oo. The 24-hour LCc0 values from replicate tests were 24.4 at 15 °/oo
salinity and 74.2 mg/Jl at 25 °/oo salinity. These values were significantly
different (non-overlapping 95? confidence intervals). Potera (1975) suggested
that the lower salinity may have stressed the copepods, resulting in a lower LC
value.
Neff et al. (1976) also determined the static 96-hour LC,Q of toluene to
grass shrimp, Palaemonetes pugio. This value, based on initial nominal concen-
trations, was 9-5 mg/£, which is lower than the 24-hour LC values reported by
Potera (1975).
Caldwell et al. (1976) determined the 48 and 96-hour LC of toluene to
larvaL stages of the dungeness crab (Cancer magister) under flow-through expo-
sure conditions. The 48 and 96-hour LC^ values were 170 and 28 mg/Jl, respec-
tively.
Static acute LCcn values for mysid shrimp (Hysidopsis bahia) have been
5U —
reported by the U.S. EPA, (1980). The 24 and 48 to 96-hour LC50 values were 64.8
and 56.3 ppm, respectively. The "no effect" concentration was 27.7 ppra.
Additional information concerning this test was not available.
The 48-hour static LC of toluene to larvae of the Pacific oyster
(Crassostrea gigas) was reported to be 1050 mg/Jl (LeGore, 1974). This test was
conducted with filtered seawater (25.3 to 30.8 °/oo salinity) at 20 to 21.5°C
using 30,000 larvae per exposure concentration.
17-17
-------
17.3.2. Sublethal Effects.
17.3.2.1. FISH — Very little information is available concerning the E jb-
lethal effects of toluene exposure on fish. Morrow et al. (1975) studied the
effects of several aromatic hydrocarbons, including toluene, on the 'evela of Na+
and K* in the blood of young coho salmon (Oncorhynchus kisutch) in seawater.
Static exposure to 30 ppm toluene caused a small increase in these blood cations,
reaching a maximum at about 2 hours after beginning exposure. The Na+ concen-
tration returned to the control level by 3 hours. Blood K+ decreased after
2 hours but was still elevated at ^ hours, the last sampling period. The toluene
exposure concentration of 30 ppm was sufficient to cause some mortalities and
behavioral effects. The authors suggested that toluene increased membrane
permeability, particularly in the gills. In the hypertonic seawater medium, this
change would result in ion influx and water loss in the fish, perhaps accounting
for the initial rise in blood ion concentration.
Brenniman et al. (1979) conducted a series of experiments to determine the
effects of toluene exposure on blood gas physiology, hippuric acid content, and
histopathology of goldfish (Carassius auratus). The fish used in these experi-
ments were exposed to two or more toluene concentrations under flow-through
conditions using dechlorinated tapwater.
For the pathology study, groups of six fish were exposed for up to 30 days
to 0, 5, 10, and 21 ppm toluene (Brennim^n et al., 1979). No gross or micro-
scopic lesions were observed in fish during the first week of exposure. After
the first week, ascites developed in 3 fish at 21 ppm and in 2 fish at 10 ppm. In
exposed fish that survived 15 to 30 days, about 50J had a white epidermal exudate
of unknown origin, and some fish at all toluene concentrations had gross lesions
in gill, liver, or gall bladder. Excessive mucus production in gills occurred in
all fish at 21 and 10 ppm and in 50? of the fish at 5 ppm. Microscopic lesions
were found in gills (fusion), liver (decreased cytoplasmic nuclear ratio), and
kidney (tubular vacuolization) of many exposed fish buc not in control fish.
Exposed fish did not eat food and had livers that were paler and smaller than
control fish.
For the blood gas study, groups of 3 or ^4 fish were exposed for H hours to 0,
60, or 80 ppm toluene (Brenniman et al., 1979). The blood samples were analyzed
for pH, percent oxygen saturation, partial pressures of carbon dioxide (pCQ ) and
oxygen (p ), and bicarbonate. The results are presented below:
°2
17-18
-------
Mean Values
Toluene Cone.
(ppm)
0
60
80
"°2
42.33
I6.25a
15.633
Rco2
11.50
23.25a
19.27
PH
7.56
6.90a
6.96a
0 -Saturation
2 (?)
'18.67
27.00a
20.33a
Bicarbonate
9-83
5.10
*4.17a
p < 0.05 when compared to control.
Toluene exposure caused significant changes in all parameters (Brenniman
efc al., 1979). The authors suggested that the decreased pn , increased p, , and
U f-\ \j U fj
resultant acid-base imbalance may have been due to lowered u and CO- exchange at
the gills. Two proposed mechanisms for impaired gas exchange vere lowered
respiratory rate and gill damage. The former mechanism is less likely because
sublethal toluene exposure has been shown to increase the respiratory rate in
fish (Sloof, 197C, 1979; Thomas and Rice, 1979). The latter mechanism is
supported by the authors' observation that toluene caused excess mucus produc-
tion and fusion of gill lamellae in gills.
The whole-fish content of hippuric acid was measured in fish exposed in
groups of 6 fish to 0, 5, 10, or 21 ppm toluene for 96 hours (Brenniman et al.,
1979). This experiment was conducted to determine whether the fish were able to
metabolize toluene ultimately to hippuric acid, as occurs in mammals
(Chapter 12.). The results, presented below, indicated that hippuric acid was
elevated at all the toluene concentrations tested and that this metabolic pathway
occurs in goldfish.
Toluene Concentration
(ppm)
0
5
10
21
Mean Hippuric Acid Concentration
(ppm)
1539-50
3608.67
3536. 67a
2829- 17a
a
P < 0.05 when compared to control.
The pattern of decreasing hippuric acid concentration with increasing toluene
concentration was attributed to increasing stress and lower metabolic efficiency
17-19
-------
as toluene concentration increased. Hippuric acid was elevated above the control
levels, however, even at the highest toluene concentration.
The only other information available relevant to toluene metabolism in fish
is provided by Ohmcri et al. (1975), who investigated the comparative in vitro
metabolism of a toluene analog, £-nitrotoluene, by liver homogenates of rats and
eels. The species of eel was not specified. Both species were able to metabo-
lize £-nitrotoluene (PNT) to £-nitrobenzoic acid (PNB acid), via oxygenation of
PNT to jg-nitrobenzyl alcohcl (PNB alcohol), to £-nitrobenzaldehyde (PNB
aldehyde), and finally to PNB acid. The rate of the overall reaction (PNT to PNB
acid) in eel liver, however; was only 3^$ (at 25°C) to 1)6$ (at 37°C) of the rate
in rat liver. The rate of formation of PNB alcohol from PNT in eel liver was 29%
(at 25°C) to 16$ (at 37°C) of the rate in rat liver. This step was the rate-
limiting step for the overall reaction because the formation of PNB acid from PNB
alcohol was faster in eels than in rats.
Thomas and Rice (1979) measured the effects of flow-thrcugh toluene expo-
sure on the respiratory rate and oxygen consumption of pink salmon (Oncorhynchus
gorbuscha) fry at two temperatures (4°C, 12°C) in seawater. The fish were placed
in sealed chambers fitted with a water inlet and outlet, mesh electrodes (for
measuring opercular breathing rate), and oxygen electrodes (for measuring oxygen
concentration of inflowing and outflowing water). After determining the S^-hour
LCj-,. (5.38 ppm), the authors exposed fry to several toluene concentrations,
expressed as percentages of the LC,-,.. Significant increases in opercular
breathing rate at 12°C occurred at exposure concentrations of 91) and 69? of the
LC50, but not at ^45 or 30$ of the LC5p. The breathing rate remained elevated
throughout the 15-hour exposure period only at 9^$ of the LC,_0, at which concen-
tration 6 of 23 fish died. The breathing rate at a toluene exposure concentra-
tion of 69$ of the LC_n reached a maximum at 3 hours and returned to control
level by 15 hours. Additional experiments showed that exposures to 71$ of the
LCc-Q increased oxygen consumption. The percent increase in both oxygen consump-
tion and breathing rate was greater at ^°C than at 12°C. The authors suggested
that these effects were due to the energy requirements for metabolism of toluene
and that this requirement was greater at the lower temperature. The threshold
for an effect on breathing rate at 12°C was estimated to be about 16$ of the LC5Q,
or about 2.5 ppm.
Sloof (1978, 1979) conducted similar experiments to determine the sensi-
tivity of a biological monitoring system using fish respiratory rates as an
17-20
-------
indicator of water pollution by toluene and other chemicals. Adult rainbow trout
(mean weight 56 g) were acclimated to dechlorinated tapwater at 20 + 1°C and
tested individually in sealed flow-through chambers equipped with stainless
steel mesh electrodes for measuring breathing rate. After the normal breathing
rate for a fish over a 3 day period had been determined, toluene contaminated
water was added continuously and the breathing rates were monitored over a period
of 1*8 hours. Measurements were taken at the same time of day during the pre-
exposure and exposure periods, A toxic effect was considered to have occurred if
the respiration frequency of at lea.it 75% of the test fish exceeded the prede-
termined individual normal frequencies measured at the same hourly interval. The
lowest toluene concentration that caused an increase in respiratory rate was
2.5 rae/JU This concentration is identical to the estimated threshold concentra-
tion for an effect on breathing rate in pink salmon (Thomas ana Rice, 1979).
Leung and Bulkley (1979) investigated the effects of 100 \ii/i toluene on the
rate of opercular movement by 8-day-old embryos of the Japanese medaka, Oryzias
medaka. The basal (unexposed) rate was determined for each of three embryos and
then toluene was added to the culture medium to obtain a nominal concentration of
100 112,/i,. The rate was then determined for each embryo at about 5 minute
intervals for 40 minutes. The average rate before exposure w&s zero
movements/minute. The average of 8 counts (each 1 minute long) over 40 minutes
after beginning exposure was 2.28 movements/minute. The standard deviation was
so great, however, that this increase was not statistically significant.
The sublethal effects of toluene on medaka were also investigated by Stoss
and Haines (1979). The exposure techniques and lethal effects reported by these
authors have been discussed in Section 17*3-1-1 • Static exposure of eggs to
initial nominal concentrations of 11 and 82 mg toluene/2, resulted in a signifi-
cant delay in time to hatching and a decrease in the proportion of embryos that
hatched successfully. Exposure to 41 ng/JZ. and greater caused numerous develop-
mental abnormalities, including disruption of cell cleavage patterns, defor-
mation of eyes, appearance of isolated tlood islands in the circulatory system,
and abnormal heart structure, t?il flexures, and visceral organ formation and
placement. No abnormalities were observed in embryos exposed to 16 mg toluene/S,.
Subchronic embryolarval toxicity tests have been conducted with freshwater
fathead minnows (Devlin et al., 1981) and saltwater sheephead minnows (Ward et
al., 1981). Devlin et al. (1982) exposed embryos under flow-through conditions
to H to 15 mg/ii, toluene for 36 days. Larval growth was the most sensitive
17-21
-------
indicator of toxicity, with significant inhibition of larval growth occurring at
toluene concentrations as low aa 6 mg/£.. No effects were observed at 4 mg/JL.
The maximum acceptable toxicant concentration (MATC) was, therefore, between 4
and 6 mg/J, for this species.
Ward et al. (1981) conducted flow-through toxicity tests with embryos of
sheepshead minnows exposed to 1 to 19 mg/J, toluene for 28 days after hatching.
Exposure to 7.7 mg/fc and greater caused a significant decrease in hatching
success and survival of Juveniles. There were no effects on growth of surviving
fish. As a result, the MATC was >3.2 <7-7 mg/Z.. The 96-hour LC for this
species was between 277 and 485 ppm (Section 17.3.1.2.). The ratio between acute
and sub-chronic toxicity was between 36 and 152, indicating that chronic effects
occur at concentrations much lower than acute effects.
In summary, the lowest toluene concentration shown to cause sublethal
effects in fish was 2.5 ppm, the concentration that caused an increased breathing
rate in trout (Sloof, 1978, 1979) and salmon (Thomas and Rice, 1979). This va]ue
is .somewhat below the lowest acute LCj-r, value reported for any fish species
(3.08 ppm for coho salmon, see Table 17-1). An embryo-larval test with sheeps-
head minnows (U.S.. EPA, 1980) showed that subchronic toxic effects occurred at
7.7 ppm but not at 3-2 ppm and that the ratio of the acute LC to the subchronic
MATC for this species was between 1.7 and 4.0. Another embryo-larval test with
fathead minnows (Devlin et al., 1982) showed that subchronic effects occurred at
6 mg/£, but not at 4 mg/H, and that the ratio of the acute LC to the subchronic
-'U
MATC was between 3 and 18. Although acute-chronic ratios may vary greatly among
species, this information suggests that chronic toxic effects may occur in coho
salmon and other sensitive species at concentrations well below 3 ppa.
17.3.2.2. INVERTEBRATES — Berry et al. (1978) conducted a series of
experiments to determine the effects of 24 hours of exposure to sublethal concen-
trations of water-soluble fractions (WSFs) of gasoline, benzene, xylenes, and
toluene on oxygen consumption by fed and unfed larval stages of the mosquito,
Aedes aegypti. Control experiments with untreated animals showed that there was
no significant difference in 0 consumption between fed and unfed larvae. Treat-
ment with the WSF of 1 mi/i gasoline, however caused an increased 0^ consumption
in fed, but not unfed, larvae relative to untreated controls. Treatment of fed
larvae with individual WSFs of benzene (1 mi,/£), xylenes (0.3 m£/£,), or toluene
(0,1 to 0.5 mA/H) had no effect on 0_ consumption relative to fed controls. A
WSF mixture of benzene, xylenes, and toluene and a mixture of benzene and toluene
17-22
-------
(0.2 mil/jt, for each compound) caused significant increases in 0- consumption.
Exposure to a WSF mixture of benzene and xylenes or toluene and xylenes (0.2 mJl/£
for each compound) had no effect. The authors also conducted experiments on the
uptake of %-labeled toluene in fed and unfed animals, as well as uptake of ^H-
toluene by fed larvae in the presence or absence of benzene (Section 15.3.).
Maximum -^H-toluene counts were equal in fed and unfed larvae, but were reached
more quickly (1 hour versus ^ hours) by the fed animals. The ^H-toluene counts
in larvae, expressed as the percentage of the initial water counts, were greater
in the benzene and toluene mixture than in the solution containing toluene alone.
The authors concluded that the effects of gasoline on 0 consumption were due to
the enhanced uptake and synergistic effects of toluene and benzene, two of the
major aromatic components of gasoline. They also suggested that the presence of
food accelerated the uptake of toluene through absorption of toluene to the
consumed food particles.
Blunuo (1978) investigated the effects of toluene on the swimming activity
and survival of barnacle (Balanus eburneus) larvae. Groups of larvae were
exposed for 1 hour in specially constructed tubes to 10, 20, 30, 40, 50, 60, 70,
80, and 90? of th-3 water soluble fraction (WSF) made by saturating seawater wjth
toluene. The tubes were designed so that actively swimming photopositive larvae
would be attracted to light at the top of the tube. After 1 hour of exposure, the
inactive larvae were collected from the bottom of the tubes and stained with a
vital dye (neutral red) to determine percent mortality. The remaining portion,
containing the active larvae, was then collected and counted. The interpolated
concentration that immobilized 50$ of the larvae was 12.5? of the WSF. All
larvae were immobilized at 30? WSF and higher. About 33-1/3$ of the larvae were
immobilized at 10? WSF, the lowest concentration tested. The percent mortality
of the immobilized larvae ranged from about 3? at 10? WSF to a maximum of 12$ at
90? WSF. The author also measured the effects of WSFs that had been aged in
covered containers for 1 day in a refrigerator or exposed to air for up to
3 days. The percent WSF that immobilized 33-1/3? of the larvae was 10? in the
fresh solution, 37.5? in the refrigerated solution, and 90? in the evaporated
solution. Additional experiments showed that aeration of the WSF for 6 hours
lowered the toxicity to the same extent as 3 days of exposure to air.
Bakke and Skjoldal (1979) investigated the effects of toluene on activity,
survival, and physiology of the isopod, Cirolana boreaJis. For determination of
median effective .times (ET,-ni partial or complete narcotization as endpoint),
17-23
-------
groups of 15 isopods were exposed in duplicate to nominal initial concentrations
of 0, 0.0125, 1.25, 5.7, 12.5, 25, and 125 ppm toluene for ^ days. The exposure
medium (33-5 to 3H.5 °/oo salinity seawater at 8 to 10°C) was changed every
2 days. The interpolated or extrapolated ET50 values were as follows:
Toluene
Concentration /r1 50 .
ippmj (hours)
0
0.0125
1.25
5.7 MOO
12.5 69
25 26
125 3
No effects on activity were observed in animals exposed to 1.25 ppm or less
(Bakke and Skjoldal, 1979). The authors also investigated the recovery of
isopods after exposure for varying periods to 12.5 or 125 ppm toluene. Exposure
to 125 ppm for 1 hour caused complete inactivity, but all animals recovered
within 12 hours after transfer to clean water. Exposure for 2 or more hours to
125 ppm caused partial or complete mortality. All isopods could recover after
exposure to 12.5 ppm for 30 hour-s but not longer. Additional experiments showed
that there was no significant effect of M days of exposure to up to 5.7 ppm
toluene on oxygen consumption, ATP concentration, or energy charge. Exposure to
12.5 ppm resulted in a progressive decrease in ATP level and energy charge over
8 days of exposure, at which time all organisms had died. Exposure to the
rapidly lethal concentration of 125 ppm toluene showed no effect on ATP level or
energy charge * These results Hith 12.5 and 125 ppm were essentially the same as
those reported by the authors in a previous paper (Skjoldal and Bakke, 1978).
Bakke and Skjoldal (1979) concluded that the effect of toluene on activity was
much more sensitive as an indicator of sublethal toluene toxicity than its
effects on respiration, ATP level, and energy charge.
In sucmary, the lowest toluene concentration shown to cause sublethal
effects in invertebrates was 5.7 ppm, the concentration that caused narcotiza-
tion of isopods (Bakke and Skjoldal, 1979). This concentration is somewhat
higher than the 96-hour LCc0 of 1.3 ppm for bay shrimp (see Table 17-1) reported
by Benville and Korn (1977). The latter concentration is the lowest reported to
have toxic effects on freshwater- or marine invertebrates. Although the chronic
toxicity of toluene to aquatic invertebrates has not been studied, it is probable
17-2'!
-------
that chronic effects could occur in sensitive invertebrate species at concentra-
tion below Jf.3 ppm. This conclusion is supported by the fact that chronic
effects in fish occurred at concentrations well below the acutely toxic concen-
trations (Section 17.3-2.2.).
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Biological Effects. 0. Huzinger and S. Safe, Eds., Pergamon Press. Vol. 1,
pp. 501-506.
SLOOF, W. (197S). Detection limits of a biological monitoring system based on
fish respiration. Bull. Environ. Contain. Toxicol. 23(^-5): 517-523.
STOSS, F.W. and HAIHES, T.A. (19?9). The effects of toluene on embryos and fry
of the Japanese medaVca Oryziaa latipes with a proposal for rapid determination of
maximum acceptable toxicant concentration. Environ. Pollut. 20(2): 139-1*18.
THOMAS, R.E. and RICE, S.D. (1979). The effect of exposure temperatures on
oxygen consumption and opercular breathing rates of pink salmon fry exposed to
toluene, naphthalene, and water-soluble fractions of Cook Inlet crude oil and
No. 2 fuel oil. Mar. Pollut. T9_: 39-52.
U.S. EPA (U.S. ENVIRONMENTAL PROTECTION AGENCY) (1980). Ambient Water Quality
Criteria for Toluene. Publication No. EPA '410^5-80-075. U.S. Environmental
Protection Agency. Washington, DC.
WALLEN, I.E., GREEN, W .C. andLASATER, R. (1957). Toxicity to Gambusia affinis
of certain pure cneoiicals in turbid waters. Sewage Indust. Wastes.
29(6>: 695-711.
WARD, G.S., PARRISH, P.R. and KIGBY, R.A. (1981). Early life stage toxicity
tests with a saltwater fish: Effects of eight chemicals on survival, growth, and
development of sheephead minnows (Cyprinodon variegatus). J. Toxicol. Environ.
Health. 8: 225-240.
17-29
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18. HEALTH EFFECTS SUMMARY
18.1. EXISTING GUIDELINES AND STANDARDS
18.1.U Air. The Occupational Safety and Health Administration (OSHA) currently
limits occupational exposure to toluene to 200 ppm as an 8-hour, time-weighted-
average (TWA), with an acceptable ceiling concentration of 300 ppm
(HO CFR 1910.1000); the acceptable maximum peak above the ceiling concentration
is 500 ppm for a maximum duration of 10 minutes. The National Institute for
Occupational Safety and Health (NIOSH, 1973) currently recommends an exposure
limit of 100 ppm as an 8-hour TWA with a ceiling of 200 ppm. An 8-hour TWA
concentration of 100 ppm is also recommended by the American Conference of
Governmental Industrial Hygianists (ACGIH, I960) as a Threshold Limit Value
(TLV) for toluene; the short-term (15 minute) exposure limit recommended by the
ACGIH is 150 ppm. ACGIH (1980) has further noted that there may be significant
contribution to the overall exposure by the cutaneous route.
Threshold limit values that have been established for occupational exposure
to toluene in other countries are listed as follows (Verschueren, 1977):
USSR 13 ppm (50 mg/m3) 1972
Czechoslavakia 52 ppm (200 mg/m;;) 1969
West Germany (BDR) 200 ppm (750 mg/m^) 197'*
East Germany (DDR) 52 ppm (200 mg/m::) 1973
Sweden 98 ppm (375 ing/nT3) 1975
There are no standards for general atmospheric pollution by toluene in the
United States, although a National Ambient Air Quality Standard specifies that
nonmethane hydrocarbons shall not exceed 0.24 ppm (160 i/g/nr) as a maximum 3-
hour average concentration (6 to 9 a.m.), more than once per year (40 CFR 50).
Ambient air quality standards have, however, been promulgated for toluene in
other countries. These foreign standards are summc.rized as follows
(Verschueren, 1977):
Country Concentration Averaging Time
USSR
0.15 ppm (0.6 mg/nr) 20 min
0.15 ppm (0.6 mg/m3) 24 hr
West Germany (BSD) 15 ppm (60 mg/m3) 30 min
5 ppm (20 mg/m3) 24 hr
18-1
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East Germany (DDR) 0.5 ppm (2.0 mg/rrl 30 min
0.15 ppm (0.6 mg/nr) 24 hr
Bulgaria 0.15. ppm (0.6 mg/m^) 20 min
0.15 ppm (0.6 mg/ra3) 24 hr
Hungary 13.3 ppm (50.0 mg/m^) 30 min
;s 5.3 ppm (20.0 mg/m^) 24 hr
•Hungary (protected areas) 0.16 ppm (0.6 mg/in^) 30 min
0.16 ppm (0.6 mg/m3) 24 hr
Yugoslavia 0.16 ppm (0.6 mg/m^)
0.16 ppm (0.6 nag/or)
20 min
24 hr
18.1.2. Water. The Committee on Safe Drinking Water of the National Academy of
Sciences concluded in 1977 that toluene and its major metabolite, benzoic acid,
were relatively nontoxic, and that there was insufficient toxicological data
available to serve as a basis for setting a long-term ingestion standard (WAS,
1977). It was recommended that studies be conducted to produce relevant informa-
tion. Toluene has recently been considered for a second time by a reorganized
Toxicology Subcommittee of the Safety Drinking Water Committee of the National
Academy of Sciences (U.S. EPA, 1980a), but the results of the deliberations of
thia group have net yet been made public.
The U.S. EPA (1980a) has recently derived an ambient water criterion level
for toluene of 1^.3 mg/2.. This criterion is intended to protect humans against
the toxic effects of toluene ingested through water and contaminated aquatic
organisms, and is based on an Acceptable Daily Intake (ADI) calculated from the
maximum-no-effect dose reported in the Wolf et al. (1956) subchronic oral study
in rats-and an uncertainty factor of 1000. The criterion level for toluene can
alternatively be expressed as 424 mg/X, If exposure is assumed to ue from the
consumption of fish and shellfish products alone.
18,1.3. Food. Toluene has been approved by the Food and Drug Administration for
use as a component of articles intended for use in contact with foo^ (i.e., an
indirect food additive). Articles that contain residues of toluene may be used
in producing, manufacturing, packing, processing, preparing, treating,
packaging, transporting, or holding food. The use of toluene in the food
industry is summarized as follows:
Component of adhesives 21 CFR 175.105
Adjuvant substance in resinous and
polymeric coatings for polyolefin films
used as food contact surfaces 21 CFR 175.320
18-2
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Component of the uncoated or coatacl
surfaces of paper and paper-board
articles Intended for use with
dry foods " 21 CFR 176.1GO
Used in the formulation of semirigid
and ri^id acrylic and modified acrylic
plasfj.c articles 21 CFR 177.1010
Additive for cellophane (residue limit
0.1*) 21 CFR 177.1200
Additive for 1,4-cyclohexylene dimethy-'
lene terephthalate and 1 , 4-eyclo-
hexylene diroethylene isophthalate
copolymer 21 CFR 172,1240
Solvent for 4,4'-isopropylidenediphenol-
epichlorohydrin resins with a minimum
molecular weight of 10,000 (residue
limit £1000 ppm in the finished resin) 21 CFR 177.1440
Solvent for polysulfide polymer-polyepoxy
resins 21 CFR 177.1650
Solvent for poly(2,6-dimethyl-1,4-
phenylene)oxide resins (residue limit
0.2$ by weight) 21 CFH 177.2460
Blowing agent adjuvant used in the manu-
facture of foamed polystyrene (residue
limit £0.35? by weight of finished
framed polystyrene) 21 CFR 178.3C"0
Toluene has also been exempted from the requirement of a tolerance when it
is used as a solvent or cosolvent in pesticide formulations that are applied to
growing crops (40 CFR 180.1001).
18.2. INHALATION EXPOSURES
As detailed in Chapter 11 of this report, many studies have reported the
effects on humans of inhalation exposures to toluene. Because most of these
studies involved relatively small numbers of human subjects, they failed to
precisely define the levels or durations of the exposures, and/or did not
consider the potential role of exposures to other toxic-ants. None of these
studies would be suitable for human risk assessment if taken individually. In
combination, however, they constitute a considerable body of human experience
and provide a relatively consistent pattern of dose-response relationships.
18.2.1. Effects of Single Exposures. The effects on humans of single exposures
to toluene for periods of up to 8 hours are relatively well documented. Data on
both toluene glue sniffers (Press and Done, 1967a, 1967b; Wyae, 1973; Lewis and
Patterson, 1974; Helliwell and Murphy, 1979; Hayden et al., 1977; Oliver and
Watson, 1977; Barnes, 1979) and workers accidentally exposed to high levels of
18-3
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toluene (Lurie, 1919; Browning, 1965; Longley et al., 1967; Reisen et al., 1975)
indicate that exposure to air saturated or nearly.saturated with toluene can
cause a spectrum of effects, from lightheadedness to unconsciousness, in a very
short period of time. Deaths attributed to the deliberate inhalation of toluene
have been reported - in at least 21! cases (Winek et al., 1968; Chiba, 1969;
Nomiyama and Nomiyama, 1978). Although most of these reports do not provide
quantitative exposure estimates, glue sniffers are probably exposed to nearly
saturated air-vapor mixtures of about 30,000 ppm toluene. The occupational
report of Longley et al. (1967) indicated that a loss of consciousness occurred
within minutes after exposure to atmospheres estimated to contain 10,000 ppm
toluene at waist level and 30,000 ppm toluene at floor level. The acute inhala-
tion toxicity data on experimental mammals, summarized in Table 12-1, suggest
that exposure periods of several hours to toluene levels greater than 4000 ppm
may be lethal. Based on the results of longer term human studies discussed
below, short exposures to concentrations of up to 1500 ppm are not likely to be
lethal (Wilson, 19*43; Ogata et al., 1970, see following discussion). The single
report by Gusev (1965) of effects on EEC activity in 1 individuals exposed to
0.27 ppm for 6 minute intervals may be a subtle indication of the perception of
toluene at this low level but does not have any apparent toxicologic signifi-
cance.
For single exposure periods that approximate a normal working day (7 to
8 hours), von Oettingen et al. (19^2a, 19^2b) and Carpenter et al. (19W pro-
vide relatively consistent information on sublethal dose-response relationships.
As summarized previously in Table 10-1, von Oettingen et al. (.19*123, 19H2b) noted
a range of subjective complaints from 8 hour exposures to toluene concentrations
ranging from 50 ppm (drowsiness) to 800 ppm (severe fatigue, nausea, incoordina-
tion, etc., with afte" effects lasting at least several days). Although the
terminology used by Carpenter et al. (19*1*0 is somewhat different from that used
by von Oettingen, the effects noted seem comparable over the common exposure
range (200 to 800 ppm). Although the consistency between these two studies is
reassuring, it should be noted that, even combined, both studies involve
exposures of only five individuals who were placed on multiple exposure/recovery
schedules. The impact tnat such multiple exposures could potentially have on the
results cannot be determined. Given the small number of individuals involved in
the exposures to toluene, an attempt to generalize for the human population a
detailed dose-response gradient comparable to that presented in Table 11-1 does
18-11
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not seem justifiable. When these studies are considered along with the results
of Ogata and coworkers (1970) and Gamberale and Hultengren (1972), however, it
seems reasonable to conclude that exposure periods of 8 hours or less to toluene
concentrations below 100 ppm may result in mild subjective coaplaints (fatigue
or headache) but are not likely to induce observable effects. Concentrations
above 100 ppm may cause impaired reaction time (200 ppm x 3 hours, Ogata et al.,
1970; 300 ppm x 20 minutes, Gamberale and Hultengren, 1972). At concentrations
of 300 to 800 ppm and above, gross signs of incoordination may be expected (von
Oettingen et al., 1942a, 19J42b; Carpenter et al., 19W.
Accidental acute overexposure to toluene may be limited to some extent by
the organoleptic or irritant properties of the compound. Gusev (1965) reports
ranges of maximum imperceptible concentrations and minimum perceptible concen-
trations of 0.35 to 0.79 ppm and 0.40 to 0.85 ppm, respectively. May (1966)
reports a minimum perceptible concentration of 37 ppm. The reasons for this
discrepancy between the Russian and American values are not apparent. Although
the Russian study entailed a total of 30 subjects and 7M observations and the
American report involved 16 individuals (number of observations not specified),
it is unlikely that the difference in the reported detectable levels is due
simply to sample size. In any event, toluene appears to be detectable in the air
at levels below those causing impaired coordination (i.e., >100 ppm). In addi-
tion, Carpenter and coworkers C^M) reported that toluene caused mild throat and
eye irritation at 200 ppm and also caused lacrimation at 400 ppm.
In summary, the estimated dose-response relationships for the acute effects
of single short-term exposures to toluene are presented below:
10,000 to : Onset of narcosis within a few minutes. Longer
30,000 ppm exposures may be lethal.
>4,000 ppm : Would probably cause rapid impairment of reaction
time and coordination. Exposures of 1 hour or
longer might lead to narcosis and possibly death.
1,500 ppm : Probably not lethal for exposure periods of up to
8 hours.
300 to 800 ppm : Gross signs of incoordination may be expected
during exposure periods up to 8 hours.
18-5
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100 ppm : Lacrimation and irritation to the eyes and throat.
100 to 300 ppm : Detectable signs of inooordination may be expected
during exposure periods up to 8 hours,
200 ppm : Mild throat and eye irritation.
50 to 100 ppm : Subjective complaints (fatigue or'headache) but
probably no observable impairment of reaction time
or coordination.
>37 ppm : Probably perceptible to most humans.
From the above discussion, it should be evident that these approximations are
crude composites and contain several areas of uncertainty and overlap.
18.2.2. Effects of Intermittent Exposures Over Prolonged Periods. Limited
information is available on the effects of subchronic or chronic continuous
exposures to toluene on humans or experimental animals. Most of the studies
either involve occupational exposures or are designed to mimic occupational
exposures. Consequently, while the data described below may be directly applic-
able to estimating effects from occupational exposures, an additional element 01'
uncertainty must be considered in any attempt to estimate the effects of
continuous exposures that may occur from ambient air.
Wilson (19*13) provides the only acceptable data on the effects of repeated
occupational exposures to toluene over a period of weeks (Section 11.1,1.2.). In
this study, the workers were classified into three groups by the levels of
toluere to which they were exposed: 50 to 200 ppm, 200 to 500 ppm, and 500 to
1500 ppm. The effects noted at the various levels were essentially the same as
those seen in single exposures. In the low exposure group, the reports of
headache and lassitude are consistent with symptoms noted by von Oettingen and
coworkers (1942a, 19U2b) over the same range of exposure. Although Wilson (19^3)
did not attribute these effects to toluene exposure, his failure to include an
unexposed control group makes this judgment questionable in view of the
von Oettingen data. In the middle and high exposure groups, the reports of
headache, nausea, and concentration-related impairment of coordination and reac-
tion time are also consistent with the symptoms reported by von Oettingen and
coworkers (19423, 1942b) and Carpenter and coworkers dg'lt) for short-term
single exposures. The major discomforting feature of the Wilson (19^3) report is
that it involved only 100 out of a total of 1000 workers. It is unclear whether
the remaining 900 workers evidenced any symptoms of toluene exposure.
18-6
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The only other study that reports effects of repeated exposures to toluene
fo»* relatively short periods of time is that presented by Greenburg and coworkers
(1912). In this study, repeated occupational exposures to toluene at levels of
100 to 1100 ppm for periods of 2 weeks to 5 years were associated with enlarged
livers In 13 of 61 airplane painters. This incidence of liver-enlargement was
reported to be 3 times that of a control group of 430 workers not exposed to
toluene. Because Greenburg and coworkers (1942) were not able to associate liver
enlargement with clinical or laboratory evid-ence of disease, because the
painters were also exposed to significant quantities of other volatile paint
•components (Table 11-9), and because the liver effect has not been corroborated
by other investigators (e.g., Parmeggiani and Sassi, 1954; Suhr, 1975), the
hepatomegaly reported by Greenburg should be given relatively little weight in
risk assessment.
Other reports of repeated occupational exposures to toluene involvu periods
of several years. For mean exposure levels above 200 ppm, all of the available
studies except that of Suhr (1975) report some evidence of neurologic effects
(Capellini and Aleasio, 1971; Panaeggiani and Sassi, 1954; Munchinger, 1963;
Rouskova, 1975).
The Suhr (1975) study involved a group of 100 pi-inters exposed to 200 to
400 ppm toluene for over 10 years. Compared to a group of 100 non-exposed
individuals, no significant differences were seen in symptoms of CNS depression
or sphallograph tests, which are designed to measure muscular coordination. An
interpretation of the significance of the Suhr (1975) study is confounded,
uowever, by several factors. As discussed in Sections 11.1.1.2. and 11.3-, the
limitations of this study include an undefined control group, uncertainties
involving the time of reflex reaction and sphallograph testing (i.e., blood
toluene levels may have declined significantly if the workers were examined
before or after the work shifts), and the use of an apparently unvalidated device
(sphallograph) for the detection of slight disturbances of muscular
coordination.
The other studies that do report effects at equal or higher levels of
exposure can be challenged for various reasons. The report of "nervous hyper-
excitability" in 6 of 11 exposed to 200 to 800 ppm toluene for "many years"
(Parmeggiani and Sassi, 1954) does not seem to be characteristic of toluene
intoxication. This report is from the Italian literature, however, and a full
text translation has not yet been made available for this review. The Capellini
18-7
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and Alessio (1971) study, which associated stupor, nervousness, and insomnia
with occupational exposure to 250 (210 to 300) ppm toluene for several years,
involved only a single worker. The "organic p.sychosy-ndrome" diagnosed by
Munchinger (1963) in workers exposed to 300 and iJ30 pp.m toluene for 18 and
12 years, respectively, is supported by the results of Rorschach tests and
Knoepfel's 13-Error tests. Because Munchinger did not use a control group,
however* the utility of this study is limited. The changes in EEC response to
photic stimulation that were reported by Rouskova (1975) in workers exposed to
>250 ppm toluene for an average of 13.5 years'also involved exposure to unspeci-
fied levels of 1,1,1-trichloroethane. Thus, the interpretation of the dis-
crepancies between the study by Suhr (1975) and these other reports is problema-
tic. Considering the relatively well documented CNS effects of single exposures
to toluene at levels above 200 ppm (Section 18.1.1.) and the effects noted by
Wilson (19^3) at comparable levels for much shorter periods of time, it would
seem imprudent to accept the Suhr (1975) data as a "no-obs-vrved-effect level" for
human risk assessment.
An alternative approach could be to use the study by Capellini and Alessio
(1971) in which no CNS or liver effects were noted in a group of 17 workers
occupationally exposed to 125 (80 to 160) ppm toluene for "diverse years." In
addition to the problems of small sample size, failure to precisely define the
duration of exposure, and lack of a control group, the use of this study is
compromised by reports of effects in two other groups of workers at lower levels
of toluene exposure. Matsushita and coworkers (1975) reported impaired per-
formance in neurological and muscular function tests in a group of 38 feaale
shoemakers who had been exposed to 15 to 200 ppm toluene for an average of
3 years and 4 months. In addition, 19 of 38 exposed women, compared to 3 of 16 in
the control group, complained of dysmenorrhea. The second group of workers was
composed of 100 car painters who had been occupat.ionally exposed to an average of
30.6 ppm toluene for an average of 14.8 years. As reported by Hanuj.r,en and
coworkers (1976) and Seppalainen and coworkers (1978), the exposed workers had a
greater incidence of CNS symptoms and impaired performance on tests for intelli-
gence and memory, as well as for visual and verbal ability. Both of the studies
on this group of worker used control groups or approximately 100 unexposed
individuals. The major problem with the reports of adverse effects on the female
shoemakers and male car painters is that both groups were exposed to other
potentially toxic agents. The female shoemakers were exposed to "alight" levels
18-8
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of gasoline (Matsushita et al., 1975) and, as detailed in Table 11-3, the raale
car painters were exposed to several other organic solvents.
Tl*e subchronic and chronic data on experimental mammals are of only limited
use in helping to resolve the uncertainties in the human data. Jenldns and
coworkers (1970), and CUT (1980) report no-observable-effect levels (NOELs) in
experimental mammals 1085 PF°> (8 hours per day, 5 days per week for 6 weeks) and
300 ppm (6 hours per day, 5 days per week for 24 months), respectively. As
m~?
discussed above in this section, a NOEL of 1085 ppca is contradicted by human
experience, suggesting that humans are more sensitive tnan experimental mammals
to toluene exposure. Similarly, the continuous-exposure NOEL of H)7 ppm for 90
days in rats, guinea pigs, dogs, and monkeys (Jenkins et al., 1970), and the
2 .year interaittant exposure NOELS of 30 ppm and 100 ppm in rats (CUT, 1980), do
not, by themselves, negate the concerns with neurological effects reported in
humans at lower levels.
18.3. ORAL EXPOSURES
Very little information is available or. the acute, subchronic, or chronic
effects of toluene in experimental mammals. As summarized in Table 12-1, acute
oral LD^s in adult rats range from 5500 mg/kg to 7530 mg/kg. Using the cubed
root of the body weight ratios for interspecie? conversion (U.S. EPA, 1980b;
Freireieh et al., 1966; Rail, 1969), an approximate lethal dose for humars can be
estimated at 983 mg/kg (5500 mg/kg • (70 kg • 0.^ kg) 3). The conversion
factor, as used here, assumes that humans are more sensitive than rats, which, as
discussed above, is consistent with the available data on inhalation exposure.
This estimate of the approximate lethal dose is also consistent with the report
by Francone and Braier (195*0 that leukemia patients were able to tolerate
cumulative doses of up to 130,000 ng of toluene given over a 3-week period
(approximately 88 mg/kg/day).
The only subchronic oral data are reported in the study by Wolf and
coworkers (1956), indicating a NOEL in rats at 590 mg/kg/day, given 5 days per
week for 6 months.
18.H. DERMAL EXPOSURES
Studies on the dermal toxicity of toluene are inadequate for quantitative
risk assessment. Qualitatively, the little information that is available sug-
gests that moderate dermal contact with liquid toluene (i.e., exposure of human
forearm skin to toluene for 1 hour on C successive days) may cause skin damage
but does not result in overt signs of toxicity (Malten et al., 1968). Similarly,
18-9
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the acute and subchronic data en toluene exposure in experimental mammals do not
suggest that toluene is a potent toxicant on dermal contact. A method for
quantitatively using such data to estimate equivalent human dose-response rela-
tionships, however, has not been fully formulated or validated.
As discussed in Section 13.1.-, exposure to toluene vapor results Jn rela-
tively little densal absorption compared to absorption across the lungs, **
18.5. RESPONSES OF SPECIAL CONCERN
I8i5.1. Carcinogenicity. CUT (1960) concluded that exposure to 30, 100, or
300 ppm toluene for 2*4 laonths did not produce an increased incidence of neo-
plaatic, proliferative, inflammatory, or degenerative lesions in Fischer 3^
rats. It should be noted, however, that this study has been considered
inadequate for carcinogenicity evaluation because the highest level tested was
not a maximum tolerated dose. Also, the high spontaneous incidence (165) of
raononuclear cell leukemia in aging Fischer JkH male rats reported by Coleman and
coworkers (1977) suggests that this strain may be inappropriate for the study of
a chemical that might be myelotoxic.
Other studies suggest that toluene is not carcinogenic when applied topi-
cally to the shaved skin of animals. Toluene is used extensively as a solvent
for lipophilic chemicals being tested for carcinogenic, potential; negative
control studies employing 100J ",oluene have not elicited carcinogenic effects.
Also, no evidence of a promotion effect was r.cted when toluene was painted on the
skin of mice twice weekly for 20 weeks following initiation with 7,12-dimethyl-
benz-[a]-anthracene (Frei and Stephens, 1968; Frei cind Kingsley, 1968).
The above data are not adequate for assessing the potential carcinogenicity
of toluene with great assurance and they cannot be used for supporting carcino-
genicity as a valid biologic endpoint in quantitative risk assessment.
18.5.2. Mutagenicity. Toluene has yielded negative results in a battery of
microbial, mammalian cell, and whole organism test systems as indicated in the
following:
Differential Toxicity/DNA Repair Assays
Escherichia ccli
Salmonella typhimurium
Reverse Mutation Testing
Salmonella typhimuriun (Ames test)
Escherichia coli WP2 assay
Saccharomyces cerevisiae D7
18-10
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Mitotic Gene Conversion/Crossing Over
Saccharomyoes cerevisiae D4, D7
Thymidine Kinase Assay
L5178Y mouse iymphoma cells
Micronucleus Test
mouse
Dominant Lethal Assay
mouse
Assays for sister-chronsatid exchange (SCE) and cytogenetic effects in human
and animal systems have provided inconsistent results. In vitro studies' have
shown that toluene treatment did not alter SCE frequencies in cultured Chinese
hamster ovary cells (Evans and Mitchell, 1980), and that SCEs and chromosome
aberrations were not induced in cultured human lymphocytes (Gerner-Smidt and
Friedrich, 1978). Increased frequencies of SCEs and/or aberrations in
lymphocytes from workers who were chronically exposed to similar levels of
toluene have, however, been reported by some investigators (100 to 200 ppm,
Funes-Craviota et al., 1977; 200 to 300 ppm, Eauchingsr et al., 1982), but not by
others (200 to 400 ppm, Forni et al., 1971; 7 to 112 pp-n, Maki-Paakkanen et al.,
1980). In the Russian literature, chromosome aberrations were reported in the
bcne marrow cells of rats that were exposed subcutaneously (Dobrokhotov, 1972;
Lyapkalo, 1973) and via inhalation (Dobrokhotov and Enikeev, 1977) to toluene,
but these findings were not corroborated in a Litton Bionetics, Inc. (1978) study
with rats following intraperitoneal injection. Differences in doses employed
and experimental design (e.g., numbers of cells scored) may account (at least in
part) for the conflicting results, but it should be noted that it is probable
that part of the exposure in the Funes-Craviota et al. (1977) study was to
benzene-contaminated toluene, and that the purity of the toluene used in the
Russian studies was not stated.
18.5.3. Teratogenicity. Toluene was reported in a recent abstract from NIEHS to
induce cleft palates at a level of 1.0 m£/kg (approximately 866 mg/kg) following
oral exposure to mice on days 6 to 15 of gestation (Nawrot and Staples, 1979).
This effect reportedly did not appear to be due merely to a general retardation
in growth rate. Levels of 0.3 and 0.5 mS,/kg (approximately 260 and 433 mg/kg)
toluene had no teratogenic effect, but the number of mice exposed and nunber of
fetuses examined were not stated. Nawrot and Staples (1979) also noted a
significant increase in embryonic lethality at all dose levels and a significant
18-11
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reduction in fetal weight at the. two higher dose levels. No frank signs of
maternal toxicity were seen at any dose level; however, at the highest dose,
decreased maternal weight gain was reported in mice exposed on days 12 to 15 of
gestation. A complete copy of this report has not been made available for review
but has been submitted for publication.
Three other studies have concluded that toluene is not teratogenic in mice
(Hudak and Ungvary, 1978) or rats (Hudak and Ungvary, 1978; Litton Bionetic .,
1978; Tatrai et al., 1979) following inhalation exposure. Hudak and Ungvary
(1978) and Tatrai et al. (1979) have noted, however, an increased incidence of
skeletal anomalies and signs of retarded skeletal.development in the rats that
were not considered malformations as such. Embryotoxicity was also indicated by
low fetal weights in mice and some rats (Hudak and Ungvary, 1978). At the high
exposure levels in the study by Hudak and Ungvary (1978), increased maternal
mortality was noted in rats (399 ppm, 2*4 hours/day, days 1 to 8) and mice
(399 ppm, 24 hours/day, days 6 to 13). No increased maternal mortality was noted
by either Hudak and Ungvary (1978) or Tatrai et al. (1979) at lower exposure
levels in rats (266 ppm, 8 hours/day, days 1 to 21; 266 ppm, 24 hours/day,
days 7 to 1*0 or mice (133 ppm, 24 hours/day, days 6 to 13). In the study by
Litton Bionetics, Inc. (1978), no signs of maternal toxicity were noted in rats
exposed to 100 or 400 ppm, 6 hours/day, on days 6 to 15 of gestation.
The extrapolation of these results to define potential human risk is an
uncertain process. The dose that produced cleft palates in mice on oral expo-
sure, 866 mg/kg, is only slightly higher than the NOEL in rats, 590 mg/kg/day.
Although inhalation exposure to toluene has not been shown to be tera-
togenic, embryotoxicity is an endpoint of concern. The effects noted in rats and
mice at the high exposure level (400 ppm) in the study by Hudak and Ungvary
(1978) may be of limited use in human risk assessment because of the occurrence
of maternal mortality. The lowest effect level not associated with maternal
mortality was 133 Ppm, 24 hours/day, on days 6 to 13, which caused low fetal
weights in mice. No fetal effects were noted in the study by Litton Bionetics,
Inc. (1978), however, when rats were exposed to 100 ppro or 400 ppm, 6 hours/day,
on days 6 to 15 of gestation, or in the Tatrai et al. (1979) study when rats were
continuously exposed to 266 ppm toluene on days 7 to 14. As is the case with
oral exposure studies, a quantitative approach for using this type of data in
human risk assessment has not been validated.
18-12
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j
HAIDEK, J.W., PETERSON, R.G. and BRUCKNER, J.V.. (1977). Toxicology of toluene
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18-18
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TECHNICAL REPORT DATA
(rleaie read Jnururiiom on the reverse htfori- completing!
1. REPORT NO.
EPA-600/8-82-008 F
3. RECIPIENT'S ACCESSION NO.
PB 84-100056
'-? AND SUBTITLE
HEALTH ASSESSMENT DOCUMENT FOR
TOLUENE—Final Report
6. REPORT DATE
August 1983
6. PERFORMING ORGANIZATION CODE
'. AOTMORIS)
9. PERFORMING ORGANIZATION NAME AND ADDRE~SS
Syracuse Research Corporation
Center for Chemical Hazard Assessment
Merrill Lane
Syracuse, NY 13210
. PERFORMING ORGANIZATION REPORT NO
10. PROGRAM EuEMENT NO.
IV CONTRACT/GRANT NO.
68-02-3277
12. SPONSORING AGENCY NAME AND ADDRESS
U.S. Environmental Protection Agency
Environmental Criteria and Assessment Office
Office of Research and DeveloDment
Research Triangle Park, NC 27711
13. TYPE OF REPORT AND PERIOD COVERED
4. SPONSORING AGENCY CODE
EPA/600/22
IS-SUPPLEMENTARY NOTES
j^e hg-jj.^ effect of primary concern with regard to exposures of humans to
toluene is dysfunction of the central nervous system (CNS). Occupational exposures in
the range of 200 to 1,500 ppm have elicited dose-related CNS alterations. Although
myelotoxicity was previously attributed to toluene, recent evidence indicated that
toluene is not toxic to the blood or bone marrow; myelfctoxic effects are considered to
have been the result of concurrent exposure to benzene.
Available evidence is inadequate for assessing the carcinogenic potential of
toluene. Although a 24-month inhalation exposure of rats to 300 ppm did not produce any
positive carcinogenic effects, various design deficiencies precluded the usefulness of
this study in assessing carcinogenic potential.
Toluene has been shown to be non-mutagenic in a battery of microbial, mamma-
lian cell, and whole organism test systems. Animal exposure studies suggest that
toluene has low teratogenic potential. However, tmbryototcicity has been shown to be an
endpoint of concern. The reproductive effects of toluene is a category recommended for
additional research.
Based on available exposure estimates, the only group at possible hign risk
are workers exposed at or near the Threshold Limit Value (100 ppm).
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