Introduction
National Industrial Chemicals Notification and
Assessment Scheme
Benzene
________________________________________
Priority Existing Chemical
Assessment Report No. 21
September 2001
Commonwealth of Australia 2001
ISBN 0 642-51896-3
This work is copyright. Apart from any use as permitted under the Copyright Act 1968
(Cwlth), no part may be reproduced by any process without written permission from
AusInfo. Requests and inquiries concerning reproduction and rights should be directed to
the Manager, Legislative Services, AusInfo, GPO Box 84, Canberra ACT 2601.
Priority Existing Chemical Number 21
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Preface
This assessment was carried out under the National Industrial Chemicals Notification and
Assessment Scheme (NICNAS). This Scheme was established by the Industrial Chemicals
(Notification and Assessment) Act 1989 (the Act), which came into operation on 17 July
1990.
The principal aim of NICNAS is to aid in the protection of people at work, the public and
the environment from the harmful effects of industrial chemicals.
NICNAS assessments are carried out in conjunction with Environment Australia (EA) and
the Therapeutic Goods Administration (TGA), which carry out the environmental and
public health assessments, respectively.
NICNAS has two major programs: the assessment of the health and environmental effects
of new industrial chemicals prior to importation or manufacture; and the other focussing on
the assessment of chemicals already in use in Australia in response to specific concerns
about their health/or environmental effects.
There is an established mechanism within NICNAS for prioritising and assessing the many
thousands of existing chemicals in use in Australia. Chemicals selected for assessment are
referred to as Priority Existing Chemicals.
This Priority Existing Chemical report has been prepared by the Director (Chemicals
Notification and Assessment) in accordance with the Act. Under the Act manufacturers and
importers of Priority Existing Chemicals are required to apply for assessment. Applicants
for assessment are given a draft copy of the report and 28 days to advise the Director of any
errors. Following the correction of any errors, the Director provides applicants and other
interested parties with a copy of the draft assessment report for consideration. This is a
period of public comment lasting for 28 days during which requests for variation of the
report may be made. Where variations are requested the Director's decision concerning
each request is made available to each respondent and to other interested parties (for a
further period of 28 days). Notices in relation to public comment and decisions made
appear in the Commonwealth Chemical Gazette.
In accordance with the Act, publication of this report revokes the declaration of this
chemical as a Priority Existing Chemical, therefore manufacturers and importers wishing to
introduce this chemical in the future need not apply for assessment. However,
manufacturers and importers need to be aware of their duty to provide any new information
to NICNAS, as required under section 64 of the Act.
Copies of this and other Priority Existing Chemical reports are available from NICNAS
either by using the prescribed application form at the back of this report, the website
www.nicnas.gov.au or ordering directly from the following address:
GPO Box 58
Sydney
NSW 2001
AUSTRALIA
Benzene iii
Priority Existing Chemical Number 21
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Overview
Benzene (CAS No. 71-43-2) was declared a Priority Existing Chemical on 7 April 1998 in
response to occupational and public health concerns.
Benzene occurs naturally in fossil fuels and is produced incidentally in the course of natural
processes and human activities that involve the combustion of organic matter such as wood,
coal and petroleum products. The main industrial use of benzene is as a starting material for
the synthesis of other chemicals. Most benzene feedstock is imported, but some is
manufactured at an Australian steelworks as a by-product of coal coking. Large quantities
of benzene are produced during the refining of petroleum and retained as a component of
petrol. Petrol vehicle emissions are the predominant source of benzene in the environment.
Benzene is volatile and water-soluble and is considered biodegradable. Its major release is
to the atmosphere, where it will break down in a matter of weeks. Direct release to the
aquatic compartment is expected to be minor and significant removal will occur from
volatilisation. Benzene release to soil is likely to be marginal. Concentrations in aquatic
systems are expected to be far lower than of concern and a low aquatic risk is predicted.
Due to the low expected exposure, a low environmental risk to terrestrial organisms is
predicted. The short atmospheric lifetime of benzene indicates concentrations will not occur
at levels harmful to the atmosphere. While widespread transport within the troposphere is
possible, the chemical is not expected to reach the stratosphere and therefore would not
have an influence on global warming or ozone depletion.
In animals and humans, benzene is absorbed by all routes of exposure, although dermal
absorption is limited by its rapid evaporation from the skin. It is metabolised in the liver
and several other organs, including the bone marrow. The parent molecule is eliminated
with exhaled air. The metabolites are excreted in the urine.
In animals, benzene is not highly acutely toxic. Chronic exposure can result in central
nervous system depression, immunosuppression, bone marrow depression, degenerative
lesions of the gonads, foetal growth retardation, damage to genetic material and solid
tumours in several organs.
In humans, acute exposure to high concentrations of benzene vapours can result in irritation
of the skin, eyes and respiratory system and in central nervous system depression. Chronic
exposure can result in bone marrow depression and leukaemia, particularly acute myeloid
leukaemia, and possibly an increased risk of non-Hodgkin's lymphoma and multiple
myeloma. Structural and numerical chromosome aberrations have been detected in
peripheral blood cells of workers exposed to high levels of benzene. For bone marrow
depression, the lowest observed adverse effect level in humans is 7.6 parts per million
(ppm), based on minimal blood count changes in otherwise healthy workers. No threshold
has been established for the genotoxic and carcinogenic effects of benzene.
Epidemiological evidence indicates that the risk of leukaemia increases with exposure and
is significantly elevated at cumulative exposures above 50 ppm-years, corresponding to an
8-hour time-weighted average exposure above 1.25 ppm over a working life of 40 years.
Chronic benzene toxicity has been attributed to the formation of reactive metabolites that
appear to exert their toxic effect in combination, with no one metabolite accounting for all
of the observed effects.
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Benzene is currently listed in the NOHSC List of Designated Hazardous Substances with
the following classification: `Flammable', `Carcinogen, Category 1' and `Toxic: Danger of
serious damage to health by prolonged exposure through inhalation, in contact with skin
and if swallowed'. Category 1 carcinogens are those substances known to be carcinogenic
to humans. Based on the assessment of health effects, this report has concluded that
benzene also meets the NOHSC Approved Criteria for Classifying Hazardous Substances
for classification as a skin, eye and respiratory system irritant and as a mutagenic substance
in Category 3.
The public is exposed to benzene through the inhalation of indoor, in-vehicle and outdoor
air contaminated with the chemical through releases that predominantly derive from vehicle
exhaust, petrol evaporation and tobacco smoke. The 24-hour average lifetime exposure in
the Australian urban population is estimated at 5.2 parts per billion (ppb). It is one-fifth
higher in passive smokers exposed to tobacco smoke at home, at work and in their cars (6.1
ppb) and almost three times as high (15.2 ppb) in the average smoker.
Benzene-induced bone marrow depression is not expected to present a significant public
health risk. Based upon low-dose extrapolation of relevant quantitative risk estimates and
the above-mentioned exposure estimate, the excess lifetime risk of benzene-induced
leukaemia in the Australian urban population is estimated to be in the order of one case per
10,000 with increased risk in sensitive subpopulations or at higher exposure levels.
However, the estimated excess risk is based on substantial uncertainties in the exposure
assessment which should be validated through collection of monitoring data.
As benzene is an established human carcinogen for which no safe level of exposure has
been established, it is recommended that any increase in public exposure be avoided and
that measures be taken to reduce exposure where this is practicable. The establishment of a
national ambient air benzene level would facilitate these objectives.
Occupational exposure to benzene is predominantly by the inhalation route. It occurs
primarily in the petroleum, steel, chemical and associated industries and in laboratories
using the chemical for research or analysis. Occupational exposure to benzene can also
result from the contamination of workplace environments with petrol vapours, engine
exhaust or tobacco smoke, for example, in vehicle mechanics, professional drivers and
hospitality workers. It is estimated that current long-term occupational exposures to
benzene are less than or equal to 0.7 ppm in the steel and associated industries and during
maintenance of phenol plants; less than 0.1 ppm in the upstream petroleum industry (oil
and gas production); less than 0.5 ppm in the chemical industry and in laboratory workers;
less than 0.2 ppm in vehicle mechanics; less than 0.7 ppm in the downstream petroleum
industry (refining, distribution and marketing of petroleum products); and less than 0.05
ppm in people who work in roadside or in-vehicle environments contaminated with vehicle
exhaust or in indoor environments contaminated with tobacco smoke.
The occupational risk characterisation found no cause for concern about acute health effects
or bone marrow depression, given the control measures which are already in place in
Australian workplaces. However, there is cause for concern about the risk for leukaemia in
all workers with repeated occupational exposure to benzene. There is no known threshold
for the carcinogenic effects of benzene, but because the risk for leukaemia increases with
exposure, it can be reduced by controlling exposure to the highest practicable standard.
With regard to occupational health and safety, it is recommended that the national exposure
standard for benzene be revised. It is recommended that an eight-hour time-weighted
average of 0.5 ppm be adopted. It is further recommended that the current hazard
classification be amended to include classification as `Irritating to eyes, respiratory system
and skin' (risk phrase R36/37/38) and as a mutagenic substance in Category 3 (risk phrase
Priority Existing Chemical Number 21
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R40: `Possible risks of irreversible effects, Mutagen Category 3'). Occupational exposures
to benzene should be minimised by improving workplace control measures and by using
the best available technology.
This report has identified the need to reduce public exposure to air benzene levels as much
as practicable. Public health recommendations include measures to reduce indoor benzene
levels, such as proper sealing of attached garages and minimising environmental tobacco
smoke. In order to better characterise the risk to the public from benzene exposure, personal
and ambient air monitoring is recommended and a national ambient air standard should be
set.
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Contents
PREFACE iii
OVERVIEW iv
ABBREVIATIONS AND ACRONYMS xv
INTRODUCTION 1
1.
1.1 Declaration 1
1.2 Objectives 1
1.3 Sources of information 1
1.4 Peer review 2
2. BACKGROUND 3
2.1 Introduction 3
2.2 International perspective 3
2.3 Australian perspective 3
2.4 Assessments by other national or international bodies 5
3. APPLICANTS 6
4. CHEMICAL IDENTITY AND COMPOSITION 7
4.1 Chemical name (IUPAC) 7
4.2 Registry numbers 7
4.3 Other names 7
4.4 Molecular formula 7
4.5 Structural formula 7
4.6 Molecular weight 8
4.7 Composition of commercial grade product 8
5. PHYSICAL AND CHEMICAL PROPERTIES 9
5.1 Physical state 9
5.2 Physical properties 9
5.3 Chemical properties 9
6. METHODS OF DETECTION AND ANALYSIS 11
6.1 Characterisation 11
6.2 Detection and analysis 11
6.3 Atmospheric monitoring methods 11
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6.4 Biological monitoring methods 13
7. MANUFACTURE, IMPORTATION AND USE 14
7.1 Manufacture and importation 14
7.2 Manufacturing processes and end use 15
7.2.1 Petroleum industry 15
7.2.2 Steel and associated industries 19
7.2.3 Chemical industry 20
7.2.4 Laboratory uses 22
7.2.5 Coincidental production 23
7.3 Summary 23
8. ENVIRONMENTAL RELEASE, FATE AND EFFECTS 24
8.1 Environmental release 24
8.2 Environmental fate 24
8.2.1 Atmospheric fate 24
8.2.2 Aquatic fate 27
8.2.3 Terrestrial fate 28
8.2.4 Biodegradation 29
8.2.5 Bioaccumulation 30
8.3 Effects on organisms in the environment 31
8.3.1 Aquatic organisms 31
8.3.2 Terrestrial organisms 33
8.4 Summary 34
9. KINETICS AND METABOLISM 35
9.1 Absorption 35
9.1.1 Animal studies 35
9.1.2 Human studies 36
9.2 Distribution 38
9.2.1 Animal studies 38
9.2.2 Human studies 39
9.3 Metabolism 40
9.3.1 General metabolic pathways 40
9.3.2 Formation of phenolic metabolites 42
9.3.3 Formation of trans,trans-muconaldehyde 43
9.4 Elimination and excretion 44
9.4.1 Animal data 44
9.4.2 Human data 46
9.5 Comparative kinetics and metabolism 47
9.5.1 Oral studies 47
Priority Existing Chemical Number 21
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9.5.2 Inhalation studies 48
9.5.3 Dermal studies 49
9.5.4 In vitro studies 49
9.6 Summary 50
10. EFFECTS ON LABORATORY MAMMALS AND OTHER TEST SYSTEMS 51
10.1 Acute toxicity 51
10.2 Irritation and corrosivity 52
10.3 Sensitisation 52
10.4 Repeated dose toxicity (other than carcinogenicity) 52
10.4.1 Short-term exposure 52
10.4.2 Long-term exposure 55
10.5 Reproductive toxicity 56
10.5.1 Effects on fertility and lactation 56
10.5.2 Developmental toxicity 58
10.6 Genotoxicity 63
10.7 Carcinogenicity 64
10.8 Summary and conclusions 69
11. HUMAN HEALTH EFFECTS 71
11.1 Acute toxicity 71
11.2 Irritation 72
11.3 Sensitisation 72
11.4 Repeated dose toxicity (other than carcinogenicity) 72
11.4.1 Neurological effects 72
11.4.2 Effects on the immune system 72
11.4.3 Cardiovascular effects 73
11.4.4 Haematological effects 73
11.4.5 Reproductive effects 78
11.4.6 Other health effects 81
11.5 Genotoxic effects 81
11.6 Carcinogenicity 83
11.6.1 Cohort studies 83
11.6.2 Case-control studies 96
11.6.3 Ecological studies 101
11.7 The Illawarra leukaemia cluster 102
11.8 Summary and conclusions 102
12. MODES OF ACTION 104
12.1 Activation of benzene metabolites 104
12.1.1 Activation of phenol 105
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12.1.2 Activation of hydroquinone and catechol 105
12.1.3 Role of cyclooxygenase 106
12.1.4 Formation of reactive oxygen species 106
12.2 Reactivity of benzene metabolites 108
12.2.1 Genotoxicity 108
12.2.2 Oxidative stress 110
12.2.3 Modulation of cellular function 111
12.3 Critical biological effects 112
12.3.1 Bone marrow toxicity 112
12.3.2 Leukaemia 112
12.3.3 Tumours in Zymbal, Harderian, lacrimal and mammary
glands 113
12.4 Interindividual variations in susceptibility 114
12.4.1 Gender effects 114
12.4.2 Genetic polymorphisms 115
12.4.3 Environmental influences 117
12.5 Summary 118
13. HEALTH HAZARD ASSESSMENT 120
13.1 Acute effects 120
13.1.1 CNS effects 120
13.1.2 Skin, eye and respiratory tract irritation 120
13.2 Repeated dose effects (other than carcinogenicity) 120
13.2.1 CNS effects 120
13.2.2 Immunosuppression 121
13.2.3 Bone marrow depression 121
13.2.4 Fertility effects 122
13.2.5 Developmental effects 123
13.2.6 Other non-neoplastic effects 123
13.3 Genotoxicity 123
13.4 Carcinogenicity 124
13.4.1 Leukaemia 124
13.4.2 Solid tumours 125
13.5 Summary and conclusions 126
14. CLASSIFICATION FOR OCCUPATIONAL HEALTH AND SAFETY 128
14.1 Physicochemical hazards 128
14.2 Health hazards 128
14.2.1 Acute toxicity 128
14.2.2 Irritant and corrosive effects 129
14.2.3 Sensitising effects 129
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14.2.4 Effects from repeated or prolonged exposure 129
14.2.5 Reproductive effects 130
14.2.6 Mutagenic effects 131
14.2.7 Carcinogenicity 132
14.3 Summary 132
15. ENVIRONMENTAL EXPOSURE 133
15.1 Point source releases to air 133
15.1.1 Petroleum industry 133
15.1.2 Steel and associated industries 136
15.1.3 Aluminium industry 137
15.1.4 Chemical industry 139
15.1.5 Fossil fuel burning for power generation 141
15.1.6 Other point sources 142
15.1.7 Summary 143
15.2 Diffuse releases to urban air 144
15.2.1 Emissions estimation 144
15.2.2 Predicted environmental concentration in urban air 147
15.3 Indoor air concentrations 149
15.3.1 Homes 149
15.3.2 Non-residential buildings 152
15.3.3 Motor vehicles and other means of transportation 153
15.4 Concentrations in water and soil 154
15.4.1 Water 154
15.4.2 Soil 156
15.5 Summary 156
16. PUBLIC EXPOSURE 157
16.1 Direct exposure 157
16.2 Indirect exposure via the environment 157
16.3 Exposure assessment 159
16.4 Summary and conclusions 162
17. OCCUPATIONAL EXPOSURE 164
17.1 Petroleum industry 164
17.1.1 Petroleum production and refining 164
17.1.2 Petrol distribution and marketing 166
17.1.3 Petroleum and petrol cleaning operations 168
17.1.4 Conclusions 168
17.2 Steel and coal tar distillation industries 168
17.2.1 Coke ovens 168
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17.2.2 Coal gas by-product plants 169
17.2.3 Coal tar distillation 169
17.2.4 Conclusions 170
17.3 Chemical industry 170
17.3.1 Ethane and naphtha (gas oil) cracking 170
17.3.2 Bulk distribution 171
17.3.3 Butadiene rubber manufacture 172
17.3.4 Styrene and phenol manufacture 172
17.3.5 Conclusions 173
17.4 Laboratory use for research or analysis 174
17.5 Contaminated workplace environments 174
17.5.1 Petrol vapours and vehicle exhaust 174
17.5.2 Environmental tobacco smoke 175
17.5.3 Conclusions 176
17.6 Aluminium industry 176
17.7 Summary 177
18. RISK CHARACTERISATION 178
18.1 Environmental risks 178
18.1.1 Atmospheric risk 178
18.1.2 Aquatic risk 179
18.1.3 Terrestrial risk 179
18.2 Occupational health risks 180
18.2.1 Acute effects 180
18.2.2 Effects from repeated exposure 180
18.2.3 Uncertainties involved 183
18.2.4 Areas of concern 184
18.3 Public health risks 184
18.3.1 Bone marrow depression 184
18.3.2 Leukaemia 185
18.3.3 Uncertainties involved 186
18.3.4 Conclusions 186
18.4 Risk assessments by other national or international bodies 187
19. RISK MANAGEMENT 190
19.1 Environmental and public health controls 190
19.2 Occupational health and safety controls 191
19.2.1 Regulatory controls 191
19.2.2 Current control measures 195
19.3 National transport regulation (ADG Code) 198
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20. DISCUSSION AND CONCLUSIONS 199
20.1 Environmental exposure and risks 199
20.2 Health effects 199
20.3 Public exposure and health risks 201
20.4 Occupational exposure and health risks 202
20.5 Data gaps 205
21. RECOMMENDATIONS 206
22. SECONDARY NOTIFICATION 210
APPENDIX 1 211
REFERENCES 218
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Abbreviations and Acronyms
American Conference of Governmental Industrial Hygienists
ACGIH
Australian Dangerous Goods
ADG
Australian Institute of Petroleum
AIP
absolute lymphocyte count
ALC
acute lymphatic leukaemia
ALL
acute myeloid leukaemia
AML
acute non-lymphocytic leukaemia
ANLL
atmosphere
atm
light aircraft gasoline
Avgas
bioconcentration factor
BCF
benzene poisoning
BP
benzene/toluene/xylenes
BTX
body weight
BW
centigrade
C
Chemical Abstracts Service
CAS
colony forming units of erythrocyte progenitor cells
CFU-E
colony forming units of granulocyte/macrophage progenitor cells
CFU-M
confidence interval
CI
chronic lymphatic leukaemia
CLL
centimetre
cm
cm2 square centimetre
cm3 cubic centimetre
Chemical Manufacturers Association
CMA
chronic myeloid leukaemia
CML
central nervous system
CNS
colony stimulating factor
CSF
cytochrome-P450
CYP
deoxyribonucleic acid
DNA
Environment Australia
EA
median effective concentration
EC50
European Inventory of Existing Chemical Substances
EINECS
Environment Protection Authority
EPA
environmental tobacco smoke
ETS
gram
g
gas chromatography
GC
gas chromatography-mass spectrometry
GC-MS
gestation day
GD
Good Laboratory Practices
GLP
granulocyte/macrophage colony stimulating factor
GM-CSF
glutathione
GSH
glutathione-S-transferase
GST
hour
h
hectare
ha
haemoglobin
Hb
haematocrit
Hct
Priority Existing Chemical Number 21
xvi
International Agency for Research on Cancer
IARC
interleukin-1
IL-1
International Programme on Chemical Safety
IPCS
International Uniform Chemical Information Database
IUCLID
International Union for Pure and Applied Chemistry
IUPAC
Kelvin
K
kilogram
kg
Michaelis-Menten constant
Km
kilometre
km
km2 square kilometre
sorption coefficient
Koc
kilopascal
kPa
kilotonne
kt
litre
L
lymphocyte
LC
median lethal concentration
LC50
median lethal dose
LD50
lowest observed adverse effect level
LOAEL
leaded petrol
LP
liquid pressurised gas
LPG
m3 cubic meter
mean corpuscular volume
MCV
myelodysplastic syndrome
MDS
milligram
mg
millilitre
mL
megalitre
ML
millimolar
mM
multiple myeloma
MM
micronucleus
MN
mole
mol
material safety data sheet
MSDS
nicotinamide adenine dinucleotide phosphate
NADPH
National Environment Protection Council
NEPC
National Environment Protection Measures
NEPM
nanogram
ng
National Health Interview Survey
NHIS
non-Hodgkin's lymphoma
NHL
National Industrial Chemicals Notification and Assessment Scheme
NICNAS
National Institute of Occupational Safety and Health
NIOSH
nanometre
nm
nanomole
nmol
nanomolar
nM
no observed adverse effect level
NOAEL
no observed effect concentration
NOEC
National Occupational Health and Safety Commission
NOHSC
National Pollutant Inventory
NPI
NAD(P)H:quinone oxidoreductase
NQO1
non-steroidal anti-inflammatory drug
NSAID
Organisation for Economic Co-Operation and Development
OECD
odds ratio
OR
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Occupational Safety and Health Administration
OSHA
polycyclic aromatic hydrocarbon
PAH
prostaglandin E2
PGE2
protein kinase C
PKC
blood platelet
Plt
predicted no-effect concentration
PNEC
octanol/water partition coefficient
Po/w
persistent organic pollutant
POP
parts per billion
ppb
personal protective equipment
PPE
parts per million
ppm
premium unleaded petrol
PULP
red blood cell (erythrocyte)
RBC
ribonucleic acid
RNA
relative risk
RR
second
s
spontaneous abortion
SAb
secondary acute myeloid leukaemia
s-AML
subcutaneous
SC
sister chromatid exchange
SCE
small-for-gestational age
SGA
standardised incidence rate
SIR
State marketing area
SMA
standardised mortality rate
SMR
sewage treatment plant
STP
Standard for the Uniform Scheduling of Drugs and Poisons
SUSDP
tonne
t
Technical Guidance Document
TGD
time-weighted average
TWA
8-h time-weighted average
TWA8
unleaded petrol
ULP
United Nations
UN
United States Environmental Protection Agency
USEPA
upper tolerance limit of a distribution's 95th percentile
UTL95%,95%
volume/volume
v/v
volatile organic chemical
VOC
weight/weight
w/w
white blood cell (leukocyte)
WBC
World Health Organization
WHO
year
y
microgram
礸
microlitre
礚
micromolar
礛
micromole
祄 o l
8-hydroxydeoxyguanosine
8-OHdG
Priority Existing Chemical Number 21
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1. Introduction
1.1 Declaration
The chemical benzene (CAS No. 71-43-2) was declared a Priority Existing
Chemical for full assessment under the Industrial Chemicals (Notification and
Assessment) Act 1989 on 7 April 1998. It was nominated by the public because of
concerns about its human health effects and the adequacy of the current Australian
occupational exposure standard.
1.2 Objectives
The objectives of this assessment were to:
? characterise the properties of benzene;
? determine the uses of benzene in Australia;
? determine the extent of occupational, public and environmental exposure to
benzene;
? characterise the intrinsic capacity of benzene to cause adverse effects on
persons or the environment;
? characterise the risks to humans and the environment resulting from exposure
to benzene; and
? determine the extent to which any risk is capable of being reduced.
1.3 Sources of information
Consistent with the objectives, this report presents a summary and critical
evaluation of relevant information relating to the potential health and
environmental hazards from exposure to benzene. Relevant scientific data were
submitted by the applicants listed in Section 3, obtained from published papers
identified in a comprehensive literature search of several online databases up to
December 2000, or retrieved from other sources such as the reports and resource
documents prepared for the health surveillance program of the Australian Institute
of Petroleum (AIP) and the Illawarra leukaemia cluster investigation. Due to the
availability of several peer-reviewed overseas assessment reports, not all primary
sources of data were evaluated. However, relevant studies published since the cited
reviews were assessed on an individual basis.
The characterisation of health and environmental risks in Australia was based upon
information on use patterns, product specifications, occupational exposure and
emissions to the environment made available by applicants and relevant State
authorities. Information to assist in the assessment was also obtained through site
visits and telephone interviews. The site visits included two petroleum refineries,
two petrol terminals, a steelworks, a coal tar distillery, a bulk liquid storage facility
and three chemical plants.
Benzene 1
1.4 Peer review
During all stages of preparation, the report has been subject to internal peer review
by NICNAS, Environment Australia (EA) and the Therapeutic Goods
Administration (TGA). Selected parts of the report were also peer reviewed by
Professor Tom Beer, CSIRO Atmospheric Research (Sections 8 and 15); Dr
Stephen Corbett, New South Wales Department of Health (Section 11); Dr Andrea
Hinwood, Department of Environmental Protection, Western Australia (Sections 9,
11 and 13); and Professor Martyn T. Smith, University of California (Sections 9
and 12).
Priority Existing Chemical Number 21
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2. Background
2.1 Introduction
Benzene is a naturally occurring, hazardous, volatile organic compound which is
ubiquitous in the environment. It is formed from biomass under the impact of heat,
pressure and geological time. As such, it is present in fossil fuels which may release
it to air when unearthed and, in particular, when heated to combustion. Benzene is
also a product of natural processes and human activities that involve the
instantaneous thermal degradation of organic matter. These sources of entry include
bush fires, crop residue and forest management burning, petroleum refining, petrol
combustion, wood and charcoal fires, fumes from heated cooking oils, tobacco
smoke, incense, and waste incineration. In addition, benzene enters the
environment in emissions and waste streams from industrial processes and waste
disposal facilities.
2.2 International perspective
Benzene was first isolated in 1825 and gradually became widely used as a solvent
and starting material for the synthesis of a number of organic chemicals (Folkins,
1984). Benzene also became recognised as a valuable constituent of petrol because
of its antiknock properties and ability to increase the octane rating of automotive
fuels.
Until World War II, benzene was isolated from light oil, which is a by-product of
the carbonisation of coal to produce gas for heating or coke for the blast furnaces of
the steel industry. Beginning in the 1930s, new catalytic and thermal processes for
the production of aromatic hydrocarbons from crude oil were discovered and
commercialised in the petroleum industry. With the advent of natural gas in the
1960s, worldwide coal gas production started to diminish. Simultaneously, the
introduction of modern steel processing methods decreased coke production and
made it attractive to burn the light oil as fuel rather than segregate it into benzene
and other products. In consequence, the petroleum industry is now the predominant
source of benzene.
In recent years, the use of benzene-containing solvents has been practically
eliminated because of the toxicity of the chemical. Current worldwide consumption
of benzene is 30-35 million metric tonnes (t) per annum, primarily as chemical
feedstock in the production of large-scale intermediates such as ethyl benzene,
cumene and cyclohexane (Chemistry & Industry News, 1996). This figure does not
include benzene produced by the petroleum industry and retained as a petrol
component.
Commercial low-grade qualities are sometimes referred to as benzol. Benzene is
not to be confused with benzine, which is a mixture of several low-boiling
hydrocarbons obtained in the distillation of petroleum.
2.3 Australian perspective
Developments in Australia have followed the general pattern outlined above, albeit
with a delay of 1-2 decades. The recovery of benzene from coal gas is now limited
Benzene 3
to the steelworks at Port Kembla in New South Wales and Whyalla in South
Australia.
There are eight petroleum refineries in Australia: two in Brisbane and Sydney and
one in Adelaide, Geelong, Melbourne and Perth. Since the 1970s, close to 100% of
local demand for petrol has been met from crude which is low in aromatic fractions
(Tresider, 1998). As such, all Australian petroleum refineries have processes in
place to increase the content of aromatic hydrocarbons including benzene in their
petrol blendstock. Petroleum-derived benzene feedstock for the chemical industry
is not produced in Australia.
As of 1986, new petrol-driven cars had to be fitted with catalytic converters and use
unleaded fuel. An Australian Standard for petrol for motor vehicles was established
in 1990 and limited the benzene content to a maximum of 5% v/v (Standards
Australia, 1990). In 1998, the average benzene content in Australian petrol was 2.9,
2.6 and 3.3% v/v in leaded petrol (LP), unleaded petrol (ULP) and premium
unleaded petrol (PULP) respectively (AIP, 1998b). The Fuel Quality Standards Act
2000 enables the Commonwealth to make mandatory national quality standards for
fuel supplied in Australia. Among others, these will include a maximum content of
benzene in petrol of 1% v/v from January 1 2006. Meanwhile, Western Australia
and Queensland have introduced regulations limiting the benzene content in petrol
to 1% and 3.5% respectively (EA, 2000b).
In 1980, AIP contracted The University of Melbourne to set up an epidemiological
health surveillance program called Health Watch. The program covers about 95%
of the industry's 18,000 employees in refineries, natural gas plants, distribution
terminals and production sites. It consists of a prospective cohort study of all-cause
mortality and cancer incidence, in addition to a case-control study of lympho-
haematopoietic cancers and benzene exposure established in 1988 (Glass et al.,
1998, 2000; Health Watch, 1998).
Air pollution became a major concern in the 1990s and prompted environment and
health authorities from the Commonwealth, States and Territories to initiate several
research projects into ambient air quality. Early results of this research resulted in
the inclusion of benzene in the National Pollutant Inventory (NPI), which was
established by the National Environment Protection Council (NEPC) in 1998. The
NPI currently comprises 36 chemicals of health and environmental concern which
must be reported to EA if the quantity used or handled per site exceeds a threshold
limit, which for benzene is 10 t per year (EA, 1999b). More recently, the Australian
and New Zealand Environment and Conservation Council contracted the Victorian
Environment Protection Authority (EPA) to assess the available air level data and
derive a risk-based rank order of hazardous air pollutants according to their
priorities for further research (EPA Victoria, 1999). Based on a scoring system as
well as on professional judgement, benzene came first among 15 chemicals
recommended for general urban air monitoring. Benzene is also the subject of a
publication in the series of National Environmental Health Forum Monographs,
which are intended to provide plain language information about important, topical
environmental health matters (Wadge & Salisbury, 1997). Current EA initiatives
such as the Fuel Quality Review and Living Cities ?Air Toxics Program both
address a number of environmental aspects relating to benzene (EA, 2000a, 2000b).
Public concern about exposure to benzene reached a peak in 1996, when a cluster
of leukaemia cases was identified in people living in the suburbs adjacent to the
coke ovens and coal gas by-product plant at the Port Kembla steelworks. A
committee reporting to the New South Wales Department of Health was set up to
Priority Existing Chemical Number 21
4
investigate the matter. It concluded that based on the available data, it was not
possible to ascribe the cluster to a particular exposure (including benzene). The
investigation produced several useful publications relating to benzene and the risk
of leukaemia (ILISC, 1997; Westley-Wise et al, 1999).
2.4 Assessments by other national or international bodies
Although there have been restrictions on the manufacture, handling, storage and
use of benzene in Australia since 1978, this report represents the first
comprehensive risk assessment by a national agency.
Benzene has been assessed by several overseas or international bodies involved in
the review or evaluation of data pertaining to the health and/or environmental
hazards posed by chemicals. Of these, the most noteworthy are:
? The Advisory Committee to the German Chemical Society on Existing
Chemicals of Environmental Relevance (GDCh, 1988);
? The Agency for Toxic Substances and Disease Registry under the US
Department of Health and Human Services (ATSDR, 1997);
? The Commission of the European Communities (EC, 1989, 2000);
? Environment and Health Canada (Government of Canada, 1993);
? The International Agency for Research on Cancer (IARC, 1982a, 1987);
? The International Programme on Chemical Safety (IPCS, 1993);
? The UK Department of the Environment (DoE, 1994);
? The US Environmental Protection Agency (USEPA, 1985, 1998a, 1998c); and
? The OECD SIDS International Assessment Report (draft) (OECD, 2000).
Benzene 5
3. Applicants
Following the declaration of benzene as a Priority Existing Chemical, 21
companies or organisations applied for assessment of the chemical. The applicants
supplied information on the properties, import and manufacturing quantities and
uses of benzene and, in some cases, on occupational exposures and releases to the
environment. In accordance with the Industrial Chemicals (Notification and
Assessment) Act 1989, NICNAS provided the applicants with a draft copy of the
report for comments during the corrections/variation phase of the assessment. The
applicants were as follows:
Koppers Coal Tar Products Pty Ltd
Alltech Associates (Australia) Pty Ltd
PO Box 23
PO Box 6005
Mayfield NSW 2304
Baulkham Hills NSW 2153
Australian Institute of Petroleum Merck Pty Ltd
207 Colchester Rd
GPO Box 279
Kilsyth VIC 3137
Canberra ACT 2601
Mobil Oil Australia Pty Ltd
Australian Council of Trade Unions
417 St Kilda Rd
393 Swanston Street
Melbourne VIC 3004
Melbourne VIC 3000
BHP Steel ?Flat Products
Australian Manufactures Workers Union
PO Box 1854
3/440 Elizabeth Street
Wollongong NSW 2505
Melbourne VIC 3000
Bio-Scientific Pty Ltd Qenos Pty Ltd
PO Box 78 Private Bag 3
Gymea NSW 2227 Altona VIC 3018
BP Australia Holding Limited Selby-Biolab
360 Elizabeth St Private Bag 24
Melbourne VIC 3000 Mulgrave North VIC 3170
Caltex Petroleum Australia Pty Ltd Sigma-Aldrich Pty Ltd
19-29 Martin Pl PO Box 970
Sydney NSW 2000 Castle Hill NSW 2154
Terminals Pty Ltd
Crown Scientific Pty Ltd
PO Box 268
Private Mail Bag 4
Footscray VIC 3011
Moorebank NSW 2170
3M Australia Pty Ltd
Huntsman Chemical Company Australia
PO Box 144
Pty Ltd
St Marys NSW 2760
PO Box 62
West Footscray VIC 3012
Trafigura Fuels Australia Pty Ltd
ICN Biomedicals Australasia
Unit 2, 47 Epping Rd
PO Box 187
North Ryde NSW 2113
Seven Hills NSW 2147
Whyalla Steelworks (OneSteel
Manufacturing)
PO Box 21
Whyalla SA 5600
Priority Existing Chemical Number 21
6
4. Chemical Identity and
Composition
4.1 Chemical name (IUPAC)
Benzene
4.2 Registry numbers
Benzene is listed on the Australian Inventory of Chemical Substances (AICS) as
benzene.
CAS number 71-43-2
EINECS number 200-753-7
UN number 1144
4.3 Other names
Annulene
Benzol(e)
Bicarburet of hydrogen
Carbon oil
Coal naphtha
Cyclohexatriene
Mineral naphtha
Motor benzol
Phenyl hydride
Pyrobenzol(e)
4.4 Molecular formula
C6H6
4.5 Structural formula
or
Benzene 7
4.6 Molecular weight
78.11
4.7 Composition of commercial grade product
Several different grades of benzene are commercially available. The principal
impurities are toluene, xylenes and other hydrocarbons with boiling points similar
to that of benzene. The higher the grade, the lower the content of thiophene
(thiofuran) and other sulfur compounds, which foul many catalysts used in
reactions of benzene (Fruscella, 1992). The specifications for two typical import
grades and the benzene/toluene/xylenes (BTX) mixture produced at the Port
Kembla steelworks are shown in Table 4.1.
Table 4.1: Raw material specifications for some commercially available
benzene grades
Test Pure benzene Crude benzene BTX
Benzene (% v/v) >99 95 80
C9 & higher (% v/v) - <1.5 <1.6
Carbon disulfide (ppm) - <50 <4000
H2S & SO2 None - -
Non-aromatic C5-C6 (% v/v) <0.15 <0.7 <1.5
Styrene (% v/v) - - <1.8
Thiophene (ppm) <1 <6000 <6000
Toluene (% v/v) - - <12.5
Total sulfur (ppm) - - <6000
Xylenes & styrene (% v/v) - - <3.8
Priority Existing Chemical Number 21
8
5. Physical and Chemical
Properties
5.1 Physical state
Benzene is a volatile, colourless and flammable liquid with a characteristic, sweet
aromatic odour (Budavari, 1996). The odour threshold ranges from 0.8-160 ppm
(AIHA, 1989); 50% of the population can identify the odour at 2 ppm and 100% at
5ppm (Verscheuren, 1996). The physical properties of benzene are summarised in
Table 5.1.
Conversion factors (at 25癈):
1 mg/m3 = 0.31 ppm and 1 ppm = 3.2 mg/m3 (Cavender, 1994).
5.2 Physical properties
Table 5.1: Physical properties
Property Value Reference
Melting point 5.53篊 Folkins (1984)
Boiling point 80.1篊 Folkins (1984)
Density
0.885 kg/L Fruscella (1992)
? at 15篊
0.879 kg/L
? at 20篊
0.874 kg/L
? at 25篊
Vapour density 2.8 (relative to air = 1) Cavender (1994)
Vapour pressure
3.47 kPa Folkins (1984), Fruscella
? at 0篊
9.97 kPa (1992)
? at 20篊
12.6 kPa
? at 25篊
24.2 kPa
? at 40篊
35.8 kPa
? at 50篊
Water solubility (at 25篊) 1.80 g/L IPCS (1993)
3
Henry's Law constant (at 20篊) 0.56 kPa.m /mol Mackay & Leinonen (1975)
Partition coefficient (log Po/w) 1.56-2.15 IPCS (1993)
Sorption coefficient (log Koc) 1.8-1.9 IPCS (1993)
Flash point (closed cup) ?11篊 Fruscella (1992)
Autoignition temperature 560篊 Fruscella (1992)
Explosive limits
3
1.4% v/v (45 g/m ) Cavender (1994)
? lower
3
7.9% v/v (250 g/m )
? upper
5.3 Chemical properties
The six carbon atoms of benzene form a regular hexagon and all 12 atoms lie in a
single plane, with all bond angles being exactly 120?(Fruscella, 1992). The
molecule is traditionally depicted as having alternating single and double bonds
(see structure (1) in Section 4). However, as the six carbon-carbon bonds are
Benzene 9
physically and chemically identical and intermediate in length between single and
double bonds (as indicated by structure (2) in Section 4), benzene does not react as
a typical unsaturated compound.
Benzene has great thermal stability and elevated temperatures are required for its
decomposition. It undergoes substitution and addition reactions and ring cleavage.
For industrial applications, the most important reactions are alkylation with
ethylene or propylene to produce ethyl benzene or cumene, hydrogenation to
cyclohexane, nitration and sulfonation to form nitrobenzene and benzenesulfonic
acid, and halogenations. Benzene cannot be hydrolysed.
Benzene is miscible with numerous other organic solvents including alcohol,
acetone, diethyl ether, ethyl acetate, chloroform, carbon disulfide, glacial acetic
acid and oils (Budavari, 1996). Its solubility in water ranges from 1.13% v/v at
25癈 to 5.07% v/v at 107癈 (Folkins, 1984). Benzene forms binary and tertiary
azeotropes with water and a large number of organic substances (for examples, see
Folkins (1984)).
Benzene is highly flammable and potentially explosive. Combustion products
include carbon dioxide, water vapour and carbon monoxide. With a deficiency of
air or oxygen, partial decomposition and soot deposition occur (Folkins, 1984).
Vapours burn with a sooty flame.
Priority Existing Chemical Number 21
10
6. Methods of Detection and
Analysis
6.1 Characterisation
Benzene can be characterised by infrared, ultraviolet and mass spectrometry and
nuclear magnetic resonance techniques (Fruscella, 1992).
6.2 Detection and analysis
A time-honoured spot test for benzene in the workplace or surroundings involves
the treatment of a sample with nitric acid followed by ether extraction and
dissolution in a mixture of alcohol and methyl ethyl ketone. Benzene is converted
to m-dinitrobenzene which imparts a persistent red colour to the solution (Dolin,
1943, cited in Fruscella, 1992).
Standard analytical methods for benzene in air, water, soil, foods, smoke,
biological samples, petroleum products etc. rely on gas chromatography (GC) with
flame or photo ionisation detection, or on gas chromatography-mass spectrometry
(GC-MS) (Fruscella, 1992; IPCS, 1993). Benzene in water, soil and food is usually
measured by a purge and trap method by bubbling an inert gas through the sample
and collecting the chemical on an absorbent. Benzene is then desorbed and
determined. The best available GC methods are able to detect benzene at 0.1 ppb in
air or 1 ng/kg in liquid or solid media, although 3 ppb in air and 1礸/L in water are
the limits of detection in routine analysis (IPCS, 1993; NHMRC, 1996). The GC-
MS method is not quite as sensitive, but more reliable in the case of samples with
multiple components with retention times similar to that of benzene (IPCS, 1993).
6.3 Atmospheric monitoring methods
In the environment
The methods commonly used for measuring the concentration of benzene in
ambient air fall into the following two categories (EPA Victoria, 1999):
(1) discrete air sampling with subsequent laboratory analysis; or
(2) continuous or semi-continuous in-field analysis.
Among the former, the most widely used method involves the collection of air into
a stainless steel canister over a predetermined period of time such as 24 h, followed
by analysis of a concentrate of the air sample by GC or GC-MS. This method is
described in more detail by DEP Western Australia (2000).
A commonly used continuous method for in-field analysis utilises an optical remote
sensing system to determine the concentration of the chemical by means of the
differential absorption of transmitted light by gaseous compounds along the light
path. The system consists of a light transmitter and sensor placed at a given
distance apart at the monitoring site.
Alternatively, the concentration in air can be analysed by semi-continuous gas
chromatography. Samples of air are collected directly onto solid absorbents,
Benzene 11
desorbed thermally onto the GC column and analysed while the next sample is
collected.
The analytical limit of detection of the above methods typically ranges from 0.003-
0.1 ppb. All of the methods allow for the simultaneous determination of several
other gaseous air pollutants in the same sample. Discrete sampling methods
determine average pollutant levels over the sample collection time. Continuous or
semi-continuous methods enable more detailed information about concentration
variations to be obtained.
In the workplace
This section summarises the methods commonly used for the measurement of
benzene in the workplace. Other past and present techniques are described in a
recent review by Verma & des Tombe (1999a, 1999b).
For personal monitoring during full shifts or tasks, workers are equipped with a
charcoal tube or badge placed in the breathing zone. For area monitoring, the tube
or badge is placed at a fixed location in the workplace environment. Tubes are
connected with a portable metering pump, whereas badges sample the air by
diffusion. At the end of the sampling period, the tube or badge is sealed and
transferred to a laboratory, where the chemical is liberated from the absorbent by
elution or thermal desorption and quantified by GC (NIOSH, 1994). The result is
expressed as a time-weighted average (TWA) concentration in ppm or mg/m3 over
the duration of the sampling period. The analytical detection limit depends on the
airflow across the absorbent and the duration of the sampling period. The detection
limit using charcoal tube sampling and analysis according to the NIOSH method is
0.02 ppm.L, or 0.004 ppm for a sample collected over 60 min at a pump speed of
80 mL/min (IPCS, 1993). The agreement between the tube and badge methods is
not perfect, but the differences are generally of little importance (Hotz et al., 1997;
Purdham et al., 1994).
`Grab sampling' or instantaneous measurement of the concentration of airborne
benzene is conducted with colorimetric detector tubes. These are glass tubes sealed
at both ends with a graduated concentration scale etched into the outer surface. The
tubes contain a carrier material covered with chemical reagents that react with
benzene to produce a colour change whose end-point is read against the scale. Prior
to use, the seals are broken, the tube is connected to a hand pump and the pump is
operated to draw a defined amount of air through the tube. A colorimetric detector
has become available which can measure benzene at 0.2 ppm in the presence of
other hydrocarbons, with a measuring time of 8 minutes. Non-selective
photoionisation detectors can be used for instantaneous measurement of benzene
concentrations with a detection limit of approximately 0.1 ppm but, because the
detector also responds to volatile organic chemicals, they are limited to situations
where the vapour is known to be pure benzene. Recently, a benzene-selective
photoionisation detector has become available which is claimed to be able to
measure benzene at concentrations of 0.1 ppm ?200 ppm in the presence of other
hydrocarbons within approximately 1 minute. The detector uses a single use pre-
treat tube to filter out interfering hydrocarbons except for C3 alkanes and must be
calibrated against 5 ppm benzene prior to use.
A less widely used method is continuous area monitoring, which is performed by
pumping air collected at one or more fixed locations through an auto analyser
equipped with an ultraviolet spectrometer. This method delivers readings for TWA
Priority Existing Chemical Number 21
12
as well as peak concentrations and has a limit of detection of approximately 0.2
ppm (IPCS, 1993).
6.4 Biological monitoring methods
Biological monitoring for benzene exposure involves the measurement of
unmetabolised benzene in blood, urine or breath samples, of benzene metabolites in
the urine, or of protein adducts with the benzene oxide metabolite.
The concentration of benzene in venous blood and urine can be determined by GC,
with a detection limit of around 0.5 礸/L (IPCS, 1993). For the determination of
benzene in breath air, an end-exhaled sample is collected and analysed by GC-MS,
with a detection limit of 3-6 ppb (Money & Gray, 1989). However, these methods
are only suitable for research purposes, as great care must be exercised to avoid
contamination of the samples with ambient benzene.
Various metabolites are excreted in the urine, including phenol, hydroquinone and
catechol conjugates, S-phenylmercapturic acid and trans,trans-muconic acid (see
Section 9.3), although none of them is formed exclusively from benzene. These
metabolites can be quantified by GC, GC-MS or high-performance liquid
chromatography as described by Ducos et al. (1990), Hotz et al. (1997), Lee et al.
(1993), Popp et al. (1994) and others. Whereas the urinary concentration of phenol
has been widely used as an index of benzene exposure, the background levels make
it unreliable at exposures <5-10 ppm. The concentration of S-phenylmercapturic
acid or muconic acid relative to creatinine in an end-of-shift urine sample has been
shown to be a fairly good indicator of exposure in the 0.25-1 ppm range, even in
smokers (Ghittori et al, 1995; Hotz et al, 1997; Ong et al, 1996).
The metabolite benzene oxide binds to nucleophilic sites and forms phenyl cysteine
residues with proteins such as haemoglobin and albumin (see Section 9.3.1). The
concentration of such adducts in blood correlates with benzene exposure. However,
high background levels severely limit the practical use of the S-phenyl cysteine
adduct as a biological marker for benzene uptake (Yeowell-O'Connell et al, 1998).
Benzene 13
7. Manufacture, Importation and
Use
7.1 Manufacture and importation
Benzene is introduced into Australia through extraction, importation and
manufacture.
The total Australian production of crude in 1994-98 is shown in Figure 7.1. Crude
includes unrefined oil as well as condensate, which is a liquid mixture of
hydrocarbons recovered from gas wells. The mean annual and 1998 volumes are
both approximately 31,000 ML. Australian crude is reported to have a low benzene
content, estimated at about 0.1% v/v (Glass et al, 1998). As such, the annual
extraction of benzene from Australian oil and gas fields can be estimated at
approximately 31 ML. As the density of benzene is around 0.88 kg/L, this
corresponds to a quantity of 27 kilotonnes (kt) pure benzene.
Figure 7.1: Australian production of crude oil and condensate 1994-98 (AIP,
1999b)
34
33
32
ML x 1000
31
30
29
28
27
1994 1995 1996 1997 1998 M ean
The throughput of crude at Australian refineries in 1998 was 44,678 ML, of which
62% was of non-Australian origin (AIP, 1999a). Most of the imports come from oil
fields in the Pacific basin and contain approximately the same concentration of
benzene as Australian crude, that is, about 0.1% v/v (Glass et al, 1998). This
corresponds to a total input of 45 ML or 39 kt pure benzene.
From these figures, it can be concluded that Australia is a net importer of benzene
in crude to the tune of approximately 12 kt per annum.
Table 7.1 shows the throughput of benzene-containing gasoline products, that is,
leaded petrol (LP), unleaded petrol (ULP), premium unleaded petrol (PULP) and
light aircraft gasoline (Avgas), at Australian refineries in 1998. The table also gives
the average content of benzene and the corresponding quantities of pure benzene.
Data for Avgas are estimates, but have little impact on the total. Other petroleum
products such as liquefied petroleum gas, kerosene, civil aviation jet fuel, diesel oil,
fuel and heating oils and lubricants contain no or practically no (<0.02% v/v)
benzene (AIP, 1999a; IARC, 1989; Potter & Simmons, 1998).
The volume of pure benzene in petrol produced at Australian refineries in 1998 was
484 ML, corresponding to 426 kt pure benzene. As the throughput crude contained
Priority Existing Chemical Number 21
14
approximately 39 kt pure benzene, it can be concluded that the production of
benzene in the Australian petroleum industry amounted to 387 kt in 1998.
Table 7.1: Throughput of LP, ULP, PULP and Avgas at Australian refineries in
1998 (AIP, 1998b, 1999b)
LP ULP PULP Avgas Total
Petrol (ML) 4965 12,218 640 100 17,923
Benzene (% v/v) 2.9 2.6 3.3 1.0 -
Pure benzene (ML) 144 318 21 1 484
Petrol is also imported in finished form. From January 1994 through August 1999,
petrol imports averaged 680 ML per annum (DISR, 1999). There is no information
on the benzene content of imported petrol, but it is unlikely to differ much from
that of Australian ULP, which averages 2.6% v/v. As such, annual imports of
benzene as an ingredient in petrol purchased overseas is estimated at 18 ML
corresponding to approximately 15 kt pure benzene.
The Port Kembla steelworks produces 20-22 ML per annum of a commercial low-
grade benzene product called BTX. As the specifications stipulate a benzene
content of 80% v/v (Table 4.1), this corresponds to approximately 14.0-15.5 kt
pure benzene per annum. The Whyalla steelworks no longer produce BTX,
however, 0.12kt of benzene per annum, from the naphthalene still, is reinjected into
the fuel gas stream.
Benzene is also produced as a by-product stream component at two olefins
(pyrolysis) plants belonging to Qenos Pty Ltd. The total quantity amounts to
approximately 15 kt per annum, all of which is exported for use or further
processing overseas.
The only importer of benzene feedstock is Huntsman Chemical Company, whose
annual imports are stable at about 50 kt pure benzene and 30 kt crude benzene
(95% v/v), that is, approximately 80 kt pure benzene per annum.
Minor quantities not exceeding 1 t in the aggregate are imported for laboratory and
other small-scale uses, as described below.
7.2 Manufacturing processes and end use
7.2.1 Petroleum industry
Table 7.2 provides an overview of the location and ownership of the currently
operating oil refineries in Australia, as well as a summary of the processes
employed to produce benzene, their capacity, and the benzene content of locally
produced petrol. The latter is taken from a 1994 survey, which reported the
concentration in % w/w (Tresider, 1998). As such, it is not directly comparable to
the data provided in Table 7.11. The process technologies and end use of the
benzene produced are described below.
1
The factor needed to convert % w/w to % v/v varies with the density of the petrol. Based on the
average density of Australian petrol in 1999, multiplication of the concentration in % w/w with 0.84
will give an approximate concentration in % v/v (Exxonmobile personal communication, 2001).
Benzene 15
Table 7.2: Benzene processes at Australian oil refineries (AIP, 1997; Mobil,
2000; Tresider, 1998)
Benzene in
Benzene Capacity
LP/ULP/PULP (% w/w)
State Location Owner technology (kt/y)*
NSW Clyde Shell Reforming 890 2.7/ 2.4/3.6
Cracking 1558
Kurnell Caltex Reforming 1344 2.3/2.3/4.7
Cracking 2024
QLD Bulwer Island BP Reforming 588 2.5/3.7/5.0
Cracking 912
Lytton Caltex Reforming 1157 2.4/2.5/4.4
Cracking 1469
Reforming
SA Port Stanvac Mobil 1157 2.3/2.0/2.5
VIC Altona Mobil Reforming 1380 4.8/4.5/5.5
Cracking 1246
Geelong Shell Reforming 1380 3.6/3.6/5.4
Cracking 1780
WA Kwinana BP Reforming 979 1.9/2.0/2.2
Cracking 1456
* The capacity is calculated on the basis of 350 stream days per year and refers to the quantity of raw
material processed, not benzene produced.
Based on more recent information (AIP average data for 1999), ULP contains
approximately 3.01% (w/w) benzene, PULP contains 4.02% (w/w) and LP contains 3.46
(w/w) (Exxonmobile Personal Communication, 2001).
Petroleum refining
Petroleum refining involves a series of continuous, enclosed processes designed to
convert crude oil and condensate into end products such as liquefied petroleum gas,
Avgas, petrol, jet fuel, diesel, heating oil, lubricants and bitumen. The main
processes designed to augment the content of aromatics such as benzene in petrol
are shown in the flowchart in Figure 7.2 and summarised below.
Figure 7.2: Benzene production in petroleum refineries
Isobutane
Distillation
CRUDE Straight run gasoline
30-105癈
PETROL AND
Catalytic AVGAS
Naphtha reforming BLEND-
STOCKS
105-155癈
Vacuum
Catalytic
distillation Alkylation
cracking
Heavy
gas oil
340-425癈
Priority Existing Chemical Number 21
16
At all refineries, crude oil is first separated into a number of fractions by
atmospheric and vacuum distillation. Petrol is a blend of butane, refined naphthas,
isomerate, reformate, cracked gasoline and alkylate. Avgas is primarily made from
alkylate although reformate can also be used.
The straight run gasoline fraction contains a 5- to 10-fold concentrate of all the
benzene that was present in the crude, corresponding to a benzene concentration of
0.5-1% v/v.
The naphtha fraction, which contains many cyclic, saturated hydrocarbons,
undergoes catalytic reforming in a process using heat, pressure and a platinum
catalyst to convert a portion of the feedstock to aromatic compounds. The resulting
reformate typically contains 4-8% v/v of benzene (Audrey, 1994).
At the Mobil Altona refinery, part of the heavy gas oil fraction is piped to a nearby
petrochemical plant for steam cracking, as described below. This process gives rise
to a by-product known as steam cracked naphtha or pyrolysis gasoline, which
contains 6-8% benzene. This by-product stream is piped back to the oil refinery
where it is stored in floating-roof tanks and eventually exported to overseas
customers by shipping tanker.
The heavy gas oil fraction, which contains large, high boiling hydrocarbon
molecules, is cracked to a mixture of lower molecular weight compounds by means
of heat, pressure and a silica/aluminium oxide or zeolite catalyst. The benzene
content of cracked gasoline rarely exceeds 1-2% v/v, but varies depending on the
composition of the feedstock, the nature of the catalyst and the temperature and
pressure conditions. As shown in Figure 7.2, some of the output from the cracking
process is reacted with isobutane to form larger branched-chain molecules
(isoparaffins) that increase the octane rating of the final petrol blend. The alkylation
process does not augment benzene content.
Eventually, the various petrol feedstock qualities are blended to produce end
products with the desired specifications. These vary according to the likely ambient
temperatures in the area and season in question and generally require higher
concentrations of aromatic components such as benzene in colder climates.
Feedstock and end product are stored in tanks equipped with floating roofs or
connected to vapour recovery systems. The end products are distributed to larger
terminals by pipeline, in coastal tankers or bottom-loaded rail tankers and/or to
local depots and service stations in road tankers, the majority of which are bottom
loaded. In rural areas not all road tankers are bottom loaded. Terminals in Sydney,
Melbourne and Perth have vapour recovery systems to minimise vapour emissions
during truck filling operations. There were 8233 petrol retail outlets in Australia at
the end of 1998 (AIP, 2000).
End use
In Australia, all benzene produced by petroleum refiners is retained as one of several
aromatic components in automotive petrol and Avgas; most of this benzene is burnt
during normal engine operation. Figure 7.3 shows the total demand for benzene-
containing petroleum products in 1996, and its breakdown by State marketing area2.
2
The State marketing area (SMA) of Queensland includes the Murwillumbah district of NSW, which
is supplied from the refineries in Brisbane. The SMA of South Australia includes the Broken Hill-
Wilcannia district of NSW and the Murrayville district of Victoria, which are supplied from the
refinery at Port Stanvac. The SMA of Victoria includes the Riverina district of New South Wales,
Benzene 17
Figure 7.3: Demand for petrol in 1996 (AIP, 1997)
NT
NT
TAS
TAS
WA
WA
NSW
SA NSW
SA
QLD
QLD
VIC
VIC
LP: 6782 ML ULP: 10,847 ML
TAS
NT
NT
WA NSW
TAS
SA
WA
NSW
VIC
QLD
SA
QLD
VIC
PULP: 338 ML Avgas: 102 ML
As expected, the demand for petrol is highest in the most populous States of New
South Wales and Victoria. Queensland, Western Australia and the Northern
Territory account for more than one-half of the total demand for Avgas.
Since catalytic converters became mandatory on new cars in 1986, there has been a
steady increase in the demand for ULP and a corresponding decline in the demand
for LP. However, although LP contains more benzene than ULP, the corresponding
fall in benzene consumption has been counterbalanced by an overall growth in
petrol demand. PULP, which was first produced in significant quantities in 1989
and has the highest concentration of benzene (Table 7.1), accounted for only 2% of
total petrol sales in 1996, almost half of which was generated in New South Wales.
However, PULP demand is expected to grow as LP is phased out nationally by
2002 and pre-1986 cars will need to run on either PULP or lead replacement petrol,
that is, PULP pre-blended with an anti-valve seat recession additive.
The likely impact of the predicted changes in demand on the use of benzene in
petrol can be estimated on the basis of AIP's petrol sales forecasts for the decade
1998-2007 (AIP, 1998a). If current benzene concentrations are assumed to remain
which is supplied from the refineries at Altona and Geelong. The SMA of New South Wales includes
the Australian Commonwealth Territory.
Priority Existing Chemical Number 21
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unchanged throughout the period, total benzene use in petrol is estimated to
increase from 434 kt/y in 1998 to 461 kt/y in 2007. However, if a nationwide
standard is introduced limiting the maximum content in petrol to 1%, total benzene
use in petrol is estimated to fall to 176 kt/y in 2007.
Independent petrol retailers
The main imports of petrol are marketed by independent chains or supermarkets
such as Trafigura (formerly Burmah) Fuels, Liberty and Woolworths, who had 564
service stations between them at the end of 1998 (AIP, 2000). Their imports pass
through the terminals of Vopak (formerly Van Ommeren) at Port Botany in Sydney
and Hastings Point near Melbourne, Gull at Kwinana in Western Australia, and
Fletcher Challenge in Brisbane. These terminals have a petrol storage capacity of
95, 70, 53 and 13 ML respectively (DISR, 1999; Vopak, 2000).
7.2.2 Steel and associated industries
BTX
In the steel industry, BTX is a by-product from volatile fractions produced in the
coking ovens. It contains 80% v/v benzene (see Table 4.1) and is recovered in an
enclosed process which yields from 3-5 kg pure benzene per t coke produced.
The coking ovens are arranged in batteries, each of which may contain in the region
of 60 units. The ovens are sequentially charged by means of mechanical hopper
systems through special lidded holes that are closed and sealed to keep out air
during the coking cycle. This cycle takes place at 900-1100癈 for 12-24 h. On
completion of the cycle, the hot coke is removed mechanically through doors on
the sides of the oven and sprayed with flushing liquor (a dilute solution of ammonia
in water) to quench combustion upon exposure to air.
The coke oven gas contains hydrogen, methane, carbon monoxide and light oil,
which is a mixture of various aliphatic and aromatic hydrocarbons, including
benzene. The overhead gas is collected into a pipe that runs along the length of
each battery and propelled to the by-product plant. At emission, it has a
temperature of approximately 600癈 which is brought down to 80癈 by spraying
with flushing liquor. It is further cooled to 38癈, passed through an electrostatic
precipitator and an acid scrubber where tar and ammonia are removed and cooled
to a final temperature of 20癈. The gas then passes to a system of light oil
scrubbers, where most of the C5 and higher hydrocarbons are recovered by counter-
current absorption using a high-boiling (300-400癈) petroleum fraction. BTX is
recovered from the absorbent oil by steam stripping and separated from the water
by distillation. At Port Kembla, the distillation process is continuous and BTX is
collected and piped to a storage tank. At the smaller Whyalla steelworks, BTX is
separated by batch distillation and returned directly to the gas system. At both sites,
the refined coke oven gas is stored in a gasholder and used for heating.
Process waste water, which is mainly from the flushing liquor circuit and contains a
number of contaminants, including benzene, is passed through a water/oil separator
and discharged to a biological treatment plant. All storage tanks are eventually
vented to the atmosphere, but may be connected to a vent header with a sealpot
arrangement to prevent emission unless there is a build-up of pressure. Excess gas
is flared off.
Benzene 19
All BTX produced at Port Kembla is transported by road to Huntsman Chemical
Company in Melbourne for use as chemical feedstock.
Coal tar
Tar condensed from the coke oven gas and flushing liquor circuit is collected in a
system of decanting tanks and pumped to a wet tar storage tank. This tank decants
excess liquor back to the liquor circuit and transfers the tar sediment to a dry tar
tank farm. The residue from the BTX distillation, which is known as naphthalene
oil, is also pumped to the dry tar tank farm. The dry tar, which contains 0.16%
residual benzene, is shipped to Koppers Coal and Tar Products at Mayfield,
Newcastle, New South Wales, in splash top loaded rail or road tankers, or by sea
tanker.
The Newcastle plant receives in the order of 125 kt crude tar per annum containing
about 145 t residual benzene. The plant comprises two interconnected, fully
enclosed systems which separate the tar in a series of continuous distillation
processes. The distillation products include solvent naphtha (4% benzene), distilled
tar (0.5% benzene), creosote oil (0.2% benzene), naphthalene (no measurable
benzene) and coal tar pitch (no measurable benzene). Most of the solvent naphtha
representing about 80% of the benzene received is burnt as fuel. The remainder is
blended into creosote oil which is used in solvent-based industrial timber
preservatives or as feedstock in the manufacture of carbon black. Distilled tar is
used in the coatings industry. Naphthalene is exported and coal tar pitch onsold to
the aluminium industry for the manufacture of carbon electrodes.
Process waste water from the Koppers coal tar plant is passed through a water/oil
separator and discharged to a biological treatment plant. All storage tanks are
connected to fume scrubbing systems. Off-gases from the stills are burnt as fuel.
7.2.3 Chemical industry
Qenos
Ethane and naphtha (gas oil) cracking
The olefins plant at the Qenos site at Altona in Melbourne produces 10-12 kt
benzene per year as a by-product of the steam cracking of ethane and naphtha (gas
oil) to ethylene, propylene and butadiene, which are then converted into plastics
and rubbers. The Qenos (formerly Orica) olefins plant at Botany in Sydney
produces 2-3 kt benzene per year as a by-product of the steam cracking of ethane to
ethylene.
Steam cracking is a continuous, fully enclosed process which produces a variety of
products by free radical reactions. Steam and hydrocarbon feedstock are mixed and
subjected to a brief surge of extreme heat (750-900癈). The effluent is rapidly
cooled, compressed, purified in a caustic washer, dried, chilled and fractionated in
a train of distillation columns.
At the Altona plant, the by-product streams from the ethane and naphtha steam
cracking processes are combined and purified by distillation to produce a pyrolysis
gasoline containing 6-8% benzene, which is piped to the Mobil Altona refinery and
eventually exported for use overseas (Section 7.2.1).
Priority Existing Chemical Number 21
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At the Botany plant, the heavier molecules produced in the cracking process are
collected in a feed tank and further processed in a fully enclosed system which is
on stream for approximately 60 days per annum. In the process, the by-product
stream is hydrogenated and then distilled to remove light ends, which are returned
to the ethane cracking system. The end product is a pyrolysis gasoline containing
approximately 55% aromatics including 35-36% benzene. This is stored on site in a
floating-roof tank. At intervals of 5-6 months, it is piped to the bulk liquid terminal
at Port Botany and shipped overseas for further processing.
Butadiene rubber manufacture
Qenos' Altona facility also uses about 40 t benzene per year as a solvent
component in the manufacture of butadiene rubber. The benzene is purchased from
Huntsman (see below) and supplied by dedicated road tanker. It is stored in a
nitrogen-blanketed tank and pumped to the butadiene rubber plant via sealed pipes.
In the plant, butadiene is polymerised in solution in a fully enclosed batch process.
The solvent contains cyclohexane and benzene in a ratio of about 2:1 and is not
consumed in the reaction. The polymerisation process is strongly exothermic and
the reactor temperature is kept at approximately 20癈 by ammonia cooling. The
reaction is stopped with an antioxidant. The solvent is removed from the rubber-
solvent solution by steam stripping and is then condensed, purified and recycled to
the beginning of the process for feedstock blending. Waste water is steam stripped
to remove dissolved benzene prior to discharge to sewer. Off-gases containing
benzene are sent to a thermal oxidiser for destruction.
Huntsman Chemical Company
The Huntsman (formerly Chemplex) plant at West Footscray in Melbourne
converts about 80 kt benzene per annum to ethyl benzene and 10-15 kt to cumene
(isopropyl benzene). Ethyl benzene is further processed to styrene, which is used in
the production of polystyrene polymers and unsaturated polyester and vinyl ester
resin solutions. Cumene is oxidised to acetone and phenol. The phenol is used on
site in the production of phenol-formaldehyde resins. The acetone is onsold in bulk
to other manufacturers.
Huntsman purchases about 15% of their requirements for benzene in the form of
BTX produced at the Port Kembla steelworks. The remainder is imported from
Indonesia, Japan, Korea and Singapore in chemical tankers. The bulk chemical is
unloaded at Terminals Pty Ltd on Coode Island on Melbourne's waterfront where it
is kept in storage before being transported to Huntsman by dedicated road tanker. A
small part is trucked to Qenos' Altona facility for use as a solvent component in the
manufacture of butadiene rubber.
Styrene manufacture
The styrene plant was commissioned in 1977 and operates a series of four
continuous, fully enclosed processes, namely, ethylene, Litol, alkylation and
dehydrogenation. The principal feedstocks are ethane, pure benzene and BTX.
In the Litol plant, BTX is vaporised with hot hydrogen and passed through fixed
bed catalytic reactors to hydro-dealkylate toluene and xylenes to benzene and
destroy heterocyclic compounds. Pure benzene is recovered by fractional
distillation. By-product hydrocarbon gases, excess hydrogen and heavy distillation
residues are used as fuel. A waste stream rich in hydrogen sulfide is incinerated.
Benzene 21
The alkylation plant makes ethyl benzene from benzene and ethylene produced on
site by the cracking of ethane. In the first of two reactors, the alkylation is carried
out in the presence of a homogenous acidic catalyst prepared separately from
aluminium chloride. In the second reactor, recycled polyethyl benzene is trans-
alkylated to ethyl benzene. The remaining undesired components from the dilute
ethylene benzene stream are recovered, neutralised and used as fuel. Catalyst is
removed from the alkylated liquor in a 3-stage wash system. The aqueous wash
liquors containing aluminium and sodium chlorides and some hydrocarbon
contaminants are treated aerobically at the site effluent treatment plant before
discharge to sewer. The alkylation liquor is then refined in a 3-column distillation
train. Pure ethyl benzene is recovered for subsequent use in the dehydrogenation
plant. Excess benzene and the polyethyl benzene are recovered and recycled to the
reactors. The heavy distillation residue is utilised elsewhere in the complex to
lower the viscosity of other residue streams and ultimately utilised as fuel.
In the dehydrogenation plant, ethyl benzene is dehydrogenated to styrene at high
temperature and low pressure in the presence of steam. The dehydrogenated
mixture is condensed and cooled, the water is separated out, and the stream is
refined in a 3-column distillation train. Hydrogen and other gases produced in the
reactor are used as fuel. By-product benzene and toluene are recovered and sent to
the Litol plant for conversion to pure benzene. Unreacted ethyl benzene is
recovered and returned to the dehydrogenation reactor. Pure styrene is distilled and
dosed with a polymerisation inhibitor prior to storage.
Tanks containing benzene are vented to a carbon bed vapour emission control
system that recovers about 60 t of benzene per annum and returns it to the styrene
plant.
Phenol manufacture
The phenol plant was commissioned in 1968. It produces phenol and acetone in a
continuous, fully enclosed process. Cumene is formed by the reaction of pure
benzene and propylene in a fixed-bed reactor using a phosphoric acid catalyst on a
solid support. The pure benzene feedstock is either imported or produced in the
styrene plant and piped to the phenol plant. A 3-column refining section recovers
gaseous components from the cumene stream. Unreacted benzene is recycled into
the process, and cumene is sent on to the oxidation reactor. Heavy distillation
residue is utilised as fuel or as an aromatic feedstock in the Litol plant. The purified
cumene stream is partially oxidised with air to cumene hydroperoxide, which is
cleaved by acid to a mixture of crude phenol and acetone. The mixture is split into
phenol and acetone, which are purified by distillation in a 7-column refining train.
Heavy distillation residue is subjected to a 2-column system, where some
additional phenol is recovered via pyrolysis and distillation for recycling to the
refining train. Residue from this system is utilised as fuel. Spent air from the
oxidation reactor is chilled to remove most of the organic substances and then
passed through activated carbon beds before release to the atmosphere. A combined
aqueous waste stream is treated in the site effluent treatment plant prior to
discharge to sewer.
7.2.4 Laboratory uses
Seven of the applicants listed in Section 3 identified themselves as occasional
importers of reagent grade benzene. Between them, they imported approximately
500 kg benzene in 1999, which was onsold to a total of 55 end users. Of these, 27
Priority Existing Chemical Number 21
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were commercial enterprises such as contract and company in-house analytical
laboratories. Twenty-one belonged to the science or medical faculties of 15
different universities. Seven were State or Commonwealth laboratories. The
quantities purchased by individual laboratories in 1999 ranged from 0.1-150 L
(0.88-130 kg), with a mean of 10 L (8.8 kg) and a median of 2.5 L (2.2 kg).
Benzene is also present in some ready-made liquid or gaseous standards for the
calibration of gas chromatographs and other analytical instruments. The quantity of
benzene consumed through the use of such standards is estimated at less than 1 kg
per annum.
7.2.5 Coincidental production
Benzene is formed coincidentally during the burning of aromatic and non-aromatic
organic compounds contained in biomass such as crops, wood and humus, in fossil
fuels such as black and brown coal, and in petroleum products including diesel and
jet engine fuel which have a negligible benzene content prior to combustion. These
processes are important sources of entry into the environment and will be
considered in detail in subsequent sections.
7.3 Summary
Table 7.3 summarises the industrial mass balance of benzene in Australia and the
available information on its major manufacturers, importers and users, and most
significant end uses. These figures are approximate and give a general indication of
industrial use of benzene in Australia. Benzene produced coincidentally in the
course of human activities or natural processes and products containing benzene as
an impurity are not accounted for.
Table 7.3: Benzene mass balance and major manufacturers, importers and
end users in Australia in 1998-99
Kilotonnes/year (rounded)
Industry or Extrac- Manu- Con-
company End use
Import Total Export
tion facture sumption
Petroleum 30 385 25 440 - 440 Petrol
Huntsman - - 80 80 - 95 Feedstock
Steel 15 - - 15 - 0.2 Fuel
Qenos - 15 - 15 15 0.040 Solvent
Others - - 0.0005 0.0005 - 0.0005 Reagent
TOTAL 45 400 105 550 15 535 -
In 1998-99, total benzene consumption in Australia was in the order of 535 kt per
year. Of this quantity, 105 kt were imported, 45 kt were extracted from crude oil
and coal gas, and the remainder produced at eight oil refineries. Petrol accounted
for approximately 82%, chemical synthesis for 18% and all other uses combined
for less than 1% of total consumption.
Benzene 23
8. Environmental Release, Fate
and Effects
As no environmental fate and toxicity studies were submitted for assessment, this
section is based on international, peer-reviewed reports such as GDCh (1988),
Government of Canada (1993) and IPCS (1993), the International Uniform
Chemical Information Database (IUCLID) and the USEPA's ECOTOX database
(USEPA, 2000). Data within these three reports are largely the same and also
appear in the databases.
IUCLID contains non-confidential data supplied by industry to the European
Commission. They have not undergone peer review and are therefore only reported
where they are not described elsewhere but nonetheless give guidance to the fate
and effects of benzene in the environment. Results in the ECOTOX database have
been published and are generally considered reliable.
8.1 Environmental release
Benzene is ubiquitous in the environment, with numerous sources of entry
including bush fires, crop residue and forest management burning, petrol
combustion, wood fires, tobacco smoking and emissions and waste streams from
various industries. Due to the nature of benzene being produced incidentally during
natural processes and human activities, it is not possible to obtain accurate figures
in estimating national releases. However, several point source releases provided in
NPI reports for the first reporting year of 1998/99 are described in Section 15,
which also gives an estimation of diffuse releases in a model urban environment.
Overall, release of benzene will primarily be to the atmosphere through emissions
in exhaust during petrol combustion in motor vehicles, followed by releases to air
from point sources in the petroleum, steel, aluminium, chemical and other
industries. By contrast, releases to water and soil are expected to be relatively
minor, as borne out in NPI reports where the highest annual release from a single
point source to water and soil was 1100 kg and 45 kg respectively, compared with
130,000 kg to air from an oil and gas extraction plant.
8.2 Environmental fate
The Trent University (1999) Level 1 Fugacity Based Environmental Equilibrium
Model indicates that in the order of 99% of benzene will partition to air, with
0.88% and 0.05% partitioning to water and soil respectively. Negligible amounts
are expected to partition to sediments, suspended sediments, biota and aerosols.
8.2.1 Atmospheric fate
The water solubility of benzene suggests that one removal mechanism from the
atmosphere is through returning to the terrestrial and aquatic compartments in
rainwater. However, the Henry's Law constant and volatility of benzene indicate
that the chemical would rapidly volatilise back into the atmosphere where it would
be available for abiotic breakdown.
Priority Existing Chemical Number 21
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Direct photolysis
IPCS (1993) reports that direct photolysis of benzene in the troposphere is unlikely
since the UV-visible spectrum of benzene shows no appreciable absorbance at
wavelengths >260 nm. According to GDCh (1988), direct photolysis is of minor
importance for the same reason.
IUCLID provides test results for a smog chamber experiment in which light with a
wavelength >290 nm corresponding to tropospheric sunlight was used with
benzene at a concentration of 100 ppm (0.32 mg/L). Although the validity of this
test cannot be judged due to insufficient documentation, the outcome showed no
evidence of benzene degradation. After the addition of chemicals producing active
species, benzene half-lives were between 4-5 h. Using light with a higher intensity
(wavelengths >230 nm), a half-life of 6.5 h was detected. These findings indicate
that direct photolysis is minimal at environmentally significant wavelengths, stated
by Howard et al. (1991) to be >290 nm, and thus confirm that this process will not
be a major removal process for benzene in the troposphere.
Indirect photolysis
IUCLID provides details for several studies on indirect photolysis. The results of
those where a half-life was determined are presented in Table 8.1. In all tests,
hydroxyl radicals were used as the reactant, with air as the medium. Not all studies
had temperature reported. However, where available, it was 25篊. While the
validity of these studies is uncertain, it is well accepted that indirect photolysis
through reaction with hydroxyl radicals is the major degradation pathway for
benzene in air (GDCh, 1988; Government of Canada, 1993; IPCS, 1993).
Table 8.1: Half-life of benzene in the atmosphere where degraded by hydroxyl
radicals
Hydroxyl concentration Rate constant
3 3
Light source (radicals/cm ) (cm /(molecule.s) Half-life (days)
5 -12
Sun light 5 x 10 1.2 x 10 13.4
5 -12
Other* 5 x 10 1.2 x 10 13.4
6 -12
1.3 x 10 19
Sun light 7.5 x 10
6 -12
Sun light 1.1 x 10 1.3 x 10 5.6
6 -12
1.2-1.6 x 10 5.3
Sun light 1.2 x 10
* Hydroxyl radicals produced by flash photolysis and using a resonance fluorescence method.
The Dutch Environment Ministry calculated a half-life of benzene in the
atmosphere of 5.3 days assuming an average hydroxyl radical concentration of 1.25
x 106 molecules/cm3 over the Netherlands with a rate constant of 1.3 x 10-12
cm3/(molecule.s). This is reported in both IPCS (1993) and GDCh (1988), although
neither report describes the basis for the assumed hydroxyl radical concentration.
The global 24-h average hydroxyl radical concentration has been reported to be
around 5 x 105 molecules/cm3 (Calamari, 1993; GDCh, 1988). Additionally, using
the OECD Environment Monograph No. 61 (OECD, 1993), a rate constant for
benzene can be calculated at 2 x 10-12 cm3/(molecule.s) (contrary to the range of
0.8-1.4 x 10-12 cm3/(molecule.s) quoted in GDCh (1988)). Applying the global
average hydroxyl radical concentration and rate constant from the OECD
monograph and following the methodology in this monograph, gives an estimated
half-life of 8 days. This is more in agreement with the Canadian authorities where a
half-life attributable to reactions with hydroxyl radicals was calculated to be 9 days
Benzene 25
under typical urban atmospheric conditions, although the hydroxyl radical
concentration and rate constant were not reported (Government of Canada, 1993).
The global concentration used above applies to the average for the whole
troposphere. In the lower troposphere where benzene and hydroxyl radicals occur
at higher concentrations, the benzene half-life would be expected to be lower, and
is reported as 3-10 days (GDCh, 1988). Additionally, in districts with high traffic
density, where there is a higher concentration of hydroxyl radicals because of
higher concentrations of precursors, a lower atmospheric half-life can be expected,
and again 3-10 days is reported (GDCh, 1988).
For the purposes of this assessment, an atmospheric half-life of 8 days will be used
based on the globally accepted tropospheric average for the concentration of
hydroxyl radicals and the methodology and rate constant prescribed in the OECD
monograph.
These results given above are all within the range predicted in Howard et al. (1991)
where the photooxidation half-life in air has been calculated to fall between 50.1 h
(2.09 days) and 501 h (20.9 days).
The proposed degradation pathway through reaction with hydroxyl radicals is
shown in Figure 8.1 (Verscheuren, 1996).
Figure 8.1: Proposed degradation pathway of benzene in the atmosphere
OH
HO2
+ HO
O
O2
NO HO2
O
O
O
glyoxal
NO2
O2
+
OH
Endoperoxide O
O
butenedial
In the IUCLID database one study is described where ozone was used as a reactant.
In this test, air was the medium and the light source was chemiluminescence. A
sensitiser concentration of 3 x 1012 molecules/cm3 and a rate constant of 1 x 10-22
cm3/(molecule.s) were used. In an urban atmosphere, the half-life for the reaction
of benzene with ozone was calculated to be 105 years. In a rural atmosphere, the
half-life would be 327 years, using an atmospheric concentration for ozone of 9.6 x
1011 molecules/cm3. Therefore, photolysis through reaction with ozone is not
expected to be a major removal process for benzene in the atmosphere.
One test is described where atomic oxygen was used as the reactant at a
concentration of 7.2 x 104 molecules/cm3 with a rate constant of 2.8 x 10-14
cm3/(molecule.s). The half-life for this reaction between benzene and atomic
Priority Existing Chemical Number 21
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oxygen was calculated to be 10.9 years, indicating that this reaction will not be a
major removal process of benzene from the atmosphere.
One test describes the photodegradation using sulphur dioxide as the reactant. The
test was performed in air with sunlight as the light source (light spectrum >290
nm). Benzene was present at a concentration of 100 ppm (0.32 mg/L). No further
information is available on the method, so the validity of this test is unknown.
However, sulphur dioxide was present at a concentration of 10-110 ppm (0.026-
0.288 mg/L). Photodegradation was observed. IUCLID states that approximately 2
days was required for 50% degradation to CO2, although the half-life for
photodegradation of benzene is stated as 6 h.
8.2.2 Aquatic fate
Photolysis in water
Direct photolysis of benzene in aqueous solution was investigated with half-lives
observed varying from 9-673 days. However, the authors concluded that the test
method was not suitable for poorly soluble, volatile substances (GDCh, 1988).
Two direct photolysis studies are reported in IUCLID where benzene was tested
adsorbed on silica gel. In both tests the concentration of benzene was 0.32 mg/L
and the light source was not stated. Few details are reported and the validity of the
tests is unknown. However, one was irradiated at >230 nm (not environmentally
significant), and resulted in a half-life of 6.5 h. The other was irradiated at
tropospheric wavelengths (>290 nm) and showed that 5% had photomineralised to
CO2 after 17 h.
Hydrolysis
IUCLID provides two reports for abiotic degradation of benzene, both concluding
that hydrolysis is not expected to be a significant process for removing benzene.
Few details are available for these tests and validity cannot be assumed. However,
degradation by this route is not expected, as benzene has no hydrolysable groups.
Volatilisation
Volatility from water to air is summarised in several reports in IUCLID.
Based on a reported Henry's Law constant of 0.0053 atm.m3/mol and a model river
1 m deep flowing at 1 m/s with a wind velocity of 3 m/s, the half-life of benzene
was 2.7 h at 20癈.
The half-life for the evaporation of benzene from seawater was investigated in a
mesocosm containing planktonic and microbial communities. Half lives for
summer, spring and winter were reported as 3.1, 23 and 13 days respectively.
The half-life for evaporation of benzene from a 1 m thick still water column was
4.8 and 5 h at 25 and 10癈 respectively by thermodynamic calculations. The
residence half-time for well-mixed water was 37 min. This half-life of 4.8 h is also
included in the IPCS (1993) and Government of Canada (1993) reports.
An experiment in a wind-wave tank 6 m long, 0.61 m deep and 0.6 m wide with
wind velocities of around 6-13 m/s at a temperature of 20.7癈 is described. The
testing period was >50 h so that an approximate 10-fold change of solute
concentration (which was measured by gas chromatography) would occur. The
Benzene 27
mass transfer coefficients of benzene at the water-air interface were 11.4-34 cm/h
dependent on wind velocity. The volatilisation is of first order kinetics. For a wind
speed of 7.09 m/s, a half-life of 5.2 h can be calculated.
While the reliability of these results is unclear, they support that rapid volatilisation
from water will occur.
8.2.3 Terrestrial fate
Adsorption
Documentation on the adsorption of benzene to soil is limited as the exposure of
the terrestrial compartment is likely to be low.
The Government of Canada (1993) report cites Koc values for benzene ranging
from 12-213, indicating the chemical to be moderately to highly mobile in soil.
IUCLID reports a calculated soil absorption coefficient of 71, using equations
developed by Kenaga & Goring and published by the American Society for Testing
and Materials. While this reference has not been obtained, an experimental soil
absorption coefficient value of 83 is reported in IUCLID as well as in IPCS (1993).
IPCS (1993) cites a rounded log Koc range of 1.8-1.9 (Koc = 60-83), indicating fair
mobility in soil, and states that benzene is not expected to adsorb to bottom
sediments based on its Koc, solubility and volatility.
Koc values provided in IUCLID indicate that benzene may exhibit high mobility in
soils and may migrate to groundwater. Several tests are reported and are generally
described as valid, or valid with restrictions. They can be used to provide a guide as
to the adsorptive behaviour of benzene.
One report gave the results of adsorption tests using radioactive labelled test
substance on aquifer material. This test is described as valid with IUCLID noting
that the test procedure was in accordance with generally accepted scientific
standards and described in sufficient detail. The results provided log Koc values
between 2.09 and 3.01 (Koc 123-1023). Experiments were carried out in capped
glass centrifuge tubes on two American groundwater aquifer materials with the
following characteristics:
Material: Sand (%): Silt Clay Organic matter pH:
(%): (%): (%):
A 90 8.0 2.0 4.4 3.8
B 70.4 24.0 5.6 2.2 5.5
Both these materials were acidic, with material A being quite acidic. It cannot be
concluded from the IUCLID summary whether Koc was a function of pH, although
this is not expected to be the case since benzene is a neutral molecule. These results
suggest that benzene is moderately mobile.
A water-soil adsorption coefficient of 18.2 provided in IUCLID was measured in
soil-solution mixtures which were equilibrated for 24 h at 20癈 in capped
centrifuge tubes. Losses by volatilisation were avoided by sampling through the
septum of the caps. The substance amounts were corrected by the airspace of the
tubes under consideration of air volume and Henry's Law constant. Soil
characteristics were reported as 9% sand; 68% silt; 21% clay and 1.9% organic
matter. pH was not stated.
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While IUCLID also provides some calculated results, these are not reported here as
measured values are considered more reliable and the terrestrial compartment is not
expected to be a significant sink for benzene.
Volatilisation
The primary mechanisms responsible for loss of benzene from soil are
volatilisation to the atmosphere and runoff to surface water. Benzene released
below the soil surface may leach to groundwater (Government of Canada, 1993).
The volatility of benzene from soil to air is summarised in two reports in IUCLID.
In one report, the half-lives of volatilisation, without water evaporation, of benzene
uniformly distributed at a rate of 1 kg/ha to 1 and 10 cm in soil with an organic
carbon content of 1.25% were 7.2 and 38.4 days respectively. The second report is
from a model developed to predict the environmental fate of benzene following
leakage of gasoline from an underground storage tank. It estimated that some 67%
of the benzene would volatilise from the soil within 17 months, with 29% leaching
to groundwater and the remainder associating with the soil.
8.2.4 Biodegradation
IPCS (1993) provides the following insight into the biodegradation of benzene:
In surface and ground water benzene is biodegradable by microorganisms
?br>
under both aerobic and anaerobic conditions with the mechanism of
biodegradation seeming to involve the formation of catechol via cis-1,2-
dihydroxy-1,2-dihydrobenzene followed by ring cleavage.
One study on the aerobic biodegradation of benzene in groundwater utilised a
?br>
mixed bacterial culture from groundwater and soil bacteria capable of using
gasoline as a sole carbon source. Under closed agitated conditions without
added nutrients the half-life appeared to be <48 h with benzene levels falling
from 480 to 218 礸/L in this time. When ammonium nitrate was added, the
reaction was much faster, with benzene levels decreasing to 35 礸/L in 20 h.
The biodegradation of benzene in ground and river waters appears to follow
?br>
first-order rate kinetics with reported half-lives of 28 and 16 days respectively.
IUCLID provides results from several biodegradation studies which generally agree
that a significant degree of biodegradation occurs under aerobic conditions. Some
tests classify the substance as readily biodegradable. However, many of the tests
are not ready biodegradation tests and the results do not indicate degradation that
would be fast enough for benzene to be classed as readily biodegradable. While
validity cannot be assumed, they may be used to provide guidance as to the
biodegradability of benzene. As such, for the purposes of this assessment, the
chemical will be considered at least inherently biodegradable.
The majority of tests summarised in IUCLID for anaerobic degradation indicate
degradation is very slow to non-existent. This is supported in the GDCh (1988)
report where it is stated that degradation of benzene has not yet been detected in
anaerobic conditions. However, IPCS (1993) describes a report where samples of
landfill leachate incubated under methogenic conditions in an anaerobic glove box
showed a 72% reduction in benzene concentrations after 40 weeks, although no
significant benzene biodegradation occurred during the first 20 weeks of
incubation. In another study using anaerobic digesting sludge under methano-
trophic conditions, benzene was undegraded after 11 weeks. It is also reported that
Benzene 29
no toxic effects of benzene on the anaerobic digestion of sewage sludges were
observed until levels of 50-200 mg/L had been reached.
8.2.5 Bioaccumulation
Benzene is not expected to bioconcentrate to any significant degree in aquatic or
terrestrial organisms given the reported values for log Po/w of 1.56-2.15 (GDCh,
1988; ICPS, 1993). IPCS (1993) also reports a bioconcentration factor (BCF) for
freshwater algae of 30, for water fleas of 153-225 depending on the concentration
of benzene in their food, and for goldfish of 4.3.
GDCh (1988) reports measured BCF values in Clupea harengus (herring) of 2-6 in
most organs, and 31 in the gall bladder. One study outlined in this document claims
no significant biological accumulation in algae or fish. For fish, the BCF was in the
range of 1-10 after 3 days.
These conclusions are largely supported by data available from USEPA (2000) and
IUCLID. Results are available for several species of fish including Anguilla
japonica (Japanese eel), Leuciscus idus melanotus (golden orfe), Morone saxatilis
(striped bass), Salmo gairdneri (rainbow trout) and Engraulis mordax (Northern
anchovy). BCF values were all under 100, with the exception of the Northern
anchovy. This species provided BCF values of 113-505, with an outlying result of
8450. There is not enough detail to determine whether these factors are for specific
organs or the whole organism, which would impact on the analysis.
Nonetheless, based on the scale provided in Mensink et al. (1995), benzene can be
classed as slightly to moderately concentrating in fish. No data are available on
depuration rates.
Benzene appears to be more concentrating in invertebrates with results generally
indicative of a moderately concentrating chemical. Several species of invertebrates
have test results reported by USEPA (2000). An 8-day static and 9-day flow
through test on Brachionus plicatilis (rotifer) showed BCF values of 100-1000
under static conditions and 10,000 under flow through conditions. The maximum
concentration tested was 900 礸/L, well within the limit of solubility. Three results
are available for Daphnia pulex with BCF values ranging from 153-225.
Several results in IUCLID were also reported by USEPA and have not been
duplicated here. IUCLID provides information on depuration from Daphnia pulex.
Daphnids were exposed to water dosed with 10 礸/L benzene, water containing
algae preloaded by incubation with 50 礸/L benzene, or both dosed water and
preloaded algae. The reported BCF values were 225 for exposure to just dosed
water, 203 for feeding on preloaded algae and 153 after incubation in dosed water
with preloaded algae. Where exposure was through dosed water only, clearance
was 88% after 72 h. Where daphnids were exposed to dosed water and preloaded
algae, 83% clearance was reported when moved to fresh water with unloaded algae,
although the time involved in this depuration was not stated.
Limited data are available for algae, but suggest bioaccumulation will be slight,
with the ECOTOX database (USEPA, 2000) reporting BCF values of 30 for the
green algae Chlorella fusca and Chlorella fusca vacuolata.
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8.3 Effects on organisms in the environment
Of the three assessments listed at the beginning of this section, only GDCh (1988)
has any detailed discussion of the effects of benzene on organisms in the
environment. As this publication is relatively old, the USEPA's ECOTOX database
was interrogated for more recent results (USEPA, 2000). In addition, IUCLID was
consulted where limited data were reported in the other two sources, but as this is
largely unvalidated, is used for guidance only. Not all available information is
reported here due to its volume. However, the range for each trophic level will be
given with an indication of where the majority of results fall.
8.3.1 Aquatic organisms
Fish
The majority of reported results come from tests performed under static conditions.
GDCh (1988) provides 96-h results for 7 freshwater species including Leuciscus
idus melanotus (golden orfe), Lepomis macrochirus (sun perch), Pimephales
promelas (fathead minnow), Lebistes reticulatus (guppy), Carassius auratus
(goldfish), Gambusia affinis (mosquito fish) and Ictalurus punctatus (channel
catfish), with LC50 values ranging from 15-430 mg/L. Most of these fall in the 10-
100 mg/L range, indicating slight toxicity to fish. This is largely supported by more
recent data from USEPA (2000) where a 48-h LC50 to Mugil curema (white mullet)
of 22 mg/L, 96-h LC50 to fathead minnow of 12.6-24.6 mg/L and 96-h LC50 to
Poecilia reticulata (guppy) of 28.6 are reported. These results are all indicative of
slight toxicity.
Flow through tests provide more sensitive results. All flow through results are for
rainbow trout. Two tests reported in GDCh (1988) give 96-h LC50 values of 5.3 and
9.2 mg/L, while one more recent result gives a 96-h LC50 of 5.9 mg/L (USEPA,
2000). These results are indicative of moderate toxicity.
GDCh (1988) reports a 96-h LC50 of 5.8 mg/L in the saltwater species Morone
saxatilis (striped bass), which is indicative of moderate toxicity. The test conditions
are not known.
As such, benzene can be considered moderately to slightly toxic to fish under acute
exposure.
Chronic and sub-chronic data for fish appear limited with only one study reported
in GDCh (1988). Following 14 days exposure of Lebistes reticulatus (guppy) under
static conditions, a LC50 of 63 mg/L was determined.
The Government of Canada (1993) report highlights an investigation into the
chronic toxicity of benzene to the early life stages of rainbow trout, leopard frog
and the Northeastern salamander. Eggs of each species were exposed continuously
to benzene from within 30 minutes of fertilisation (embryos) through to 4 days
post-hatch (larvae). This resulted in continuous exposures of 27 days for rainbow
trout, 9 days for leopard frog and 9.5 days for Northeastern salamander. The
corresponding LC50 values were 8.3, 3.7 and 5.2 mg/L respectively.
IUCLID provides results of tests in Pimephales promelas (fathead minnow),
Morone saxatilis (striped bass) and Clupea harengus (pacific herring) for 7-day,
28-day and 17-day exposure periods respectively. The striped bass was exposed
under flow through conditions. A no observed effect concentration (NOEC) of
10.2, 3.1 and 0.49-0.88 mg/L was reported for fathead minnow, striped bass and
Benzene 31
pacific herring respectively, although those for pacific herring were the highest
concentrations tested on these fish so no real conclusions can be drawn from the
results.
Overall, these results indicate that benzene is of very low toxicity to fish from
chronic exposure.
GDCh (1988) lists some toxic effects of benzene on developmental stages and
behaviour of fish. Pacific herring demonstrated a decrease of survival time of eggs
after 48-h exposure of sexually mature females at 0.7 mg/L. However, this study
was conducted in a polluted region so other chemicals may have been responsible.
Other tests on pacific herring showed unspecified developmental abnormalities at
31-40 mg/L. Also, 24-h exposure of embryos to sublethal concentrations (up to
1.85 mg/L) under static conditions showed an effect on metabolism. Significantly
less growth of the embryos, altered oxygen consumption and greater food intake in
larvae were reported.
Sublethal effects were reported in the coho salmon at 1.8 mg/L and an increase in
the respiratory rate of chinook salmon was found at 4.4 mg/L. This effect was also
observed at the same concentration in striped bass.
Invertebrates
Invertebrates appear to be the largest group tested. GDCh (1988) provides results
for four freshwater species, of which Daphnia magna, Daphnia pulex and Daphnia
cucullata all had 48-h EC50 values >100 mg/L. One freshwater invertebrate, Aedes
aegypti (mosquito larva) had a 24-h LC50 of 59 mg/L. Of the saltwater species
reported in GDCh (1988), benzene could be considered moderately toxic to four
species: Artemia salina (salt water shrimp), Crango franciscorum (bay shrimp),
Nitroca spinepes and Palaemonetes pugio (grass shrimp), with 24- to 96-h LC50
values ranging from 20-82 mg/L. Two salt water species, Cancer magister
(Dungeness crab) and Crassostrea gigas (oyster), had 96-h LC50 values >100 mg/L.
More recently published data from the ECOTOX database (USEPA, 2000) largely
confirm the moderate to slight toxicity of benzene to aquatic invertebrates outlined
above. Moderate toxicity is reported for Ceriodaphnia dubia (water flea; 24-h EC50
= 18.4 mg/L), Gammarus fossarum (scud; 96-h LC50 = 53 mg/L) and Corixa
punctata (water boatman; 48-h LC50 = 48 mg/L), with LC50 values >100 mg/L
reported for a further three species: Daphnia magna, Lymnaea stagnalis (great
pond snail) and Viviparus bengalensis (snail).
However, one crab species (Scylla serrata) was relatively sensitive to benzene,
with three 96-h LC50 results (mortality as the end point) of 3.7, 6.1 and 7.7 mg/L.
While the majority of results indicate benzene is only moderately to slightly toxic
to aquatic invertebrates, this species shows benzene may be considered toxic to
some aquatic invertebrates.
GDCh (1988) only describes one study where chronic effects were investigated in
Daphnia magna. In a lifetime and partial lifetime test, no toxic effect of benzene
was found at a concentration of 98 mg/L.
Only one chronic test is available in IUCLID where sufficient detail is presented.
This test on a crab species (Cancer magister) indicates slight toxicity to aquatic
invertebrates. Larval stages of the crab were continuously exposed after hatching in
a flowing water laboratory culture system at benzene levels of 0.17-0.18, 1.1-1.2
and 6.5-7.0 mg/L. Benzene had little effect on the duration of the larval stages and
Priority Existing Chemical Number 21
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no effect on the size of surviving larvae. At the lowest concentration, there was no
effect on survival. At the other two concentrations, benzene led to an accelerated
mortality rate compared to untreated controls. After 10 days of exposure at the
highest concentration, most larvae died. At the middle concentration, most larvae
died before day 20 of exposure. Therefore, the 20-day NOEC was 0.17 mg/L.
Algae
Data covered in GDCh (1988) suggest benzene is only slightly to very slightly
toxic to algae. A 24-h EC50 on the green algae (Chlorella vulgaris) based on cell
division was >>100 mg/L.
Three 72-h EC50 values are reported for sea algae with cell division as the end
point. The green algae (Dunaliella tertiolecta), siliceous algae (Skeletonema
costratum) and yellow-green algae (Cricopshaera carterae) all had EC50 results
>100 mg/L. In a 3-day test in the dinoflagellata Amphidinium carterae, the EC50
with cell division as the end point was reported to be 50 mg/L, indicating slight
toxicity (GDCh, 1988).
More recent data from the ECOTOX database (USEPA, 2000) appear more
indicative of slight toxicity than the earlier studies reported in GDCh (1988). One
72-h EC50 in Selanastrum capricornutum of 29 mg/L and a 24-h EC50 for the
diatom Thalassiosira pseudonana of 40 mg/L are reported.
In summary, benzene can be classed as slightly to very slightly toxic to algae under
acute exposure.
In 8-day tests, >1400 mg/L benzene had no detectable effect on biomass in the
freshwater species Scenedesmus quadricauda and the blue alga Microcystis
aeruginosa (GDCh, 1988). With growth as the end point, the more sensitive
species Selenastrum capricornutum provided an 8-day EC50 of 41 mg/L, although a
14-day EC50 of 292 mg/L is also reported for this species (USEPA, 2000).
Predicted No-Effect Concentration (PNEC) in the aquatic environment
As there are results available for both acute and chronic exposure in three trophic
levels, the lowest NOEC for chronic exposure, in this case to the aquatic
invertebrate crab species Cancer magister, will be used with an assessment factor
of 10. While this result (NOEC = 0.17 mg/L) is based on unvalidated results from
IUCLID, it is considered that there are sufficient data available from published and
peer-reviewed sources for this test to be accepted for use in a worst-case PNEC and
that there is sufficient detail in the IUCLID report to support the results.
Therefore, the PNEC for the aquatic environment is 0.17/10 = 0.017 mg/L, or 17
礸/L.
8.3.2 Terrestrial organisms
A study in Eisenia fetida (earthworm) is reported in the ECOTOX database
(USEPA, 2000), in which an LC50 of 98 礸/cm2 was determined in adult worms
weighing 300-500 mg placed for 48 h on filter paper impregnated with a solution of
benzene in water, acetone and trichloromethane.
According to GDCh (1988), use of benzene as a solvent for plant protection agents
in bioassay tests showed that it is slightly toxic to various insect species. The LD50
for the house fly (Musca domestica) was 0.8 mg per animal. Exposure to benzene
Benzene 33
in the vapour phase exhibited toxic action in the grain weevil (Calandra granaria),
although the concentration is not reported. Benzene acted as a repellent to the
adults of certain species of flies (Diptera).
In plants, air concentrations >50 mg/m3 (>15.5 ppm) have a lethal effect. However,
all plant species investigated recovered from sublethal effects. In water, higher
concentrations of 0.9-1.3 g/L have a growth-inhibiting effect (GDCh, 1988).
It is difficult to translate the earthworm measurement to an application rate likely to
lead to adverse impacts in soil and a PNEC cannot be determined from these data.
8.4 Summary
Benzene is expected to partition predominantly to the atmosphere, with the primary
route of degradation coming from indirect photolysis through reaction with
hydroxyl radicals. Direct photolysis or reactions with oxygen or ozone are not
expected to be major removal processes from the atmosphere. Based on the
accepted global concentration of hydroxyl radicals, the degradation half-life of
benzene from the atmosphere is calculated at 8 days.
Benzene is largely abiotically stable in water, with the major removal process
expected to be volatilisation. The high water solubility and relatively low log Po/w
indicate that benzene will not adsorb significantly to organic matter and sediments.
When released to the terrestrial compartment, benzene may be relatively mobile
and may leach to groundwater if released underground, for example, from leaking
storage tanks. The chemical is unlikely to adsorb readily to soils and may readily
volatilise from soil surfaces.
Benzene may be considered biodegradable under aerobic conditions, although
under anaerobic conditions, biodegradation may be expected to be very slow.
Based on the chemical's low log Pow and experimental results, bioaccumulation is
not expected to any significant degree, and at worst, benzene can be described as
moderately concentrating.
Aquatic organisms exhibit only a low level of sensitivity to benzene, with the
chemical being slightly toxic to fish following acute exposure under static
conditions and moderately toxic under flow through conditions. Chronic exposure
of fish to benzene gave results indicative of slight toxicity. Invertebrates appear to
be the largest group of aquatic organisms tested. For the majority of species tested,
benzene was only slightly to very slightly toxic. However, one crab species was
relatively sensitive, with results in the range of a moderately toxic chemical.
Chronic results show benzene to be slightly toxic to aquatic invertebrates. Benzene
may also be classified as slightly to very slightly toxic to algae. The PNEC for the
aquatic environment is 17 礸/L.
Limited data on the toxicity of benzene to terrestrial organisms show the chemical
to be slightly toxic to various insect species and the earthworm. In plants, high
concentrations in air have a lethal effect, although all plants investigated recovered
from sublethal effects.
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9. Kinetics and Metabolism
The toxicokinetics and metabolism of benzene have been extensively investigated
in several animal species and, to a lesser extent, in humans. Studies relevant to the
toxicokinetics of benzene have been reviewed and summarised in this section. The
metabolites and their modes of action are further discussed in Section 12. A
number of reviews of benzene toxicokinetics and metabolism are available,
including IPCS (1993) and ATSDR (1997).
9.1 Absorption
9.1.1 Animal studies
Inhalation
Schrenk et al. (1941) found the absorption of benzene vapour by dogs after
inhalation exposure to be rapid. Inhalation of the vapour (800 ppm) over 4-7 h
resulted in the concentration of benzene in arterial blood approaching equilibrium
conditions by 30 minutes. Although considerable inter-animal variation was noted,
a linear relationship was demonstrated between the concentration of benzene in air
over the range from 200-1300 ppm and the equilibrium concentration in blood. In
another study, the absorbed dose after inhalation (nose-only) of [14C]-benzene
(approximately 10-1000 ppm) for 6 h by rats (F344) and mice (B6C3F1) was found
to be non-linear. The percentage of benzene absorbed decreased from 33% to 15%
in rats and from 50% to 10% in mice as the exposure concentration increased from
10 to 1000 ppm. Due to apparent physiological differences in respiration between
the two species, mice inhaled approximately twice the amount of benzene
compared to rats (Sabourin et al, 1987). Similarly, Eutermoser et al. (1986) found
that the absorption rate of benzene vapour (300 ppm) by male rats (Sprague-
Dawley) decreased with increasing duration of exposure. When determined after 1,
3 and 6 h of continuous exposure and compared to baseline values, benzene
absorption decreased to 33, 22 and 9% respectively. Male mice (Swiss) when
exposed to benzene (310 ppm) for 1, 3 and 6 h of continuous exposure and
compared to baseline values gave values of 65, 76 and 81% respectively. Thus after
the first hour, the rate of benzene uptake by rats decreased significantly compared
to mice.
Dermal
Dermal absorption of liquid benzene was investigated by Maibach & Anjo (1981)
using intact and abraded skin of rhesus monkeys. Under conditions where
evaporative losses were allowed, the application of a single dose of benzene to
intact skin resulted in absorption of 0.17% of the dose while the application of
multiple doses (11 exposures with an interval of 15 min) resulted in 0.85% of the
dose being absorbed. In contrast, abraded skin resulted in 0.91% of the applied
dose being absorbed. Similar results were obtained by Franz (1984) who found that
after a single dermal application of benzene, 0.14% and 0.09% was absorbed by
rhesus monkeys and miniature pigs respectively. It was concluded from the in vitro
studies that the major factor influencing percutaneous absorption of benzene was its
contact time with the skin. Susten et al. (1985) reported similar findings with
Benzene 35
hairless mice (HRS/J) using a skin chamber where less than 1% of the applied dose
was absorbed.
Adsorption of benzene onto soil matrices (sandy or clay soil) was found to modify
the dermal absorption of [14C]-benzene when applied topically to male rats
(Sprague-Dawley) over a 72-h period using a glass skin chamber. While the peak
plasma level of radioactivity after exposure to benzene adsorbed onto sandy soil
was comparable to that obtained for pure benzene, a statistically significant lower
plasma level was obtained for benzene adsorbed onto clay, however, neither soil
type altered the time to reach peak plasma levels which was 12 h (Skowronski et al,
1988).
Dermal absorption of benzene vapour has also been addressed. Dermal absorption
(whole-body) of benzene vapour over 2, 4 or 6 h was investigated by the use of
male nude mice attached to respirators. The dermal absorption rates for exposures
of 200, 1000 and 3000 ppm were 4.11, 24.2 and 75.5 nmol/cm2/h (0.3, 1.9 and 5.9
礸/cm2/h) respectively, demonstrating a linear relationship between the two
parameters. Dermal absorption was also found to be linear with respect to exposure
time. The dermal absorption coefficient for the mouse was determined to be 0.619
cm/h (Tsuruta, 1989). McDougal et al. (1990) exposed male rats (F344; whole-
body) to benzene vapour (40,000 ppm) for periods up to 4 h. The rats were shaved
of all fur prior to exposure and provided with latex face masks attached to a fresh
air supply during exposure. Benzene blood levels at 0.5 h were 8 礸/mL and rose to
11 礸/mL at 4 h indicating that benzene is rapidly absorbed by the dermal route.
The dermal absorption rate was determined to be 0.0191 mg/cm2/h and the dermal
absorption coefficient 0.152 cm/h.
Oral
Following the administration by gavage of [14C]-benzene (340-500 mg/kg) to
rabbits, approximately 80% of the ingested radiolabel was recovered in exhaled
breath and urine indicating substantial gastrointestinal absorption at these dose
levels (Parke & Wiliams, 1953). Similar results were obtained by the
administration of lower doses of [14C]-benzene (0.5-150 mg/kg) to rats (F344 and
Sprague-Dawley) and mice (B6C3F1) where it was determined that >97% of the
dose was absorbed (Sabourin et al, 1987).
9.1.2 Human studies
Inhalation
In a study of 23 subjects exposed to benzene vapour (47-110 ppm) over 2-3 h,
maximal absorption (70-80% of dose) occurred within 5 min of initial exposure.
Subsequent absorption declined rapidly and reached a plateau at 15 min.
Absorption remained constant for the remainder of the exposure duration at
approximately 50% (range: 20-60%) of the exposure dose (Srbova, et al, 1950).
Comparable results have been obtained in a number of other studies. Nomiyama &
Nomiyama (1974a) exposed 6 volunteers (3 males and 3 females) to benzene
vapour (52 to 62 ppm) for 4 h and showed that after an initially high absorption rate
(50-60%), the rate decreased to reach a plateau of approximately 30-40% after 3 h
of exposure. The mean retention of benzene, after allowances for respiratory
excretion, was determined to be 30.2% for a 3-h exposure. Similarly, Snyder et al.
(1981) demonstrated that during continuous exposure to benzene vapour
approximately 50% of the dose is absorbed by the lungs. Pekari et al. (1992)
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exposed 3 non-smoking volunteers to benzene vapour (1.6-9.4 ppm) for 4 h. The
absorbed dose was estimated to be 52% and 48% for the low and high dose
exposure respectively based on the average difference in concentration between the
inhaled and exhaled air.
Further evidence for the absorption of benzene by inhalation is provided by studies
of cigarette smokers. Analysis of cigarette smoke has shown the presence of
substantial amounts of benzene, with the yield within the range of 0.4-104
礸/cigarette (see Section 16.1). Analysis of breath samples from 198 smokers and
322 non-smokers showed significantly higher (p <0.001) benzene concentrations in
the breath of smokers (16 礸/m3) compared to non-smokers (2.5 礸/m3). Benzene
breath levels were significantly correlated (p <0.01) with the number of cigarettes
smoked per day (Wallace & Pelizzari, 1986; Wallace et al, 1987). Pekari et al.
(1992) found 6 non-smokers to have venous blood benzene levels of <1-2 nM
compared to 3 smokers (1 pack/day) with 4-13 nM in the morning and 5-8 nM in
the afternoon. Cessation of smoking for a period (duration not stated) resulted in a
reduction of blood benzene levels to <2 nM. In a similar study, it was found that
the mean venous blood benzene levels of 14 smokers were significantly higher (7.0
nM; range 3.7-12.1 nM) compared to 13 non-smokers (2.8 nM; range 1.4-5.8 nM);
however, the number of cigarettes consumed were not stated (Hajimiragha et al,
1989). With the exception of cigarette smoking, there were no other known
activities undertaken by the subjects that may have resulted in benzene exposure
prior to or during either study.
Dermal
A number of studies indicate that benzene is absorbed via the dermal route in
humans. A study of 2 men exposed to benzene (approximately 0.06 g/cm2 applied
to the forearm, 35-43 cm2, under occluded conditions for 1.25-2 h) determined the
dermal absorption rate to be 0.4 mg/cm2/h based on urinary excretion of phenol
(Hanke et al, 1961). Approximately 0.05% of the applied dose of [14C]-benzene
(0.0026 mg/cm2) was absorbed when applied to the forearm skin of 4 volunteers.
Absorption was determined by urinary excretion of radiolabel which indicated that
absorption was rapid. Evaporative losses during the absorption period were not
accounted for (Franz, 1984).
The absorption of benzene due to dermal exposure to petrol has been studied in car
mechanics having direct skin contact with petrol for 30-150 min during work on car
fuel systems, with the concentration of benzene in the breathing zone ranging from
0.2 ppm (detection limit) to 3.7 ppm averaged over the duration of the task. Blood
benzene levels determined 2-9 h after exposure ranged from 3-16 nM. Based on
expected benzene blood levels derived from the airborne concentrations, it was
estimated that dermal absorption accounted for up to 80% of the total absorbed
dose of benzene. The mechanics did not wear protective gloves (Laitinen et al,
1994). However, the estimation assumed that the mechanics were exposed to non-
detectable benzene air concentrations during the remainder of the working day and
would therefore have overestimated the extent of skin absorption if this were not
the case.
In an in vitro study, benzene (pure benzene, air saturated with benzene vapour or a
saturated aqueous solution of benzene) was shown to diffuse across hydrated
stratum corneum prepared from human skin. Absorption, initially preceded by a lag
phase (range: <1-1.5 h), was linear over the duration of the experiment (4 h). The
rates of benzene absorption due to pure benzene and air saturated with benzene
Benzene 37
vapour were 2.1 and 1.0 礚/cm2/h (1.8 and 0.88 mg/cm2/h) respectively. It was
further demonstrated that the barrier characteristics of human skin alter in response
to the presence of other solvents (Blank & McAuliffe, 1985). Lod閚 (1986)
determined the amount of benzene absorbed by excised human skin to be 0.17
mg/cm2 after 0.5 h and 0.93 mg/cm2 at steady state (13.5 h). The total absorption of
benzene over 13.5 h in skin and receptor fluid was 1.92 mg/cm2 and the resorption
rate (that is, the amount of substance migrating to the receptor fluid below the skin)
was determined to be 99 礸/cm2/h.
Oral
No studies were identified addressing the absorption of benzene by the oral route in
humans. Cases of accidental or intentional ingestion indicate that benzene is readily
absorbed by the gastrointestinal tract, with a dose of 125 mg/kg proving fatal (see
Section 11.1).
9.2 Distribution
9.2.1 Animal studies
Inhalation
Schrenk et al. (1941) observed that in dogs continuously exposed to the vapour,
benzene preferentially partitions to the organs and tissues with a higher fat content,
although considerable inter-animal variation was noted. The establishment of an
equilibrium between most tissues (except fat) and blood levels appeared to be rapid
(15.5 h). When exposed to various concentrations of benzene vapour (850-1320
ppm) for periods ranging from 0.65-5 days, benzene levels were highest in bone
marrow (57.6-64.1 mg/100 g tissue) followed by peritoneal fat (40.3-61.4 mg/100 g
tissue) and subcutaneous fat (39.9-48.6 mg/100 g tissue). All other tissues or
organs had substantially (generally 20-fold) lower levels of benzene. A comparable
distribution pattern was observed when dogs were exposed to 800 ppm benzene
vapour for 8 h/day for 38-272 days. Rickert et al. (1979) studied the distribution
and residence times of benzene and three major metabolites, phenol, hydroquinone
and catechol, in male rats (F344) exposed to benzene vapour (500 ppm) for up to 8
h. The steady-state benzene concentrations at 6 h were determined for the following
tissues: fat (164.4 礸/g), bone marrow (37.0 礸/g), kidney (25.3 礸/g), lung (15.1
礸/g), liver (9.9 礸/g), brain (6.5 礸/g) and spleen (4.9 礸/g), while blood
contained 11.5 礸/mL. The half-times for tissues to reach steady-state levels for
benzene were essentially the same for all tissues (0.9-2.0 h) as were the elimination
times (0.4-0.8 h), with the exception of fat which was 1.6 h. The concentrations of
phenol in blood and bone marrow were maximal within 2 h after cessation of
exposure and declined rapidly thereafter. Hydroquinone and catechol
concentrations were sustained for 9 h after exposure with higher concentrations
found in bone marrow.
Ghantous & Danielsson (1986) demonstrated the transplacental distribution of
benzene and its metabolites in mice following inhalation exposure to [14C]-
benzene. Benzene was detected in the placenta and the foetus immediately
following and for up to 1 h after exposure, as were benzene metabolites. The
metabolites did not reach the same tissue concentrations as in maternal tissues and
no metabolites were retained in the placenta or the foetus.
Priority Existing Chemical Number 21
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Dermal
Susten et al. (1985) examined the distribution of radiolabel after dermal application
of undiluted [14C]-benzene and a 0.5% (v/v) solution in rubber solvent using a skin
chamber attached to male hairless mice (HRS/J) for 4 h. Approximately 5% and
8% of the benzene in the pure sample and rubber solvent respectively remained
associated with the site of application while approximately 23% and 22%
respectively was associated with the carcass. Skowronski et al. (1988) examined
the tissue distribution of radiolabel in male rats (Sprague-Dawley) 48 h following
the topical application of benzene (300 礚) using a glass skin chamber. The highest
levels of radiolabel (expressed as % of initial dose per g of tissue) were found in
the kidneys (0.026%), liver (0.013%) and treated skin (that is, below the site of
application; 0.011%). Untreated skin gave a value of 0.002%. Subcutaneous fat
from below the area of application gave 0.008% while subcutaneous fat from a
different site gave 0.005% as did bone marrow. All other tissues and organs
examined (including the brain) accounted for less than 0.04% of the initial dose.
Oral
Analysis of rabbit tissues and organs (1 animal) 2 days after dosing by gavage with
[14C]-benzene (500 mg/kg) showed the highest level of radioactivity to occur in
muscle (1.6%), fat (1.5%), liver (0.07%), stomach (0.05%), testes (0.02%) and
kidneys (0.015%). No radioactivity was detected in the brain, spinal cord or blood
(Parke & Wiliams, 1953). Low et al. (1989) found that the distribution of radiolabel
in female rats (Sprague-Dawley) varied with the dose of [14C]-benzene
administered. At 1 h after a single dose of 0.15 or 1.5 mg/kg by gavage, radiolabel
was highest in the liver and kidneys (0.198-2.043 礸/g tissue), intermediate in
blood (0.086-0.769 礸/mL), and lowest in the Zymbal gland, nasal cavity tissue,
oral cavity tissue, mammary gland and bone marrow (0.034-0.547 礸/g tissue). In
contrast, at 15 mg/kg, the amount of radiolabel found in the mammary gland and
bone marrow had substantially increased in comparison to other tissues. At the
highest dose, bone marrow and adipose tissue had the highest concentrations of
benzene.
9.2.2 Human studies
Studies of the distribution of benzene in humans are generally limited to a number
of fatal cases of accidental or deliberate benzene exposure. Autopsy data from such
cases indicate that benzene preferentially partitions into lipid-rich tissues.
Analysis of tissue and fluid samples from a youth who died after sniffing benzene
(reagent grade) showed the following order for tissue benzene content: brain, 39
mg/kg; abdominal fat, 22.3 mg/kg; blood, 0.02 mg/mL; kidneys, 19 mg/kg; liver,
16 mg/kg; bile, 0.011 mg/mL; stomach, 10 mg/kg and urine, 0.0006 mg/mL
(Winek & Collom, 1971). Similar findings were demonstrated at autopsy of 3 cases
of acute industrial benzene poisoning indicating that benzene preferentially
distributes to lipid-rich tissues such as body fat (range: 68->120 mg/kg) and brain
tissue (range: 58-63 mg/kg) with lesser amounts in blood (range: 30-129 mg/mL),
liver (range: 15-38 mg/kg), lungs (positive findings) and bile (range: trace to 45
mg/mL) (Avis & Hutton, 1993). In a similar industrial accident involving acute
fatal benzene poisoning analysis of tissue and fluid samples revealed the following
benzene concentrations: blood, 0.0317 mg/mL; brain, 178.7 mg/kg; lungs, 22.2
mg/kg; heart, 182.6 mg/kg; liver, 378.6 mg/kg; kidneys, 75.2 mg/kg and urine,
0.0023 mg/ml (Barbera et al, 1998). In the above case reports the individuals are
Benzene 39
believed to have inhaled benzene vapour for some time before death occurred. In
one case in which an individual died suddenly during an industrial accident
involving benzene, precluding extensive inhalation of the vapour, autopsy findings
revealed the following benzene concentrations: blood, 0.0038 mg/mL; brain, 13.8
mg/kg; liver, 2.6 mg/kg (Tauber, 1970).
Limited data indicate that developing foetuses and infants may be exposed to
benzene as a result of maternal exposure. Benzene can cross the placenta and
concentrations in umbilical cord blood have been shown to be equal to or greater
than in maternal blood (Dowty et al, 1976). Due to the richly perfused nature of
breast tissue and the high fat content of human milk (approximately 4%), benzene
is expected to partition from blood into human milk from which it can transfer to
nursing infants (Fisher et al, 1997). Qualitative analysis of 12 human milk samples
revealed the presence of benzene in 8 of them (Pellizzari et al, 1982).
9.3 Metabolism
The metabolism of benzene has been extensively investigated in several species of
animals including humans. Benzene toxicity has been attributed to the formation of
reactive metabolites that appear to exert their toxic effect in combination, with no
one metabolite accounting for all of the observed effects. The metabolism of
benzene has been reviewed by Ross (1996) and Snyder & Hedli (1996).
9.3.1 General metabolic pathways
Urinalysis of several species exposed to benzene has demonstrated qualitative
similarities in the spectrum of metabolites produced, indicating that the metabolism
of benzene follows similar pathways between species. Urinary benzene metabolites
identified from rabbits, rats, mice, monkeys and humans include conjugates of
phenol, hydroquinone, catechol and 1,2,4-trihydroxybenzene while phenyl-
mercapturic acid and trans,trans-muconic acid have also been identified. The
conjugates are principally glucuronides and sulfates (Parke & Williams, 1953;
Rothman et al, 1998; Sabourin et al, 1988, 1992). Analysis of rat and human blood
samples has further revealed the presence of benzene oxide and its S-
phenylcysteine adducts following benzene exposure (Bechtold et al, 1992a, 1992b;
Lovern et al, 1997). The general metabolic pathways for benzene metabolism are
provided in Figure 9.1. The initial step in the formation of toxic metabolites is the
conversion of benzene to the benzene oxide/oxepin which can be further
metabolised to phenolic compounds or cleaved to give trans,trans-muconaldehyde.
Detoxification pathways primarily involve conversion of benzene oxide to pre-
phenylmercapturic acid and phenylmercapturic acid while the phenolic compounds
form glucuronide and sulfate conjugates.
Priority Existing Chemical Number 21
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Figure 9.1. The metabolism of benzene, with question marks indicating
suspected pathways for which definitive evidence is lacking (after Sabourin
et al. (1988) and Schlosser et al. (1993))
O
Benzene oxide
oxepin OH
HO
trans, trans-
Benzene O
O Muconic acid
?
Pre-phenylmercapturic acid O
OH ?
OH H
H
O
O trans, trans-
OH
S-N-Acetyl-Cys
Muconaldehyde
Benzene
Benzene
dihydrodiol
oxide
OH
OH
OH
S-N-Acetyl-Cys
Phenylmercapturic acid Phenol Catechol
OH
OH
HO OH
HO
1,2,4-Trihydroxybenzene
Hydroquinone
The primary site for benzene metabolism is the liver. It has been observed that
animals that have undergone partial hepatectomy metabolise less benzene and
exhibit reduced benzene-mediated toxicity compared to animals with intact livers
(Sammet et al, 1979). The initial biotransformation of benzene involves oxidation
by the action of a cytochrome-P450 (CYP) to produce the benzene oxide/oxepin
intermediate (Jerina et al, 1968). Studies of liver microsomal preparations from rats
and rabbits, using inhibitor and immunochemical techniques, have identified the
cytochrome as CYP2E1 (Johansson & Ingelman-Sundberg, 1988; Koop et al, 1989;
Nakajima et al, 1989). Similar studies with human liver microsomal preparations
have shown CYP2E1 to be the major cytochrome involved in the metabolism of
benzene by humans (Guengerich et al, 1991). Valentine et al. (1996) confirmed the
role of CYP2E1 in the in vivo metabolism of benzene using transgenic CYP2E1
knockout mice (cyp2e1-/-). Analysis of urine samples after exposure to [14C]-
benzene by nose-only inhalation showed reduced levels of urinary metabolites
compared to wild-type mice (cyp2e1+/+). The study further demonstrated that, while
oxidative metabolism of benzene occurs primarily through CYP2E1, other
cytochromes are involved.
Studies of rat liver microsomes have shown there to be high affinity (Km = 20 礛)
and low affinity (Km = 0.3 mM) binding sites for benzene (Johansson & Ingelman-
Sundberg, 1988). Nakajima et al. (1989), using monoclonal antibodies, identified
two distinct rat enzymes, a high affinity and a low affinity binding type involved in
benzene oxidation. Subsequent studies of rat microsomal P450 isozymes, CYP2E1,
CYP2C11/6, CYP1A1/2 and CYP2B1/2, by Nakajima et al. (1992) using
monoclonal antibodies showed that all four isozymes are involved in the initial
oxidation of benzene. However, while CYP2E1 has been characterised as a high
affinity enzyme with respect to benzene metabolism, CYP2B1/2 exhibits low
affinity but high capacity (Gut et al, 1996; Nakajima et al, 1989) and CYP2C11/6
Benzene 41
and CYP1A1/2 exhibit low affinity and low efficiency towards benzene (Nakajima
et al., 1992).
Several studies have demonstrated the inducible nature of CYP2E1 and subsequent
enhancement of benzene metabolism by phenobarbital, acetone or ethanol
treatment of rats (Johansson & Ingelman-Sundberg, 1988; Koop et al., 1989;
Nakajima et al., 1989). In addition, it has been demonstrated that benzene is able to
stimulate its own metabolism by inducing CYP2E1 activity (Arin?et al., 1991; Gut
et al., 1993). However, it has also been demonstrated in mice that repeated oral
exposure to benzene can diminish CYP2E1 activity (Daiker et al., 1996). One
postulated mechanism for reduced cytochrome activity, demonstrated in vitro,
requires inactivation of the cytochrome by quinones formed by oxidation of
hydroquinone, catechol and 1,2,4-trihydroxybenzene (Soucek et al., 1994).
The initial oxidation product of benzene, benzene oxide, has been estimated to have
a half-life, in vitro, of approximately 8 min in blood (Lindstrom et al., 1997). Thus
the oxide has sufficient stability to allow it to participate in a variety of reactions.
Minor reactions of benzene oxide include alkylation with DNA and RNA (Mueller
et al, 1987) and proteins (Bechtold et al, 1992a, 1992b) while epoxide hydrolase
converts it to benzene dihydrodiol (1,2-dihydroxycyclohexadiene).
The presence of benzene oxide in blood has been detected by the presence of S-
phenylcysteine adducts of haemoglobin and albumin (Bechtold et al, 1992a;
1992b). Haemoglobin adducts were detected in the blood of rats (F344) and mice
(B6C3F1) after inhalation exposure (600 ppm, 6 h/day, 5 days/week for 2 weeks) or
gavage (rats only; 0, 100, 1000 or 10,000 祄ol/kg). Albumin adducts were also
detected in the plasma of rats exposed to benzene vapour (Bechtold & Henderson,
1993). While the haemoglobin adduct has been found to be relatively stable in the
rat (F344) with decay rates consistent with the life-span of erythrocytes
(approximately 60 days), albumin adducts were found to have a half-life of 0.4
days compared to unmodified albumin (half-life approximately 3 days) (Troester et
al, 2000). Lindstrom et al. (1998) estimated the half-life of benzene oxide in blood,
under in vitro conditions, to be approximately 6.6 min in mice (B6C3F1), 7.9 min
in rats (F344) and 7.2 min in humans. When benzene oxide (0-184 礛) was
incubated with mouse, rat or human blood for 3 h it was observed that haemoglobin
adduct formation was proportional to the oxide concentration. The order of
reactivity for the oxide with haemoglobin was rat >> mouse > human. Negligible
haemoglobin adduct formation was observed with human blood. All three species
formed albumin adducts with the order being rat human > mouse.
9.3.2 Formation of phenolic metabolites
Studies with microsomal preparations, which preclude conjugation (detoxification)
pathways, indicate that the major pathway for the further metabolism of benzene
oxide involves the spontaneous rearrangement to phenol (Jerina & Daly, 1974;
Jerina et al, 1968). It has been demonstrated, using liver microsomes and
reconstituted enzyme systems, that phenol can also arise by the direct oxidation of
benzene by hydroxyl radicals derived from the reduction of molecular oxygen by
cytochrome P450 activity (Johannson & Ingelman-Sundberg, 1983). However,
Gorsky & Coon (1985) observed that when benzene is present at concentrations
approaching the Km of CYP2E1 for benzene, hydroxyl radicals do not contribute
significantly to benzene oxidation. The further oxidation of phenol by cytochrome
P450 results in hydroquinone (Koop et al, 1989; Valentine et al, 1996) and catechol
while 1,2,4-trihydroxybenzene arises from the P450-mediated oxidation of either
Priority Existing Chemical Number 21
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hydroquinone or catechol (Schlosser et al., 1993). In addition, catechol can be
produced from benzene dihydrodiol by the action of dihydrodiol dehydrogenase
(Bolcsak & Nerland, 1983).
The hydroquinone species derived from benzene, that is, hydroquinone, catechol
and 1,2,4-trihydroxybenzene, readily undergo autoxidation to their respective
semiquinone and quinone forms and the presence of peroxidases facilitate the
oxidation process (Schlosser et al., 1989; Smith et al., 1989). Quinones are
chemically reactive and capable of forming adducts with macromolecules. Further
discussion of the secondary metabolism of benzene-derived phenol and
hydroquinone species, along with their biological effects, is presented in Section
12.
The detoxification of the phenolic benzene metabolites occurs primarily by
conjugation to glutathione (GSH), glucuronide or sulfate (Parke & Williams, 1953).
Conjugation of benzene oxide with GSH by glutathione-S-transferase (GST) results
in the formation of pre-phenylmercapturic acid and, by dehydrogenation,
phenylmercapturic acid, both of which have been identified as urinary metabolites.
The major metabolites, phenol, hydroquinone, catechol and 1,2,4-
trihydroxybenzene, all form glucuronide and sulfate conjugates (Parke & Williams,
1953; Sabourin et al., 1988).
9.3.3 Formation of trans,trans-muconaldehyde
Cleavage of the oxidised aromatic ring results in the formation of trans,trans-
muconaldehyde which is subsequently converted to trans,trans-muconic acid prior
to excretion. A number of in vivo studies of several animal species, including
humans, have shown trans,trans-muconic acid to be an end-stage product of
benzene metabolism (Parke & Williams, 1953; Rothman et al., 1998; Sabourin et
al., 1988). While the opening of the benzene ring and subsequent formation of
muconic acid have been shown to occur in isolated perfused rat livers, as has the
conversion of trans,trans-muconaldehyde to trans,trans-muconic acid (Grotz et al.,
1994), the precise mechanism of ring opening remains elusive. It has been
proposed that benzene oxide, while in the oxepin state, undergoes secondary
oxidation by cytochrome P450 to produce trans,trans-muconaldehyde (Davies &
Whitham, 1977) and small quantities of trans,trans-muconaldehyde have been
found to be produced by mouse liver microsomal preparations on incubation with
benzene (Latriano et al, 1986). However, hydroxyl radicals have also been
implicated in the formation of trans,trans-muconaldehyde. Incubation of benzene
with Fenton's reagent, which produces reactive oxygen species, results in the
formation of cis,trans-muconaldehyde which, through a series of rearrangements,
yields the trans,trans-isomer (Zhang et al., 1995). An alternative proposed
mechanism for aldehyde formation requires cleavage of benzene dihydrodiol
(Latriano et al., 1986), however, the aldehyde was not produced when benzene
dihydrodiol was incubated with Fenton's reagent (Zhang et al., 1995). The
subsequent conversion of trans,trans-muconaldehyde to trans,trans-muconic acid
involves several steps requiring the action of an aldehyde dehydrogenase (Kirley et
al, 1989; Zhang et al, 1993). Conjugation of trans,trans-muconaldehyde with GSH
via hepatic GST has been demonstrated as a detoxification pathway for this
metabolite (Goon et al., 1993a, 1993b).
Benzene 43
9.4 Elimination and excretion
9.4.1 Animal data
Inhalation
Benzene was detected in the urine of dogs exposed to benzene vapour (850-1320
ppm) at levels ranging from 29.3-48.3 mg/100 g (Schrenk et al, 1941). Sabourin et
al. (1989) identified the urinary metabolites of benzene metabolism in rats and mice
following inhalation exposure to benzene vapour (nose-only) for 6 h. The results
are presented in Table 9.1.
Table 9.1: Major urinary metabolites after inhalation of benzene, expressed as
a percentage of total urinary metabolites from 24-h samples (adapted from
Sabourin et al. (1989))
Dose Phenol Hydroquinone Catechol Pre-phenyl- Muconic
Species (ppm) conjugates conjugates conjugates mercapturic acid acid
Rat (F344) 5 57 5.7 ND* 9.5 19
600 74 2.0 ND 17 4.0
5 37 33 ND 6.0 23
Mouse
(B6C3F1) 600 67 11 ND 15 5.0
* ND = not detected.
Dermal
Franz (1984) observed that peak excretion of radioactivity in the urine of rhesus
monkeys after the application of 0.5 mL of [14C]-benzene occurred during the first
2 h and decreased rapidly thereafter but remained detectable for up to 30 h.
Skowronski et al. (1988) found that after the topical application of 300 礚 of [14C]-
benzene to male rats (Sprague-Dawley) by means of a glass skin chamber, the
major excretory route for radiolabel was in the urine, with substantially lesser
amounts in faeces and expired air. Excretion in the urine was greatest during the
12- to 24-h interval after application, accounting for 58.8% of the initial dose with
68.4% recovered in 24 h and 86.2% after 48 h. In contrast, 0.2% of the initial dose
was recovered over 48 h in the faeces. Expired air accounted for 12.0% in the first
24 h with the following 24 h accounting for only a further 0.8%.
Oral
Analysis of urinary benzene metabolites from several species following
administration of [3H]-benzene by gavage has shown similar profiles of
metabolites. As indicated in Table 9.2, the principal urinary metabolites for the
species shown are conjugates (glucuronides and sulfates) of phenol and, to a lesser
extent, hydroquinone. The mouse is quantitatively different from the other species
with a substantially higher production of hydroquinone conjugates and trans,trans-
muconic acid. In addition to species differences, the table shows the effect of
changes in dose levels on urinary metabolites for rats and mice. Increasing the dose
of benzene leads to an increase in the excretion of phenol conjugates and a decrease
in hydroquinone conjugates by the mouse but no substantial change in the rat. In
contrast, trans,trans-muconic acid excretion is diminished in both the rat and the
mouse at higher doses.
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Table 9.2: Major urinary metabolites after oral administration of benzene,
expressed as a percentage of total urinary metabolites from 24-h samples
(adapted from Parke & Williams (1953), and Sabourin et al. (1989, 1992))
Dose Phenol Hydroquinone Catechol Pre-phenyl- Muconic
Species (mg/kg) conjugates conjugates conjugates mercapturic acid acid
Rat (F344) 1 70 4.0 ND* 11 13
10 71 2.8 ND 15 10
200 75 2.0 ND 18 5.0
1 30 47 ND 2.7 20
Mouse
(B6C3F1) 10 38 39 1.0 4.5 16
200 63 16 ND 11 9.0
Rabbit 340 24 4.8 2.2 No data 1.3
* ND = not detected.
Within 2 days of administering [14C]-benzene (0.34-0.5 g/kg) to rabbits by gavage,
approximately 45% of the dose was detected in expired air (43% as unchanged
benzene and 1.5% as carbon dioxide) and approximately 35% appeared in the
urine. Urinary radiolabel was predominantly in the form of conjugated phenols,
with phenol comprising approximately 23% of the administered dose and with
hydroquinone, catechol and 1,2,4-benzenetriol making up 4.8%, 2.2% and 0.3%
respectively (as conjugates). Approximately 1.3% of the dose was recovered as
trans,trans-muconic acid and a further 0.5% as phenylmercapturic acid. No
diphenyl or its derivatives were detected in the urine. The residual radioactivity
(5% to 10%) was associated with the tissues and faeces (Parke & Williams, 1953).
The elimination of benzene by the metabolic route appears to be saturable. Oral
doses of [14C]-benzene 15 mg/kg resulted in the excretion in the urine over 48 h of
>89% of the administered radioactivity by rats (F344 or Sprague-Dawley). Doses
50 mg/kg bw resulted in a dose-dependent reduction in urinary excretion and a
corresponding dose-dependent increase in exhaled 14C, predominantly as the parent
molecule. At all doses, residual 14C in the carcass amounted to less than 8%.
Excretion in the faeces did not exceed 11% of the administered dose up to the
maximum dose of 300 mg/kg. Mice (B6C3F1) demonstrated similar elimination
characteristics to rats (Sabourin et al, 1987).
Other routes
Analysis of urine from male cynomolgus monkeys administered [14C]-benzene (5,
50 and 500 mg/kg) by intraperitoneal injection revealed that urinary excretion of
radiolabel diminished with increasing dose. At 5 mg/kg an average of 56% of the
administered dose was recovered in the urine compared to 13% at 500 mg/kg over
a 95-h period. In contrast, recovery of radiolabel from the urine of chimpanzees
administered a dose of benzene (1 mg/kg) by intravenous injection was complete
after 24 h with >90% of the radiolabel collected within the first 8 h. As shown in
Table 9.3, phenyl sulfate was found to be the major metabolite (45-74% of total
urinary metabolites) for all doses. Lesser amounts of hydroquinone glucuronide,
muconic acid, phenyl glucuronide, hydroquinone sulfate and catechol sulfate were
also present. No unconjugated metabolites were detected. The amount of excreted
hydroquinone sulfate and muconic acid decreased and phenyl glucuronide and
catechol glucuronide increased as the benzene dose increased. A similar urinary
profile of metabolites was obtained with female chimpanzees administered an
intravenous dose of [14C]-benzene (1 mg/kg), although the formation of catechol
conjugates was not detected (Sabourin et al, 1992).
Benzene 45
Table 9.3: Major urinary metabolites after intraperitoneal administration of
benzene, expressed as a percentage of total urinary metabolites from 24-h
samples (adapted from Sabourin et al. (1992))
Dose Phenol Hydroquinone Catechol Pre-phenyl- Muconic
Species (mg/kg) conjugates conjugates conjugates mercapturic acid acid
5 61 27 8.0 No data 4.4
Cynomolgus
monkey 50 73 15 6.0 No data 3.1
500 78 8.9 9.9 No data 1.3
Chimpanzee 1 75 8.0 ND* 0.5 5.5
* ND = not detected.
9.4.2 Human data
Inhalation
The elimination of benzene across the lungs of 10 subjects was studied. Subjects
inhaled benzene (47-84 ppm) for 2-3 h after which breath samples were taken over
a further 5-7 h. The results showed 16.4-41.6% of the absorbed benzene to be
exhaled with the greatest rate occurring during the first hour. Excretion in the urine
accounted for a maximum of 0.2% of the absorbed dose (Srbova et al, 1950). It
appears that urinary benzene metabolites were not measured by the protocol
employed. Comparable results were produced after a 4-h exposure to benzene
vapour (52-62 ppm) where 6 volunteers (3 males and 3 females) were shown to
exhale 16.3% (men) and 17.2% (females) of the inhaled benzene (Nomiyama &
Nomiyama, 1974a). The ratio of respiratory elimination of non-metabolised
benzene to retained benzene was determined to be 114.8% for males (considered by
the authors to be unreliable) and 39.8% for females (Nomiyama & Nomiyama,
1974b). Using 4 volunteers (male non-smokers) exposed to benzene vapour (mean
daily exposure 26.2-42.2 ppm) for 5 consecutive daily 6-h periods, Berlin et al.
(1980) showed the clearance of benzene across the lungs to be biphasic with a half-
time of 2.6 h for the rapid phase and 24 h for the slow phase. At higher benzene
concentrations (99 ppm for 1 h), Sherwood (1988) identified one individual with an
initial rapid phase and 2-3 slower phases while urinary excretion displayed a
biphasic pattern.
Ghittori et al. (1993) found a linear correlation between benzene in the breathing
zone and unmetabolised benzene in the urine of workers. Subsequently, Ghittori et
al. (1995) identified a linear relationship between benzene in the breathing zone of
workers and urinary levels of trans,trans-muconic acid and phenylmercapturic
acid.
Dermal and oral
Peak excretion of radioactivity in the urine of 4 human volunteers after the
application of 0.4 ml of [14C]-benzene to the ventral forearm occurred rapidly
within the first 2 h and decreased rapidly thereafter but remained detectable for up
to 30 h (Franz, 1984).
No studies were identified that address the elimination of benzene or its metabolites
from humans after exposure by the oral route.
Priority Existing Chemical Number 21
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9.5 Comparative kinetics and metabolism
As discussed above, CYP2E1 is a high affinity, low capacity enzyme.
Consequently, the pathway for the hepatic metabolism of benzene becomes
saturated at relatively low doses. Henderson et al. (1989) found a single oral dose
of benzene of 50 mg/kg or greater, when administered to rats or mice, resulted in
saturation of the metabolic pathway with consequent loss of unmetabolised
benzene by exhalation. Rats and mice administered an oral dose of 150 mg/kg
exhaled approximately 50% and 85% respectively as unmetabolised benzene. This
loss of benzene by exhalation becomes a limiting factor in the maximal tissue
concentrations of metabolites that can be achieved following oral dosing. However,
higher tissue concentrations of benzene metabolites can be achieved by the
inhalation route. It has been observed that mice accumulate substantially more
benzene metabolites than rats during inhalation exposure. This appears to be due to
physiologic and metabolic differences between the two species. Mice have a higher
respiratory minute volume per kg body weight compared to rats allowing for the
blood benzene level to achieve equilibrium faster than in the rat (Sabourin et al,
1989, 1990). Mice also have a higher metabolic rate, based on increased oxygen
consumption (approximately 1.8 times greater than the rat), resulting in faster
removal of benzene from the circulation. This allows for higher levels of
metabolites to accumulate within body tissues compared to the rat. Doses of
benzene that lead to metabolic saturation also produce changes in the metabolic
profile of benzene metabolites (Sabourin et al, 1989; Daiker et al, 1996).
9.5.1 Oral studies
The content of water-soluble benzene metabolites in bone marrow has been
examined following oral administration of benzene to male rats and mice. Table 9.4
shows that phenol conjugates accounted for the major proportion of metabolites in
the rat and remained relatively constant over the dose range as did the mercapturic
acid derivatives. The trans,trans-muconic acid content diminished with increasing
doses of benzene and hydroquinone conjugates remained at relatively low levels. In
contrast, the mouse produced comparable bone marrow levels of phenol and
hydroquinone conjugates at the lowest dose with the amount of hydroquinone
conjugates decreasing as the benzene dose increased. Both phenyl mercapturic acid
and trans,trans-muconic acid increased with the dose of benzene (Sabourin et al,
1989).
Table 9.4: Major bone marrow metabolites after oral administration of
benzene, expressed as a percentage of total water-soluble metabolites from
pooled samples (adapted from Sabourin et al. (1989))
Pre-phenyl- Phenyl-
Hydroquinone mercapturic mercapturic Muconic
Dose Phenol
acid
Species (mg/kg) conjugates conjugates acid acid
Rat (F344) 1 75 ND* 15 ND 10
10 74 3.0 15 4.0 4.0
200 84 2.3 13 ND 0.2
1 50 50 ND ND ND
Mouse
(B6C3F1) 10 52 35 ND 13 ND
200 56 9.0 ND 27 8.0
* ND = not detected.
Benzene 47
9.5.2 Inhalation studies
Animal data
The profile of metabolites produced by male rats (F344) and mice (B6C3F1)
exposed (nose-only) to benzene vapour for 6 h at 5 ppm or 600 ppm is presented in
Table 9.1. Phenol conjugates account for the major proportion of metabolites
produced at either concentration by both species. At 5 ppm, hydroquinone
conjugates and trans,trans-muconic acid are present in higher amounts than at 600
ppm while pre-phenylmercapturic acid increases with the administered dose
(Sabourin et al, 1989).
Tissue and blood levels of non-conjugated benzene metabolites were determined in
male rats (F344) and mice (B6C3F1) after inhalation of benzene vapour (50 ppm)
for 6 h. While phenol, hydroquinone and catechol could not be detected in the liver,
lung or blood of the rat, detectable levels of phenol and hydroquinone were found
in the mouse with catechol detected only in the liver. The data for male rats and
mice are presented in Table 9.5.
Table 9.5: Major non-conjugated benzene metabolites (nmol/g tissue) in rat
and mouse tissues (adapted from Sabourin et al. (1988))
F344 rats B6C3F1 mice
Metabolite Liver Lung Blood Liver Lung Blood
Phenol ND* ND ND 0.3 0.6 1.3
Hydroquinone ND ND ND 2.1 1.2 4.3
Catechol ND ND ND 0.3 ND ND
* ND = not detected.
In contrast, conjugated derivatives of phenol, hydroquinone and catechol were
detected in substantially greater amounts in the tissues and blood of both species
(Table 9.6).
Table 9.6: Major conjugated benzene metabolites (nmol/g tissue) in rat and
mouse tissues (adapted from Sabourin et al. (1988))
F344 rats B6C3F1 mice
Metabolite Liver Lung Blood Liver Lung Blood
Phenylglucoronide ND* ND ND 6.3 1.2 ND
Cathecholglucoronide 1.0 ND ND 0.8 0.5 ND
Hydroquinoneglucoronide 0.4 ND ND 26 15 12
Phenylsulfate 1.5 15 20 28 36 36
Hydroquinone monosulfate ND ND ND 2.8 0.6 ND
Pre-phenylmercapturic acid 6.9 0.9 ND 44 2.1 2.3
Phenylmercapturic acid ND ND ND ND ND ND
Muconic acid 8.4 1.9 0.7 228 18 1.0
* ND = not detected.
As shown in the table, the level of trans,trans-muconic acid in the mouse liver was
very much greater than observed in lung tissue or blood for either species (Sabourin
et al, 1988). Henderson et al. (1989) observed that the mouse metabolised more of
an inhaled dose of benzene than the rat under comparable conditions and that a
greater proportion was converted to the putative toxic metabolites. It was found that
Priority Existing Chemical Number 21
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detoxification (conjugation) pathways were low-affinity, high-capacity whereas
toxic metabolite formation appeared to be high-affinity, low capacity.
A short-term benzene inhalation study (exposure for 6 h/day for 6 days) with male
Swiss mice showed that at 199 ppm or less, the major metabolite in blood was
phenylsulfate while above 199 ppm a dose-dependent increase in phenyl-
glucuronide occurred. At all benzene concentrations, the blood phenol level
increased in a dose-dependent manner (Wells & Nerland, 1991).
Human data
Studies of humans are generally limited to analysis of urine or blood samples of
workers occupationally exposed to benzene.
Bechtold and Henderson (1993) conducted analyses on the urine and blood of non-
smoking female workers exposed to benzene vapour. Five women exposed to
approximately 4.4 ppm for 8 h showed the presence of elevated urinary levels of
trans,trans-muconic acid (6.2 礸/mg creatinine) compared to 8 females with no
known exposure (0.27 礸/mg creatinine). Blood samples from 10 women exposed
to benzene vapour (0-23.1 ppm) showed a linear relationship between benzene
exposure levels and albumin-S-phenylcysteine adducts, however, no haemoglobin-
S-phenylcysteine adducts were detected.
9.5.3 Dermal studies
Comparative studies of the metabolism of benzene after dermal absorption were not
identified.
9.5.4 In vitro studies
The metabolism of low levels of benzene by microsomes prepared from 10 human
liver samples was investigated. When [14C]-benzene (3.4 礛) was incubated with
microsomal preparations, the major metabolites were phenol and hydroquinone
accounting for up to 48% of the recovered radiolabel while minor metabolites were
catechol and 1,2,4-trihydroxybenzene which accounted for <2% and 0.2%
respectively. A further metabolite, tentatively identified as 2,2'-biphenol,
accounted for approximately 4% of radiolabel. The CYP2E1 activities of the
individual liver samples were found to vary 13-fold as determined by a standard
hydroxylation assay with activities ranging between 0.253 to 3.266 nmol/mg/min.
When benzene was used as the substrate, a 6-fold difference between liver samples
was noted that ranged from 10% to 59%. Comparison of individual liver samples
over a 16-min incubation period showed that phenol was the major metabolite
formed with the exception of two samples where hydroquinone predominated.
These latter two samples had higher CYP2E1 activities and the sample with the
highest activity produced equal quantities of phenol and hydroquinone. The rate of
benzene metabolism by each of the 10 liver samples correlated with their CYP2E1
activity (Seaton et al, 1994). In a subsequent report by Seaton et al. (1995)
addressing the in vitro sulfonation of phenol and glucuronidation of hydroquinone
by human liver cytosolic and microsomal preparations from 10 donors, there was a
3-fold difference in the rates of conjugation for each reaction.
Benzene 49
9.6 Summary
Benzene is readily absorbed by the inhalation, oral and dermal routes in all animal
species tested. In humans, the absorption of benzene by the inhalation route is
maximal within minutes of exposure and subsequently declines to a constant level.
Dermal absorption is generally low compared to inhalation due to volatilisation,
with less than 1% of an applied dose being absorbed unless skin exposure is
prolonged. The variation in benzene absorption between individuals following
inhalation is high. Partitioning of benzene is expected to occur into lipid-rich
tissues due to the lipophilic nature of benzene. Several studies have confirmed that
benzene accumulates in the adipose tissue, bone marrow and brain of animals and
humans.
The metabolism of benzene is qualitatively similar between various animal species,
including humans, and proceeds predominantly by hepatic CYP2E1-mediated
oxidation of the aromatic ring to yield benzene oxide/oxepin. Subsequent pathways
for metabolism of the oxide/oxepin include spontaneous rearrangement to phenol
or ring cleavage to give trans,trans-muconaldehyde. Phenol can be further oxidized
to polyphenols (hydroquinone, catechol and 1,2,4-trihydroxybenzene).
Detoxification pathways involve conjugation of benzene oxide or trans,trans-
muconaldehyde with GSH while the phenolic metabolites are conjugated to either
glucuronate or sulfate. The metabolism of benzene is rapid with water-soluble
metabolites appearing in the urine within 2 h of exposure. The major urinary
metabolites from several species are conjugates of phenol followed by lesser and
variable amounts of hydroquinone conjugates and of pre-phenylmercapturic acid
and trans,trans-muconic acid. Conjugates of catechol have been detected in small
amounts in the urine of mice, rabbits and primates.
Due to the limited capacity of hepatic CYP2E1 to metabolise benzene, a substantial
proportion of absorbed benzene is eliminated unchanged in exhaled air, with the
remainder being eliminated via the urine, principally as metabolites. Urinary
excretion appears to be biphasic with a fast phase followed by a prolonged phase,
suggesting the slow removal of benzene from adipose tissue. Due to the readily
saturable nature of benzene metabolism, exposure at higher doses results in greater
elimination of unmetabolised benzene via exhalation.
While comparative studies of urinary benzene metabolites have shown common
pathways for benzene metabolism to exist between various species, physiological
as well as metabolic differences contribute to some of the observed differences.
The easily saturated nature of benzene metabolic pathways and greater respiratory
minute volume of the mouse allow the mouse to expire more of an oral dose of
benzene compared to the rat. Similarly, respiratory differences and the greater
metabolic rate of the mouse allow tissue levels of benzene metabolites to reach
higher levels compared to the rat.
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10. Effects on Laboratory
Mammals and Other Test
Systems
The aim of this section is to describe the toxic effects and corresponding effect
levels of benzene in animals. In the case of end points studied extensively in
humans (mainly haematological and genetic toxicity), the assessment is based on
recent reviews by ATSDR (1997) and USEPA (USEPA 1998a, 1998c). For other
adverse effects, individual animal studies have been reviewed for this assessment.
These include all carcinogenicity studies as well as investigations of the toxic
effects of benzene on the central nervous system (CNS), immune function,
reproductive organs and foetus.
Most of the available studies do not comply with Good Laboratory Practices (GLP)
or international standards such as the OECD Test Guidelines. In consequence, all
available publications with a relevant end point have been included in the review
irrespective of their compliance with formal quality criteria. However, studies
providing insufficient scientific detail to permit a critical appraisal of their findings
are clearly identified as such. Unless otherwise indicated, only effects that were
statistically different (p <0.05) from controls have been considered.
10.1 Acute toxicity
The acute toxicity of benzene in experimental animals is summarised in Table 10.1,
which includes the highest and the lowest values reported in the published
literature. Mortality is due to cardio-respiratory arrest from severe CNS depression
and/or cardiac arrhythmia (Nahum & Hoff, 1934).
Table 10.1: Acute toxicity of benzene
Route Species Measure* Results Sex Reference
Inhalation Mouse LC50(7 h) 9980 ppm Not specified Svirbely et al. (1943)
Rat LC50(4 h) 13,700 ppm Females Drew & Fouts (1974)
16,000 ppm Males Smyth et al. (1962)
ALD(4 h)
45,000 ppm Both sexes Carpenter et al. (1944)
Rabbit LC100(30 min)
Mouse LD50
Oral 4700 mg/kg Not specified RTECS (2000)
6500 mg/kg Males Span?et al. (1989)
810 mg/kg Males Cornish & Ryan (1965)
Rat LD50
5600 mg/kg Males Wolf et al. (1956)
9900 mg/kg Males Smyth et al. (1962)
LD50 >8200 mg/kg Roudabush et al. (1965)
Dermal Male guinea pigs
Guinea
Male and female
pig, rabbit
rabbits
SC Mouse ALD 3500 mg/kg Males Watanabe & Yoshida (1970)
* ALD = approximate lethal dose; LC50 = median lethal concentration; LC100 = concentration leading to
100% mortality; LD50 = median lethal dose; SC = subcutaneous.
Benzene 51
10.2 Irritation and corrosivity
Several rabbit tests for skin and eye irritation have been reported. From 10-20 daily
applications of undiluted benzene to the skin caused redness, oedema, skin peeling
and blistering (Wolf et al, 1956). The chemical was also reported to cause skin
irritation in a test according to OECD Test Guideline No. 404, however, further
details were not provided (Jacobs, 1992, as cited in OECD, 2000). One or two
drops of undiluted benzene applied to the eye produced moderate irritation of the
conjunctiva and very slight, transient corneal injury (Wolf et al, 1956). Smyth et al.
(1962) reported similar skin and eye lesions rated as grade 3 on a 10-point scale.
Rats exposed to benzene vapours for 6 h/day, 5 days/week for 10 weeks exhibited
lacrimation during the first 3 weeks of exposure to levels 10 ppm (Shell, 1980, as
cited in ATSDR, 1997).
10.3 Sensitisation
There are no studies of skin or respiratory sensitisation to benzene in animals.
10.4 Repeated dose toxicity (other than carcinogenicity)
10.4.1 Short-term exposure
The toxic effects of benzene have been investigated in numerous short-term studies
in mice and rats. In these studies, benzene was administered orally in vegetable oil
or drinking water for 2 days to 24 weeks, or by whole-body exposure to vapours,
usually for 6 h/day, 5 days/week. The dose levels tested ranged from 1-600
mg/kg/day by mouth and from 0.44-6600 ppm by inhalation. Repeated dose dermal
studies could not be identified.
Neurotoxicity
Evans et al. (1981) exposed male CD-1 and C57BL mice to inhalation of 0, 300 or
900 ppm benzene for 6 h/day. After the 5th exposure, the mice were observed and
scored for 7 behavioural categories at 30 and 75 min post-exposure. In both strains,
there were increases in the frequency of eating and grooming, and a decrease in
sleeping and resting. These stimulatory effects were more pronounced at 75 than at
30 min post-exposure and in the 300 than in the 900 ppm exposure groups,
indicating an association with brain concentrations below a certain level.
Immediately following single and repeated 6-h exposures of male mice to 100, 300,
1000 or 3000 ppm benzene, there were increased milk licking at 100 ppm and a
reduction in hind limb grip strength at 1000 ppm, but no effects on locomotor
activity (Dempster et al, 1984). In the absence of motor disturbances, hind limb
grip strength is a test for unconditional reflexes. Milk licking, however, may be
influenced by hunger and mucosal membrane irritation.
In groups of 10 adult male mice exposed to 0, 0.78, 3.13 or 12.52 ppm benzene for
2 h/day, 6 days/week for 30 days, tests for behaviour (time taken to run to a safety
area in a Y-maze following an electric shock) and forelimb grip strength showed
stimulation at 0.78 ppm and depression at 12.52 ppm, but no effect on locomotor
activity (Li et al, 1992). Compared to unexposed controls, the average change in
the frequency of rapid shock responders was +30% at 0.78 ppm and ?4% at 12.5
ppm. For grip strength, it was +77% and ?1% respectively. As the concentration
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of benzene in the air was not checked after the first three days of the experiment
and there were extraordinary changes in bone marrow morphology on day 30,
actual benzene exposure may have been higher than reported (USEPA, 1998c). On
the other hand, the changes in behaviour were observed already on the first 1-2
days of exposure when air level monitoring did take place.
Tegeris & Balster (1994) evaluated the acute behavioural effects in mice of a 20-
min inhalation exposure to 2000, 4000 and 8000 ppm benzene and five derivatives
(toluene, ethyl benzene, propyl benzene, m-xylene and cumene). All six chemicals
produced a nearly identical profile of CNS depressant effects that paralleled those
of the anaesthetic drug pentobarbital, except that they were short-lived, with
recovery beginning within minutes of cessation of exposure.
In mice, administration for 4 weeks of 8-180 mg/kg/day benzene in drinking water
had no behavioural effects, but induced a dose-related increase in the level of
noradrenaline, dopamine, serotonin and their metabolites in a number of brain
regions (Hsieh et al, 1988b). There was also a dose-dependent stimulation of
hypothalamic-pituitary-adrenocortical activity (Hsieh et al, 1991). Changes in brain
noradrenaline, dopamine, serotonin and/or their metabolites were also found in rats
2 h after a single oral dose of 950 mg/kg benzene or following inhalation of 1500
ppm benzene, 6 h per day for 3 days (Andersson et al, 1983; Kanada et al, 1994).
The most consistent finding in these studies was an increase in noradrenaline and
dopamine levels in the hypothalamus and other subcortical brain regions. In a rat
inhalation study, benzene also induced noradrenaline release from post-ganglionic
sympathetic nerves in the ovaries and uterus (Ungv醨y & Don醫h, 1984).
A 30-day drinking water study found a reduction in brain weight in mice at 350 but
not at 195 mg/kg/day (Shell 1992, as cited in ATSDR, 1997). No studies were
identified that specifically looked for benzene-induced morphological changes in
nervous organs or tissues.
Immunotoxicity
When administered to mice by inhalation or in drinking water, benzene suppressed
a number of lymphocyte (LC) functions. These included T- and B-LC response to
mitogens; interleukin-2 production in T-helper LC; the activity of cytotoxic,
alloreactive and suppressive T-LC; B-LC antibody production; and T-LC and
macrophage resistance to intracellular infection with Listeria monocytogenes (Fan,
1992, as cited in USEPA, 1998c; Hsieh et al, 1988a; Irons et al, 1983; Rosenthal &
Snyder, 1985, 1987; Rozen et al, 1984; Rozen & Snyder, 1985; Stoner et al, 1981,
as cited in IPCS, 1993; White et al, 1984, as cited in USEPA, 1998c). Based on the
above effects, the lowest observed adverse effect level (LOAEL) was 10 ppm by
inhalation (Rozen et al, 1984) and 12 mg/kg/day by the oral route (White et al,
1984, as cited in USEPA, 1998c). A no observed adverse effect level (NOAEL)
was not achieved, although Hsieh et al. (1988a) found a bimodal response with a
reduction in LC proliferation at 40 mg/kg/day and an increase at 8 mg/kg/day, the
lowest dose tested. However, Daiker et al. (2000) recently found no changes in
spleen LC cellularity, subtype profile or function in mice exposed to inhalation of
0.44 ppm benzene for 7 h/day, 5 days/week for 6 weeks.
In these studies in mice, immunosuppression generally occurred at exposure levels
which were also associated with reduced absolute lymphocyte counts (ALC).
However, in one 30-day study, mitogen-stimulated LC proliferation was decreased
at 12 mg/kg/day (the lowest dose tested) in the absence of any other blood or bone
marrow toxicity (White et al, 1982, as cited in USEPA, 1998c). There is no
Benzene 53
evidence of specificity with respect to antigen or immune response type. Overall,
these findings indicate that benzene-induced immunosuppression is the outcome of
a general impairment of the ability of LC to respond to antigenic stimuli by rapid
clonal expansion, with little, if any, interference with antigen recognition.
In wild cotton rats given three consecutive intraperitoneal injections of benzene at a
dosage of 0, 100, 300, 600 or 1000 mg/kg/day and a battery of tests for cellular and
humoral immune functions on days 1-9 after the last treatment, there was no
evidence of immunosuppression in any of the treatment groups (McMurry et al,
1991).
In a subacute inhalation study in male Sprague-Dawley rats exposed to 0, 30, 200
or 400 ppm benzene for 6 h/day, 5 days/week for 2-4 weeks, Robinson et al. (1997)
determined a NOAEL/LOAEL of 200/400 ppm based on spleen weight, cellularity,
total T-LC, T-helper LC, antigen-stimulated and unstimulated B-LC content, and
thymus weight. As such, rats appear to be less sensitive than mice to the
immunotoxic effects of benzene.
Effects on blood and blood forming organs
ATSDR (1997) and USEPA (1998c) have reviewed a large number of published
and unpublished study reports that address the effects of short-term exposure to
benzene on the blood and blood forming organs of mice and rats. Based on these
reviews, the overall findings can be summarised as follows:
In peripheral blood, there was a decrease in the quantity of some or all of the
?br>
formed elements, including red blood cells (RBC), white blood cells (WBC),
LC and blood platelets (Plt). In some studies, there was also a reduction in
haemoglobin (Hb) levels and the average RBC size (mean corpuscular volume
(MCV)) was either increased or decreased.
There was bone marrow hypoplasia, with decreased numbers of multipotential
?br>
stem cells and cells that differentiate into RBC, WBC and macrophages, but an
increase in immature RBC such a micronucleated polychromatic and
normochromatic RBC.
In the spleen, there was a decrease in the number of all LC types, but an
?br>
increase in haematopoiesis in general3.
There was a decrease in the weight of the thymus, which is the main site of T-
?br>
LC proliferation.
The order of susceptibility to these effects was male mice > female mice > rats. In
terms of target organ, it was spleen peripheral blood bone marrow > thymus. In
mice, the most sensitive indicators of benzene toxicity were spleen weight, bone
marrow cellularity, and WBC and RBC counts, one or more of which were affected
at concentrations around 10 ppm and above for inhalation and at 8 mg/kg/day and
above for oral exposure. In rats, the most sensitive end points were ALC and WBC
counts, which were affected at 100 ppm by inhalation and 25 mg/kg/day by oral
administration.
3
Haematopoiesis is the sum of processes involved in the production and development of the blood
cells. The haematopoietic processes are usually confined to the bone marrow, but may also take place
in the spleen and liver, for example, in foetuses and newborn animals, or when there is a substantial
increase in the demand for blood cells.
Priority Existing Chemical Number 21
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Two 2-16 week studies in the mouse showed that all haematological abnormalities
returned to normal or near-normal within 4-25 weeks post-exposure (Cronkite et al,
1985; Snyder et al, 1988).
Other effects
There are no consistent reports of respiratory, cardiovascular, gastro-intestinal,
hepatic or renal effects of short-term exposure to benzene by any route (ATSDR,
1997). Effects on reproductive organs are reviewed in Section 10.5. Mortality was
generally low and only a few studies reported decreases in body weight (BW) gain.
Other experimental animals
There is limited evidence that airborne exposure to benzene for 3-4 weeks induces
leukopoenia in guinea pigs and lymphocytopoenia, leukopoenia and impaired
cellular immunity in pigs at levels 88-100 ppm (Dow, 1982, as cited in ATSDR,
1997; Wolf et al, 1956).
10.4.2 Long-term exposure
Blood and blood forming organs
ATSDR (1997) and USEPA (1998c) have reviewed more than a dozen published
reports which describe the results of nine separate studies of the long-term effects
of benzene exposure on blood and blood forming organs. In these studies, mice or
rats were exposed to benzene for 26 weeks by oral administration in vegetable oil
or by whole-body inhalation for 5-6 h/day, 4-5 days/week, at dose levels ranging
from 1-500 mg/kg/day by mouth and from 88-300 ppm by inhalation.
The most consistent long-term effect on the blood was a reduction in RBC, WBC
and LC counts. In some studies, the number of neutrophilic granulocytes and
reticulocytes (young RBC) was increased. The bone marrow and the spleen showed
hypoplasia in some studies and an increase in haematopoietic tissue in others.
Haematological effects were recorded at the lowest dose level examined in all long-
term tests, except for one poorly reported rat study in which the NOAEL was 1
mg/kg/day by mouth (Wolf et al, 1956). This study also recorded a lower LOAEL
than any of the other available studies, namely 88 ppm by inhalation based on
WBC count and spleen weight and 10 mg/kg/day by oral administration based on
WBC count. In more adequately reported studies, the LOAEL was 100 ppm by
inhalation and 25 mg/kg/day by mouth in both mice and rats (ATSDR, 1997;
USEPA, 1998c).
Other effects
There are no consistent reports of non-neoplastic cardiovascular, liver or kidney
abnormalities from long-term exposure to benzene by any route (ATSDR, 1997).
There was chronic irritation of the forestomach epithelium in male rats and mice
and hyperplasia of the Harderian gland4 and pulmonary alveolar epithelium in male
and female mice in 2-year, but not in 17-week oral gavage studies (NTP, 19865).
Lesions occurred at 200 mg/kg/day in rats and at dose levels 25 mg/kg/day in
4
A tear gland in the median angle of the eye which is rudimentary in humans.
5
The major findings in the studies conducted by the National Toxicology Program (NTP) have been
published by Huff et al. (1989).
Benzene 55
mice. Reproductive effects are described below. The median survival time and BW
gain were generally reduced in a dose-dependent manner.
Other experimental animals
There is limited evidence that airborne exposure to benzene for 35-38 weeks
induces leukopoenia and increased spleen weight in guinea pigs and leukopoenia in
rabbits at dose levels 80-88 ppm (Wolf et al, 1956).
10.5 Reproductive toxicity
10.5.1 Effects on fertility and lactation
Data on fertility and lactation are available from three repeated-dose toxicity tests,
three one-generation fertility studies and a limited number of other studies.
Repeated-dose toxicity and one-generation fertility studies
In a 13-week inhalation study, Ward et al. (1985) exposed groups of 150 mice and
50 rats per sex to inhalation of 0, 1, 10, 30 or 300 ppm benzene for 6 h/day, 5
days/week. There was clear evidence of haematological toxicity at the highest dose
level in both species and sexes, but no consistent exposure-related trends in
mortality, clinical observations or mean BW data. The testes and ovaries from 20
mice/sex/group and from 10 rats/sex exposed to either 0 or 300 ppm benzene were
examined microscopically. In mice from the highest exposure group (300 ppm),
there were 4 animals with cystic ovaries, 7 with bilateral testicular atrophy or
degeneration, 6 with decreases in the number of spermatozoa in the epididymal
ducts and 9 with an increase in abnormal sperm forms. Similar lesions of doubtful
biological significance were seen in both sexes at lower dose levels. No
abnormalities were found in the gonads of rats exposed to 300 ppm benzene.
A study in mice administered benzene at 25, 50 or 100 mg/kg/day by gavage for 2
years found the following number of animals with epithelial hyperplasia or
follicular atrophy of the ovaries (NTP, 1986):
Ovarian lesions: 0 mg/kg/day 25 mg/kg/day 50 mg/kg/day 100 mg/kg/day
No. of mice examined 47 44 49 48
Epithelial hyperplasia 12 39 31 29
Senile atrophy 15 35 32 22
The statistical significance of these findings is not reported. However, when
analysed for this assessment, the increase in the incidence of epithelial hyperplasia
was significant at all dose levels, whereas the incidence of senile atrophy was
significantly elevated at 25 and 50, but not at 100 mg/kg/day (p <0.05; test for
exact confidence limits). Testes were not examined microscopically, as they had no
grossly visible lesions. A parallel study in rats found no macroscopic abnormalities
in the gonads, even at the highest dose level tested (100 mg/kg/day in females, 200
mg/kg/day in males) (NTP, 1986).
In an early inhalation study, Wolf et al. (1956) observed sedation, growth
depression, mortality and a moderate increase in testis weight in male rats exposed
to 6600 ppm benzene for 13 weeks. The testes were normal in rats exposed to 88 or
2200 ppm for 30 weeks. At these dose levels there were mild lesions of the blood
and lymphatic system, but no mortality. In guinea pigs and rabbits exposed to 80-
88 ppm benzene for 35-38 weeks, there was no mortality, mild haematological
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changes and a slight increase in testis weight and in mild degenerative lesions of
the seminiferous tubules. Further details were not reported and it is unclear whether
these findings were statistically significant.
In female mice, a single intraperitoneal injection of benzene at the maximum
tolerated dose of 1250 mg/kg did not reduce the number of offspring and litters
produced in a reproductive capacity test involving the observation of 35 treated and
untreated breeding pairs for 347 days (Bishop et al, 1997).
In a one-generation fertility study, groups of 26 female rats were exposed to 0, 1,
10, 30 or 300 ppm for 6 h/day, 5 days/week for 10 weeks prior to mating and then
daily on days 0-20 of gestation and days 5-20 of lactation (Kuna et al, 1992). In the
dams, there was no exposure-related effect on BW gain, clinical observations or
necropsy findings and no fertility-related effects. When the neonates were
examined at weaning on day 21 postpartum, there was a dose-related, 6-9%
increase in relative kidney weight in female offspring of dams exposed at 10 ppm
and above. Female offspring of dams exposed to 300 ppm benzene also had a 10%
BW reduction and a 14% reduction in absolute liver weight.
In another fertility study, female rats were kept in inhalation chambers where they
were exposed for 24 h/day to 0, 0.3, 1.6, 6.3, 15, 18, 20 or 200 ppm benzene
(Gofmekler, 1968). Exposure began 10-15 days prior to mating, when males were
introduced into the chambers for 6-10 days, and continued throughout the entire
pregnancy period until spontaneous delivery. There were no pregnancies at the
highest dose level. In dams exposed to 0.3-20 ppm benzene, the average litter size
was 7.5 compared to 8.4 in the controls, but there was no exposure-related effect on
the birth weight of the pups.
Other studies
In early experimental studies, benzene caused degenerative changes in the testes
and severely hypoplastic ovaries, degenerated ovarian follicles and chromosomal
damage and mitotic interruption in the ova when administered by subcutaneous
injection or inhalation to male and female mice and female rabbits (Hett & Mark,
1938; Vara & Kinnunen, 1946). The dose levels used in mice were not given, but
were high enough to induce marked leukopoenia. Rabbits were administered 1000
mg/kg/day for 10 days.
In a study in adult mice, testicular germ cell suspensions were examined for DNA
content by flow cytometry at 1, 2, 3, 4 and 10 weeks after a single sublethal dose of
1-7 mL (880-6160 mg) benzene/kg administered by oral gavage (Span?et al,
1989). These doses had no effect on body or testis weight, but resulted in a dose-
dependent reduction in the relative cell count in the primary spermatocyte and
spermatid fractions. The primary spermatocyte fraction was most affected at 2
weeks, the round spermatid fraction at 3 weeks and the elongated spermatid
fraction at 4 weeks post-treatment, as one would expect from a cytotoxic insult
resulting in a transient reduction in the number of differentiating spermatogonia.
Conclusions
Overall, the above studies indicate that benzene exposure may cause degenerative
changes in the gonads of mice, whereas there is insufficient evidence of similar
effects in other species. There was also epithelial hyperplasia in the ovaries of mice
in the NTP (1986) 2-year oral bioassay. However, this is likely to represent a
preneoplastic lesion as ovarian tumours occurred with a significant positive trend in
Benzene 57
this study and epithelial hyperplasia was found in other organs with neoplastic
lesions, namely the Harderian gland and the lungs.
Compound-related testicular atrophy or degeneration was observed in male mice
exposed to 300 ppm benzene by inhalation. Ovarian atrophy was observed in mice
at 25 mg/kg/day by mouth and cystic ovaries at 300 ppm by inhalation. In both
sexes, these lesions occurred at dose levels that were associated with
haematological effects, but not with mortality or other signs of generalised toxicity.
The available data on reproductive capacity are inconclusive.
The changes in body, liver and relative kidney weights observed by Kuna et al.
(1992) in 21-day old female neonates of rats exposed to inhalation of benzene
during pregnancy and lactation are modest, but nonetheless indicative of
developmental toxicity. Because of the study design it cannot be determined
whether these effects were lactational or the result of exposure in utero.
10.5.2 Developmental toxicity
Standard tests
Developmental toxicity tests have been conducted in mice, rats and rabbits exposed
to benzene by inhalation, mouth or subcutaneous injection during the gestation
period (Table 10.2). All foetuses were examined for external defects and in all but
two studies (Exxon Chemical Company, 1986, as cited in USEPA, 1998c;
Watanabe & Yoshida, 1970) for visceral and skeletal abnormalities as well.
Overall, there were no major structural abnormalities in the foetuses, except in one
study in the mouse in which a single SC injection of a maternally toxic dose of
2600 mg/kg benzene on GD 13 was associated with cleft palate and jaw
malformations (Watanabe & Yoshida, 1970). However, several inhalation and oral
studies conducted in mice or rats found evidence of other foetal effects at dose
levels where no toxic effects were recorded in the dams. These include a small (4-
6%), but statistically significant reduction in foetal BW (Coate et al, 1984; Murray
et al, 1979; Seidenberg et al, 1986) and a significant increase in the frequency of
minor skeletal abnormalities (Green et al, 1978; Murray et al, 1979). Moreover, in
two studies on which little experimental detail is available, there was an increase in
resorptions in rats (Litton Bionetics, 1977, as cited in USEPA, 1998c) and a
decrease in foetal BW in mice (Nawrot & Staples, 1979), in both cases in the
absence of any signs of maternal toxicity.
In rabbits, continuous inhalation of 310 ppm benzene was associated with
abortions, an increase in resorptions or foetal deaths, a decrease in foetal BW and
an increased incidence of minor abnormalities in the presence of maternal toxicity
(reduced BW gain), whereas 155 ppm had neither foetal nor maternal effects
(Ungv醨y & T醫rai, 1985).
Priority Existing Chemical Number 21
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Table 10.2: Summary of developmental toxicity tests*
Species Study design Daily dose Foetal effects Maternal effects Reference
Benzene
None Decreased Hgb
Mouse SC injection on GD 8-9 or GD 1760 mg/kg Matsumoto et al.
12-13 (1975)
Decreased BW (3%) Decreased Hgb
8-11 pregnancies per group 3520 mg/kg
Decreased placenta weight (5%) in GD 12- Decreased WBC count
13 group
Delayed ossification in GD 12-13 group
Inhalation, 7 h/day, GD 6-15 500 ppm Decreased BW (6%) None Murray et al.
26-30 pregnancies/group Unspecified increase in `minor skeletal (1979)
variants'
Oral gavage 3 times daily, 800 mg/kg Decreased BW None Nawrot &
GD 6-15 Staples (1979)
1300 mg/kg Increase in resorptions Increase in mortality
No. of pregnancies not given
Decreased BW
2600 mg/kg Increase in resorptions Increase in mortality
Decreased BW
59
2600 mg/kg Increase in late resorptions Increase in mortality
Oral gavage 3 times Nawrot &
Decreased BW
daily,GD 12-15 Staples (1979)
No. of pregnancies not given
155 ppm No information
`Weight retardation' (25 vs. 7% of foetuses)
Inhalation, 24 h/day, GD 6- Ungv醨y & T醫rai
Delayed ossification (10 vs. 5% of foetuses)
15 (1985)
15 exposed pregnancies
115 control pregnancies 310 ppm No information
`Weight retardation' (27 vs. 7% of foetuses)
Delayed ossification (11 vs. 5% of foetuses)
1300 mg/kg None
Oral gavage, GD 8-12 Decreased BW (4%) Seidenberg et al.
28 pregnancies/group (1986)
2600 mg/kg Decrease in WBC count in all
Single SC injection on GD Watanabe &
Increased incidence of cleft palate and jaw
dams
11, 12, 13, 14 or 15 Yoshida (1970)
malformations in offspring of dams injected
No difference in fall in WBC
15 pregnancies per group on GD 13 compared to foetuses of dams
count or in BW gain between
No controls injected on GD 11-12 or 14-15
dams with or without malformed
External foetal examination
foetuses
only
Table 10.2: Continued
Species Study design Daily dose Foetal effects Maternal effects Reference
Rat Inhalation, 6 h/day, GD 6-15 10 ppm Litton Bionetics
Increase in resorptions None
(1977), as cited
26-31 pregnancies/group
in EPA (1998c)
40 ppm Increase in resorptions None
Green et al.
None
100 ppm Missing sternebrae (9/18 vs. 1/16 litters)
Inhalation, 7 h/day, GD 6-15
(1978)
14-18 pregnancies/group
None
300 ppm Delayed ossification of sternebrae (10 vs.
2% of female foetuses)
Decreased BW (10%) Decreased BW gain
2200 ppm
Decreased crown-rump length (5%) Lethargy
Delayed ossification of sternebrae (11 vs.
1% of female foetuses)
Missing sternebrae (11/15 vs. 2/14 litters)
Decreased BW (12%) Hud醟 &
Decreased BW gain (57%)
313 ppm
Inhalation, 24 h/day, GD 9-
Delayed ossification (11 vs. 0% of foetuses) Ungv醨y (1978)
14
Fused sternebrae and extra ribs (9 vs. 1% of
19 exposed pregnancies
60
foetuses)
28 controls
Decreased BW (5%) T醫rai et al.
Inhalation, 24 h/day, GD 7- Decreased BW gain (27%)
50 ppm
(1980)
14 Decreased placenta weight (9%)
17-20 pregnancies/
Resorbed or dead foetuses (42 vs. 6%) Mortality (3/20 vs. 0/48)
150 ppm
exposure group
Decreased BW (28%) Decreased BW gain (45%)
46 control pregnancies
Skeletal abnormalities (57 vs. 5% of Increased relative liver weight (9%)
foetuses) Decreased placenta weight (7%)
Resorbed or dead foetuses (32 vs. 6%) Mortality (1/22 vs. 0/48)
500 ppm
Decreased BW (20%) Decreased BW gain (55%)
Skeletal abnormalities (66 vs. 5% of Increased relative liver weight (14%)
foetuses) Decreased placenta weight (16%)
Resorbed or dead foetuses (29 vs. 6%) Mortality (3/22 vs. 0/48)
1000 ppm
Decreased BW (22%) Decreased BW gain (41%)
Priority Existing Chemical Number 21
Skeletal abnormalities (55 vs. 5% of Increased relative liver weight (10%)
foetuses) Decreased placenta weight (20%)
Table 10.2: Continued
Species Study design Daily dose Foetal effects Maternal effects Reference
Rat Inhalation, 7 h/day, GD 6-15 10 ppm Kuna & Kapp
None Increased BW gain (33%) on GD 15-
Benzene
14-15 pregnancies/ (1981)
20
exposure group
Decreased BW gain (34%) on GD 5-
50 ppm Decreased BW (14%)
11 control pregnancies
15
Increase in foetuses with skeletal and/or
visceral variations (18 vs. 3%)
Decreased BW gain (37%) on
500 ppm Decreased BW (18%)
GD 5-15
Decreased crown-rump length (7%)
Increased BW gain (40%) on GD 15-
Increase in foetuses with skeletal and/or
20
visceral variations (21 vs. 3%)
Coate et al.
None
Inhalation, 7 h/day, GD 6-15 1 ppm None
(1984)
32-38 pregnancies/group
None
2 control groups 10 ppm None
None
40 ppm None
None
100 ppm Decreased BW (6%)
61
Exxon Chemical
None
Oral gavage, GD 6-15 50 mg/kg None
Company
20-22 pregnancies/group
(1986), as cited
Decreased feed consumption
250 mg/kg
External foetal examination None
in EPA (1998c)
only
Decreased BW gain
500 mg/kg Decreased BW
Decreased feed consumption
Decreased BW gain
1000 mg/kg Decreased BW
Decreased feed consumption
Alopecia
500 ppm
Rabbit Murray et al.
None
Inhalation, 7 h/day, GD 6-18 Increased feed and water
(1979)
18-19 pregnancies/group consumption
Ungv醨y & T醫rai
Inhalation, 24 h/day, GD 7-20 155 ppm None None
(1985)
11-15 exposed pregnancies/
group 310 ppm Abortions (6/15 vs. 0/60 dams) Decreased BW gain (62%; not
Resorbed or dead foetuses (16 vs. 5%) corrected for the effect of
60 control pregnancies
Decreased BW (17%) abortions)
`Minor anomalies' (86 vs. 34% of foetuses) Increased relative liver weight (17%)
* BW = body weight; GD = gestation day; Hgb = haemoglobin; SC = subcutaneous; WBC = white blood cell.
Where available, information on the incidence or magnitude of effects compared to non-exposed controls is shown in brackets.
Other studies
According to Ungv醨y (1985), continuous inhalation of benzene (125 ppm),
benzene plus toluene, or benzene plus xylenes had foetotoxic effects in rats, but
only in the presence of maternal toxicity. Exposure to 830 ppm benzene over 48 h
on GD 10-13 increased the severity of maternal toxicity and incidence of
malformations induced by a single oral dose of 250-500 mg/kg acetyl salicylic acid
administered at the end of the exposure period.
Keller & Snyder (1986, 1988) investigated the effects of low level maternal
exposure to benzene on the blood and blood forming organs of mouse foetuses,
neonates and young adults. Groups of 5-10 dams were exposed to inhalation of 0,
5, 10, or 20 ppm benzene for 6 h/day on GD 6-15. Tests on the progeny comprised
RBC, WBC, differential blood cell count, and blood cell morphology; Hb and
haematocrit (Hct); quantification of colony forming units of erythrocyte (CFU-E)
and granulocyte/macrophage (CFU-GM) progenitor cells; and microscopic
examination of blood forming tissue in the liver, bone marrow and spleen. The
number of progeny examined included 2/sex/litter/dose on GD 16, 2/sex/litter/dose
on day 2 after birth, and 1/sex/ litter/dose at 6 weeks after birth.
In 16-day old foetuses exposed to 20 ppm benzene in utero, liver CFU-E was
depressed in both sexes. In peripheral blood from the 2-day old neonates, there was
a dose-related, marked decrease in the number of nucleated RBC. At 20 ppm, there
was also an increase in CFU-E (males only), CFU-GM, non-dividing and dividing
granulocytes in hematopoietic liver tissue, and in non-dividing granulocytes in
peripheral blood. In 6-week old young adult progeny, bone marrow CFU-E was
depressed and spleen CFU-E increased in males exposed to 10 but not to 20 ppm in
utero. In the 20 ppm group, there was a decrease in early nucleated RBC in the
bone marrow and an increase in blast cells in the spleen. There were no effects on
BW or BW gain, feed consumption and clinical signs in the dams, or on BW and
structural abnormalities in the foetuses at any dose level.
In a subsequent study on the interaction between alcohol and inhaled benzene in
mice, CFU-E was significantly depressed in the liver of 16-day old male (but not
female) foetuses exposed in utero to 10 ppm benzene for 6 h/day on GD 6-15
(Corti & Snyder, 1996). This study comprised a total of 9 exposed and 12 control
litters.
The embryotoxicity of benzene and its major metabolites has also been investigated
in vitro in GD 10-12 rat conceptuses. There were no toxic effects at concentrations
of 0.4-0.8 mM (32-64 mg/L) benzene (Brown-Woodman et al, 1994; Chapman et
al, 1994). Phenol was not toxic at 1.6 mM, but caused 100% lethality at 0.2 mM in
the presence of several CP450-dependent bioactivating systems. In the absence of
metabolic activation, catechol, hydroquinone, and quionone each produced 100%
lethality at 0.1 mM and the combination of phenol and hydroquinone showed a
greater than additive effect (Chapman et al, 1994).
Conclusions
In several studies in pregnant animals exposed to benzene by inhalation or
ingestion, there was a small, but statistically significant decrease in foetal BW and
an increase in the incidence of minor skeletal abnormalities at dose levels at which
there was no evidence of maternal toxicity. Major structural abnormalities and
abortions only occurred at dose levels that also caused marked toxicity in the dams.
As such, benzene can be characterised as foetotoxic, but not teratogenic. Based on
Priority Existing Chemical Number 21
62
adequately reported rat studies that found foetal effects in the absence of any signs
of maternal toxicity, the inhalation NOAEL for foetal growth disturbances is 40
ppm (Coate et al, 1984), with a LOAEL of 100 ppm (Coate et al, 1984; Green et al,
1978). Reliable oral effect levels cannot be determined from the available data.
In a small number of pregnant mice, inhalation of 10-20 ppm benzene resulted in
specific adverse effects on multipotential haematopoietic stem cells (colony
forming units) and other blood cells in the liver, bone marrow or spleen of the
offspring (Corti & Snyder, 1996; Keller & Snyder, 1986, 1988). These effects
occurred in the absence of any other signs of developmental toxicity and at levels
similar to those that are known to be toxic to the blood and blood forming organs of
adult mice (Section 10.4).
In vitro studies indicate that some benzene metabolites, including catechol,
hydroquinone and quinone (but not phenol) are substantially more toxic to rat
embryos than benzene itself.
10.6 Genotoxicity
The toxic effects of benzene on human genetic material have been investigated in
numerous in vivo studies which are addressed in Section 11.6 below. As such, the
assessment of studies conducted in animals and various in vitro systems is limited
to an overview of the most significant findings. Unless otherwise indicated, the
information presented is summarised from ATSDR (1997), IARC (1987), IPCS
(1993) and USEPA (1998a).
In vitro tests
Tests with benzene itself have predominantly produced negative results in
conventional in vitro gene mutation assays in bacteria and mammalian cell systems,
with and without metabolic activation. In vitro assays for chromosome aberrations
have also generally been negative, unless special precautions were taken to prevent
the evaporation of benzene from the test system (Randall et al, 1993). Likewise,
conventional in vitro tests for DNA breaks, unscheduled DNA synthesis and DNA
synthesis inhibition have produced inconsistent results. However, sister chromatid
exchanges (SCE), micronuclei (MN) and unscheduled DNA synthesis have been
induced in vitro by metabolites such as catechol, hydroquinone and/or quinone, and
DNA adducts with phenol, hydroquinone and quinone have been detected in a
number of in vitro systems. Benzene itself has recently been shown to induce
morphological transformation, gene mutations through base substitutions, and
aneuploidy in Syrian hamster embryo cells, but is less potent than its metabolites
(Tsutsui et al, 1997). In the alkaline single cell gel electrophoresis (Comet) assay,
pronounced, contact time-dependent DNA damage has been detected in non-
cycling (G0) human LC after treatment not only with catechol, hydroquinone,
quinone, 1,2,4-trihydroxybenzene or muconic acid, but also with benzene itself
(Anderson et al, 1995).
Tests in Drosophila
Benzene was consistently negative in the sex-linked recessive lethal test in
Drosophila melanogaster, which is a specific, but insensitive test for the potential
of chemicals to cause heritable gene mutations and chromosome aberrations.
However, benzene has been shown to induce a statistically significant number of
Benzene 63
so-called delayed lethal mutations, which may be the result of heritable mutations
in one rather than in both DNA strands of the X chromosome (Kale & Kale, 1995).
In vivo tests in rodents
There is ample evidence that benzene is genotoxic in a broad spectrum of in vivo
tests in rodents, in which the chemical was administered by inhalation, oral gavage
or parenteral injection. These include tests for SCE and MN induction in peripheral
blood cells, bone marrow cells, foetal liver cells, lung fibroblasts (Ranaldi et al,
1998), and Zymbal gland cells (Angelsanto et al, 1996); gene mutations in LC, lung
and spleen cells; chromosome aberrations in LC, bone marrow cells, spleen cells,
and spermatogonia; and DNA adducts in nucleated blood and bone marrow cells.
Furthermore, many of these effects have been shown to be mitigated by inhibitors
of benzene metabolism and reproduced by benzene metabolites such as
hydroquinone and 1,2,4-trihydroxybenzene.
In an in vivo chromosome aberration study in male mice, the sensitivity and dose
response to a single oral dose of benzene was found to differ markedly between
bone marrow cells and differentiating spermatogonia, as illustrated in Figure 10.1
(Ciranni et al, 1991).
Figure 10.1: Chromatid aberrations excluding gaps in mouse bone marrow
cells (broken lines) and spermatogonia (solid lines) at 6-48 h after oral
treatment with 880 mg/kg benzene (left) and at 24 h after oral treatment with
88, 220, 440 or 880 mg/kg benzene (right) (Ciranni et al, 1991)
25 25
Per cent aberrant cells
20 20
15 15
10 10
5 5
0 0
0 200 400 600 800 1000
0 6 12 18 24 30 36 42 48
Dose (mg/kg)
T i m e (h )
Sensitivity to SCE and MN induction was 2- to 3-fold higher in male than in
female mice and male sensitivity to MN induction was markedly decreased by
castration and restored by testosterone treatment (Luke et al, 1988, as cited in
USEPA, 1998c). Immature mice showed no gender difference in sensitivity to MN
induction (Siou & Conan, 1980, as cited in USEPA, 1998c).
10.7 Carcinogenicity
Table 10.3 highlights the principal findings in the 23 carcinogenicity tests that have
been reported in the open literature. They include oral gavage studies in B6C3F1,
RF/J and Swiss mice and F344, Sprague-Dawley and Wistar rats and inhalation
studies in AKR, C57BL, CBA, CD-1 and HRS mice and Sprague-Dawley rats.
Priority Existing Chemical Number 21
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Table 10.3: Principal findings in inhalation (I) and oral gavage (O)
carcinogenicity studies in mice and rats
Strain I/O Protocol Principal findings* Reference
Mice
AKR No increase in tumour incidence
I Snyder et al.
0, 100 ppm for 6 h/day, 5
(1980)
days/week for life (72 weeks)
I No increase in tumour incidence
0, 300 ppm for 6 h/day, 5 Snyder et al.
days/week for life (28 weeks) (1978)
O
B6C3F1 NTP (1986)
0, 25, 50, 100 mg/kg/day for 5 Harderian gland tumours, lung
days/week, 103 weeks tumours, lymphoma, mammary
gland carcinoma, ovarian granulosa
cell and mixed benign tumours,
preputial gland carcinoma, Zymbal
gland carcinoma
C57BL I 0, 300 ppm 6 h/day, 5 Lymphoma, ovarian tumours, Cronkite et al.
days/week for 16 weeks, with Zymbal gland carcinoma (no (1985)
life-long observation (about statistical analysis)
110 weeks)
Lymphoma
I Snyder et al.
0, 300 ppm for 6 h/day, 5
(1980)
days/week for life (70 weeks)
I Zymbal gland carcinoma
0, 300 ppm 6 h/day, 5 Snyder et al.
days/week, 1 out of every 3 (1988)
weeks for life (118 weeks)
I No increase in tumour incidence
0, 1200 ppm 6 h/day, 5 Snyder et al.
days/week for 10 weeks, with (1988)
life-long observation (about
146 weeks)
CBA? I 0, 100 ppm for 6 h/day, 5 Unspecified, non-hepatic, non- Cronkite et al.
days/week for 16 weeks, with haematopoietic tumours (1989)
life-long observation (about
135 weeks)
I 0, 300 ppm for 6 h/day, 5 Non-hepatic, non- haematopoietic Cronkite et al.
days/week for 16 weeks, with tumours (including Harderian gland (1989)
life-long observation (about carcinoma, lung adenocarcinoma,
115 weeks) mammary gland carcinoma,
neoplasms resembling acute
myeloblastic and chronic
granulocytic leukaemia, Zymbal
gland carcinoma)
I 0, 300 ppm for 6 h/day, 5 Lung adenoma, lymphoma, Farris et al.
days/week for 16 weeks, with preputial gland carcinoma (1993)
life-long observation (78
weeks)
CD-1 I 0, 300 ppm for 6 h/day, 5 Sporadic cases of suspected Goldstein et al.
days/week for life (not further myeloid leukaemia (p = 0.147) (1982)
specified)
I Lung adenoma
0, 300 ppm for 6 h/day, 5 Snyder et al.
days/week 1 out of every 3 (1988)
weeks for life (about 60
weeks)
I 0, 1200 ppm for 6 h/day, 5 Lung adenoma, Zymbal gland Snyder et al.
days/week for 10 weeks, with carcinoma (1988)
life-long observation (about
130 weeks)
HRS I 0, 400 ppm for 6 h/day, 5 No leukaemia or lymphoma in either Stoner et al.
days/week for 26 weeks (1980), as cited
hr/hr (leukaemia-prone) or hr/-
in Cronkite et al.
(leukaemia-resistant) strains
(1985)
RF/J O 0, 500 mg/kg/day for 5 Lymphatic neoplasms, lung Maltoni et al.
days/week, 52 weeks tumours, mammary gland (1989)
carcinoma (no statistical analysis)
Swiss O 0, 500 mg/kg/day for 5 Lung adenomas, mammary gland Maltoni et al.
days/week, 78 weeks carcinoma, Zymbal gland carcinoma (1989)
(no statistical analysis)
Benzene 65
Table 10.3: Continued
Strain I/O Protocol Principal findings Reference
Rat
F344 O NTP (1986)
0, 50, 100, 200 mg/kg/day in Oral cavity tumours, skin tumours,
males and 0, 25, 50, 100 Zymbal gland carcinoma
mg/kg/day in females for 5
days/week, 103 weeks
No increase in tumour incidence
I Snyder et al.
0, 100 ppm for 6 h/day, 5
Sprague-
(1984)
days/week for life (123
Dawley
weeks)
I No increase in tumour incidence
0, 300 ppm for 6 h/day, 5 Snyder et al.
(1978)
days/week for life (99
weeks)
I 0, 200-300 ppm for 4-7 Oral cavity carcinoma, Zymbal Maltoni et al.
h/day, 5 days/week, 104 gland carcinoma (no statistical (1989)
week analysis)
O 0, 50, 250 mg/kg/day, 5 Mammary gland tumours (lowest Maltoni et al.
days/week, 52 weeks dose level only), Zymbal gland (1989)
carcinoma in females (no statistical
analysis)
O 0, 500 mg/kg/day, 5 days/ Forestomach carcinomas, liver Maltoni et al.
week, 104 weeks angiosarcomas, nasal and oral (1989)
cavity carcinomas, skin carcinomas,
Zymbal gland carcinoma (no
statistical analysis)
Wistar O 0, 500 mg/kg/day, 5 Nasal and oral cavity carcinoma, Maltoni et al.
days/week, 104 weeks Zymbal gland carcinoma (no (1989)
statistical analysis)
* Positive findings were statistically significant (p <0.05) unless otherwise indicated.
Carries a virus causing spontaneous lymphoma in 90% of animals by 52 weeks of age.
Carries a virus yielding a high incidence of lymphoma from exposure to radiation, immunosuppression
and certain carcinogens.
?br>
Highly susceptible to radiation-induced thymic lymphoma.
There was a frequent association between benzene exposure and the occurrence of
solid tumours in epithelia of the mouth, nasal cavities, lung alveoli, Harderian,
Zymbal, preputial and mammary glands, and the ovary.
With regard to the blood and lymphatic system, the incidence of lymphoma was
elevated in several studies conducted in B6C3F1, C57BL, CBA and RF/J mice.
There was also a statistically significant increase in the incidence of lesions
resembling acute myeloblastic and chronic granulocytic leukaemia in a study in
CBA mice exposed to 300 ppm benzene for 16 weeks (Cronkite et al, 1989). In
addition, 3/40 CD-1 mice exposed to 300 ppm and 1/40 Sprague-Dawley rats
exposed to 100 ppm benzene developed suspected myeloid leukaemia after 27-38
weeks of exposure (Goldstein et al, 1982; Snyder et al, 1984). However, the
increase in lymphoma incidence was limited to strains where this is a common
spontaneous tumour type and the lesions resembling leukaemia may not have been
malignant but rather an intense proliferation of myeloid cells caused by infections
or necrotic processes in benzene-induced tumours in other organs (Farris et al,
1993). Furthermore, early findings of lymphoma or leukaemia-like lesions in a
given strain have not been consistently reproduced in later studies (Farris et al,
1993; Snyder et al, 1988).
Some of the target organs in rodents such as the forestomach, Harderian, Zymbal
and preputial glands have no anatomical equivalent in humans. Moreover, human
exposure to benzene is not associated with tumours of the mouth, nasal cavities or
lung alveoli (see Section 11). However, as there is limited evidence of an elevated
risk of malignant melanoma and breast cancer in humans exposed to benzene-
containing products, skin and mammary tumours are further analysed below.
Priority Existing Chemical Number 21
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Skin tumours
The incidence of skin tumours was increased in F344 and Sprague-Dawley rats in
2-year oral gavage studies (NTP, 1986; Maltoni et al, 1989). By contrast, no skin
tumours developed in groups of 10 mice after oral, subcutaneous or topical
application of 800 mg/kg benzene followed 4 weeks later by topical application of
the tumour promoter 12-o-tetradecanoylphorbol-13-acetate 3 times a week for 20
weeks (Bull et al, 1986). Furthermore, although benzene was once widely used as a
solvent in tests for skin cancer induction in mice resulting in large numbers of
controls being topically exposed to benzene alone, there has been no indication that
it induced skin tumours in these models (IARC, 1982a).
In F344 rats, skin tumours were found on the face, back, flank, and other locations.
Microscopically, they represented a spectrum from pure squamous cell papillomas
or carcinomas to mixed tumours containing basal cell, sebaceous gland or hair
follicle elements. By incidental tumour tests, the incidence was elevated in male
rats at 200 mg/kg/day (12/50 vs. 1/50 in controls; p <0.01), but not at 50 mg/kg/day
(7/50) or 100 mg/kg/day (5/50), or in female rats treated with 25, 50 or 100
mg/kg/day. Based on mortality and BW data, high dose male rats were probably
exposed to benzene levels that exceeded the maximal tolerated dose (NTP, 1986).
In Sprague-Dawley rats, skin carcinomas (not further specified) occurred in 9/40
male animals administered 500 mg/kg/day by oral gavage for 2 years. The
incidence was zero in male controls and treated females (Maltoni et al, 1989). The
authors did not comment on the statistical significance of these results, however,
when analysed for this assessment, the difference in incidence between exposed
and control males was statistically significant (p <0.05; test for exact confidence
limits). Compared to their controls, male rats had an increased survival rate but a
reduction in BW that ranged from 6-18% during the course of the study (Maltoni et
al, 1983).
Mammary gland tumours
Mammary tumours have been found in B6C3F1, CBA, RFJ and Swiss mice and
Sprague-Dawley rats (Cronkite, 1986; NTP, 1986; Maltoni et al, 1989).
In a 2-year oral bioassay in B6C3F1 mice, benzene induced a significantly elevated
incidence of carcinomas and carcinosarcomas in mid- and high-dose females, with
a trend for dose-dependence (Table 10.4). The carcinomas often showed extensive
squamous cell metaplasia, whereas the carcinosarcomas contained a prominent
spindle-cell component resembling malignant fibroblasts. The historical incidence
of mammary gland carcinoma in this strain is approximately 1% (NTP, 1986).
Table 10.4: Mammary gland lesions in female B6C3F1 mice in a 2-year oral
carcinogenicity study (NTP, 1986)
Lesions Controls 25 mg/kg/day 50 mg/kg/day 100 mg/kg/day
Hyperplasia 2/49 (4%) 4/45 (9%) 2/50 (4%) 1/49 (2%)
Carcinoma 0/49 (0%) 2/45 (4%) 5/50 (10%)* 10/49 (20%)
Carcinosarcoma 0/49 (0%) 0/45 (0%) 1/50 (2%) 4/49 (8%)*
* p <0.05 (incidental tumour tests).
p <0.01 (incidental tumour tests).
Among male and female CBA mice exposed to 100 ppm benzene for 6 h/day, 5
days/week for 16 weeks, 20% had developed mammary gland tumours at follow-up
Benzene 67
102 weeks after the last exposure (Cronkite, 1986). Details on tumour incidence in
concurrent or historical controls were not given and the histopathology of the
tumours was not described, although a later publication refers to them as
adenocarcinomas (Cronkite et al, 1989).
In female RF/J mice administered 500 mg/kg/day by oral gavage for 52 weeks, the
incidence of mammary carcinomas was 22.5%, compared to 2.5% in controls. In
female Swiss mice receiving the same treatment for 78 weeks, the incidence was
47.5% compared to 5.0% in controls (Maltoni et al, 1989). The statistical
significance of these findings is not discussed in the paper. When analysed for this
assessment, the incidence in exposed females was significantly different from
controls (p <0.05; test for exact confidence limits) in Swiss but not in RF/J mice.
In female Sprague-Dawley rats given benzene by oral gavage for 1 year, the
incidence of total/malignant mammary tumours was 53.3/13.3% in controls,
73.3/13.3% in animals treated with 50 mg/kg/day, and 45.7/20.0% in animals
treated with 250 mg/kg/day. In female rats given 500 mg/kg/day for 2 years, the
incidence was 32.5/17.5% compared to 42.0/14.0% in controls (Maltoni et al,
1989). The tumours comprised fibroadenomas, adenocarcinomas and carcino-
sarcomas similar to the spontaneous mammary gland tumours commonly found in
ageing female Sprague-Dawley rats (Maltoni et al, 1983). The investigators did not
report on the statistical significance of their findings. When analysed for this
assessment, there was no difference between any of the groups in the incidence of
either total or malignant mammary tumours (p>0.05; test for exact confidence
limits).
Conclusions
The available carcinogenicity studies provide clear evidence of a causal
relationship between benzene exposure and malignant neoplasms in mice and rats.
The tissues most commonly involved are various glandular or non-glandular
epithelia of the oral cavity, nasal cavity, lungs and skin (Table 10.3). The incidence
of lymphoma was increased in several studies, but only in mice where this is a
common spontaneously occurring tumour type. In one study in mice, there was a
significant increase in bone marrow lesions described as resembling myeloblastic
or granulocytic leukaemia (Cronkite et al, 1989), but this may have been the result
of an intense inflammatory response (Farris et al, 1993). As such, a proven
reproducible animal model for benzene-induced leukaemia is not available.
The lowest exposure levels associated with an increase in tumour incidence in
rodents was 100 ppm by inhalation for 16 weeks in CBA mice and 25 mg/kg/day in
a 2-year oral gavage test in B6C3F1 mice and F344 rats (Cronkite, 1989; NTP,
1986). However, there was no increase in tumour incidence in two out of three
inhalation tests in rats exposed to 100-300 ppm benzene for 99-123 weeks (Maltoni
et al, 1989; Snyder et al, 1978, 1984).
There was an increased incidence of epithelial skin tumours in male rats in two 2-
year oral bioassays. In both studies, however, the increase only occurred at the
highest dose level tested (200 and 500 mg/kg/day respectively), which may have
exceeded the maximum tolerated dose. Mammary gland carcinomas were increased
in female mice at 50 and 100 mg/kg/day in a 2-year and at 500 mg/kg/day in a 78-
week test.
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10.8 Summary and conclusions
Taken together, the tests summarised above clearly demonstrate that benzene is not
highly acutely toxic to experimental animals, whereas it is a potent, multi-organ
toxicant by repeated administration. The target organs include the CNS, skin, eyes,
immune system, blood and blood forming organs, gonads and developing foetus.
Benzene is also toxic to genetic material and induces a variety of solid tumours,
including mammary cancer in female mice.
The only consistently reported acute systemic effects are CNS depression and
cardio-respiratory arrest. In rats, the median lethal dose is 810-9900 mg/kg by
mouth and 13,700 ppm by 4-h inhalation.
Topically, benzene appears to be irritating to the skin and eyes.
Of the available repeated dose oral studies, only the US National Toxicology
Program's 2-year bioassays in mice and rats have been conducted and reported in
full compliance with GLP and other internationally recognised quality standards
(NTP, 1986). In these studies, benzene administered by oral gavage induced
leukopoenia and lymphocytopoenia and an increase in the incidence of malignant
tumours at the lowest dose level tested, namely 25 mg/kg/day in male and female
mice and female rats and 50 mg/kg/day in male rats. In other oral studies of a lesser
quality, benzene produced leukopoenia in mice and rats and signs of
immunosuppression in mice at dose levels from 8-12 mg/kg/day.
With regard to repeated exposure by inhalation, which is the predominant route in
humans, the studies available for assessment were either poorly reported or
inadequate for the determination of dose-response relationships for other reasons,
such as an insufficient number of animals or range of exposure levels. Nonetheless,
the weight of evidence indicates that the following approximate effect levels are
likely to apply:
In mice but not in rats, subtle signs of neurobehavioural stimulation may be
?br>
detectable at vapour concentrations around 1 ppm, whereas gross CNS
impairment only occurs at and above 1000 ppm. ;
There are functional disturbances of the immune system at and above 10 ppm
?br>
in mice, but no such effects in rats below 400 ppm. The NOAELs were
determined to be 0.44 and 200 ppm for mice and rats respectively;
Abnormal blood counts and morphological abnormalities in blood forming
?br>
organs are found at and above 10 ppm in mice (including mouse foetuses
exposed in utero) and at and above 100 ppm in rats. As effects were observed
at all concentrations tested, a NOAEL could not be determined;
There are degenerative changes in the gonads at 300 ppm in mice, but not in
?br>
rats. The NOAEL was determined to be 30 ppm for mice ;
Benzene is foetotoxic, but not teratogenic in rats and mice exposed during
?br>
pregnancy at levels in the 100-500 ppm range, with an inhalation NOAEL for
foetotoxicity of 40 ppm in rats; and
The incidence of solid tumours is increased in mice exposed to 100-300 ppm
?br>
benzene for 16 weeks, but not consistently in mice exposed to 1200 ppm for 10
weeks or in rats exposed to 100-300 ppm for 99-123 weeks.
The relevance of these findings for human risk characterisation will be examined in
Section 13, in the context of the interspecies variations in benzene metabolism
Benzene 69
addressed in Section 9, the human health effects reviewed in Section 11, and the
molecular mechanisms of action discussed in Section 12.
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11. Human Health Effects
The literature on human health effects of benzene is extensive and contains data on
hundreds of thousands of people. This section summarises and reviews studies that
are relevant to the characterisation of the toxic effects of benzene and the
corresponding effect levels. Because of the nature of the available studies, the
review is predominantly based on findings in people who were exposed to benzene
at work or held jobs with the potential for exposure to the chemical.
The findings reported below must be interpreted with caution, as they rely on
inherently uncertain information about the exposure of individuals or populations
to benzene, which was either inferred or, at best, estimated from limited monitoring
data. Furthermore, in the vast majority of cases there was co-exposure to other
chemicals. These may be hazardous in their own right or inhibit the metabolism of
benzene to toxic metabolites, thus resulting in either an over- or underestimation of
the toxic potential of benzene. For example, the aromatic organic solvent toluene
may interfere with the metabolism of benzene as well as cause brain atrophy and
developmental toxicity (IPCS, 1985; Wilkins-Haug, 1997); some of the polycyclic
aromatic hydrocarbons (PAHs) that occur in petroleum, coal gas, coal tar and
vehicle exhaust are genotoxic and cause anaemia, immunosuppression and non-
melanoma skin cancer (IPCS, 1998); and 1,3-butadiene found in vehicle exhaust is
genotoxic and may increase the risk of blood and lymphatic cancers (IARC, 1999).
Moreover, many studies are not controlled for confounding by smoking, although
tobacco smoke contains benzene (see Section 16.1) and several studies have found
an association between active smoking and leukaemia and reproductive effects
such as semen quality and pregnancy outcome (Brownson et al, 1993; Vine, 1996;
Werler, 1997).
Unless otherwise mentioned, all results were statistically significant in comparison
with unexposed controls (p <0.05). In occupational studies, chronic inhalation
exposures refer to 8-h TWA (TWA8) concentrations. Technical terms used to
describe epidemiological study designs and statistics have the meaning given in
Last (1995).
11.1 Acute toxicity
Cases of acute intoxication have occurred because of workplace accidents and in
persons sniffing benzene-containing products for recreational purposes (Avis &
Huton, 1993; Barbera et al, 1998; Tauber, 1970; Winek & Collum, 1971). The
approximate lethal dose is 20,000 ppm by inhalation for 5-10 min, or 125 mg/kg by
ingestion, whereas exposure to 25 ppm for 8 h is reported to be without clinical
effects (Gerarde, 1960; Thienes & Haley, 1972, as cited in IPCS, 1993). No
adverse effects were reported in three kinetic studies in healthy volunteers exposed
to benzene levels of 26-42 ppm for 6 h, 52-62 ppm for 4 h or 47-110 ppm for 2-3 h
(Berlin et al, 1980; Nomiyama & Nomiyama, 1974a; Srbova et al, 1950). Clinical
signs at higher exposure levels include generalised symptoms such as dizziness,
headache and vertigo at levels of 250-3000 ppm, leading to drowsiness, tremor,
delirium and loss of consciousness at 700-3000 ppm (ATSDR, 1997; USEPA,
1998c). Unless fatal, the CNS symptoms are reversible following cessation of
exposure. Autopsy findings are typical of cardio-respiratory arrest.
Benzene 71
11.2 Irritation
Aspiration of liquid benzene has been observed to cause immediate pulmonary
oedema and bleeding at the site of contact (Gerarde, 1960). Benzene vapours have
been reported to cause eye and mucous membrane irritation in workers exposed at
33-59 ppm and irritation of the skin, nose, mouth and throat at levels 60 ppm
(Midzenski et al, 1992; Yin et al, 1987a). Acute tracheitis, laryngitis, bronchitis and
massive haemorrhage of the lungs were observed in a youth who died from an
overdose of intentionally inhaled benzene (Winek & Collum, 1971). Second degree
burns to the face, trunk and limbs were reported in chemical cargo ship crew
accidentally exposed to fumes at a concentration resulting in death within minutes
(Avis & Hutton, 1993).
11.3 Sensitisation
There are no reports of skin or respiratory sensitisation to benzene in humans.
11.4 Repeated dose toxicity (other than carcinogenicity)
11.4.1 Neurological effects
Yin et al. (1987a) found a dose-dependent increase in the prevalence of dizziness
and headache in a survey of female Chinese workers in the footwear and printing
industries. This study included 87 unexposed controls and two groups exposed to
benzene at levels ranging from 1-40 ppm (40 cases) or 41-210 ppm (47 cases). In
the two groups combined, benzene levels averaged 59 ppm. Both groups were co-
exposed to low levels of toluene (16 ppm).
Peripheral neuropathy was reported in a small number of Turkish workers with
benzene-induced aplastic anaemia or preleukaemia (Baslo & Aksoy, 1982). At a
benzene-manufacturing petrochemical plant in Estonia, frequent headaches at the
end of the shift, tiredness, sleep disturbances and memory loss occurred in 61% of
workers exposed to levels in the 2-16 ppm range for several years (Kahn &
Muzyka, 1973). In a survey of deck crew on nine Norwegian petroleum product
tankers, headache, dizziness or nausea were reported by 5/11 workers exposed to
>0.3 ppm benzene whereas there were no CNS complaints in 10 workers exposed
to 0.3 ppm (Moen et al, 1995). Psychological examinations in 28 men exposed to
a mixture of benzene (0.56-1.8 ppm), toluene (2.1-9.8 ppm) and xylenes (0.43-12
ppm) indicated diminished function of some cortical centres and impaired motor
reaction time (Sikora & Langauer-Lewowicka, 1998). Varelas et al. (1999) used
computed tomography imaging to visualise abnormal calcifications and cortical
atrophy in the brains of 122 petrol station workers, taxi and bus drivers in central
Athens. The subjects had been in their present employment for a minimum of 3 and
an average of 16-17 years. Whereas blood lead levels were unremarkable in all
three groups, there was mild to moderate cortical atrophy in 19/37 petrol station
workers, 14/44 taxi drivers and 14/41 bus drivers. The prevalence in petrol station
workers was higher than in taxi and bus drivers and unrelated to smoking or
alcohol habits. None of these studies included an unexposed control group.
11.4.2 Effects on the immune system
There was a decrease in circulating IgA and IgG immunoglobulins, accompanied
by an increase in IgM and an elevated occurrence of leukocyte auto-antibodies, in
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72
painters co-exposed to benzene, toluene and xylenes at air levels ranging from 3-
57, 21-71 and 27-680 ppm respectively (Lange et al, 1973a, 1973b). In workers co-
exposed to benzene, toluene and xylenes at air levels that averaged from 1-35, 2-32
and 4-28 ppm respectively over an 11-year period, total LC and T-LC counts were
slightly lower in workers exposed for 55-122 months than in an unexposed control
group, whereas there were no differences in LC function as determined by LC
transformation and tuberculin tests (Moszczynsky & Lisiewicz, 1984).
11.4.3 Cardiovascular effects
Kotseva & Popov (1998) conducted a routine cardiological examination of a
sample of male and female petrochemical workers aged 20-60 years. It included
118 workers concomitantly exposed to 20 ppm benzene and low levels of toluene
and petrol as well as 154 workers concomitantly exposed to <3 ppm benzene, 32
ppm xylenes and low levels of toluene and petrol. Compared to unexposed controls
matched for age, sex, salt intake, smoking and body mass index, the prevalence of
arterial hypertension and minor electrocardiographic abnormalities was
approximately twice as high in the exposed groups.
11.4.4 Haematological effects
Benzene has been known to be toxic to the blood for more than a hundred years
and in the past was sometimes given orally to leukaemia patients to reduce WBC
count (ATSDR, 1997; Landrigan, 1996).
Occupational exposure
Table 11.1 summarises a number of surveys of non-cancerous blood disorders in
workers exposed to airborne benzene. Overall, these studies point to a strong
association between recent or current exposure to airborne benzene and the
occurrence of decreased ALC, WBC, RBC and Plt counts, Hb and haematocrit
(Hct), and an increase in MCV. Such cases are sometimes described as `benzene
poisoning' (BP). Depending on the pattern and magnitude of these changes and the
histological findings in a bone marrow biopsy, they may be clinically diagnosed as
lymphocytopoenia, leukopoenia, anaemia, thrombocytopoenia, pancytopoenia,
agranulocytosis, myelofibrosis, or aplastic anaemia. They may be accompanied by
clinical signs such as paleness, increased susceptibility to infections, and a
tendency to bruising and bleeding. BP is generally reversible upon cessation of
exposure, except aplastic anaemia which may be fatal or progress to acute myeloid
leukaemia (AML) (Aksoy, 1989).
Among the studies summarised in Table 11.1, three surveys comprising a total of
795 workers found no adverse haematological effects from long-term benzene
exposure at levels averaging 0.55, 0.81 and 0.53 ppm respectively (Collins et al,
1997; Khuder et al, 1999; Tsai et al, 1983). These studies have limitations with
respect to blood analysis methodology, exposure assessment and/or control for
confounders such as smoking and co-exposure to other chemicals. Nevertheless,
taken together they indicate that the NOAEL for bone marrow toxicity is likely to
be >0.5 ppm.
Benzene 73
Table 11.1: Summary of haematological effects in workers exposed to airborne benzene
Industry Condition(s) observed Comments Reference
Country Benzene exposure (TWA8)*
Chemical USA Range = 0.01-1.40 ppm for an Collins et al.
In 200 exposed compared to 268 non-exposed workers there was no
average of 7.3 years (1991)
consistent benzene-related effect on haematology surveillance
indicators
USA Mean (range) = 0.55 (0.01-88) ppm, Collins et al.
In 387 exposed compared to 553 non-exposed workers there was no
(1997)
with <5% of workers exposed to difference in the prevalence of decreased ALC, RBC, WBC or Plt
levels >2 ppm counts, decreased Hb levels, or increased MCV values
USA Fishbeck et al.
Mean >24 ppm for an average 10/10 workers had increased MCV values and 9/10 also had
(1978)
of 9.6 years decreased Hb levels
USA 2/282 exposed workers died from Townsend et al.
From <2 to about 30 ppm for 1-20 Marginally lower RBC count and total bilirubin in 282 exposed
(1978)
leukaemia during the study
years workers compared to an equal number of matched controls
period (1967-74)
Coke oven USA Hancock et al.
0.1-31.4 ppm No differences in WBC, RBC or Hb values between groups of 17-37
by-products (1984)
workers with no, low (<2 ppm-years), intermediate (2-20 ppm-years)
or high (>20 ppm-years) exposure
Footwear Turkey Aksoy et al.
Exposed to adhesives. No
15-210 ppm for 3 months Increased incidence of reduced WBC and/or Plt or CBC counts in
manufacturing (1971)
correlation with duration of
217 workers compared to 100 controls matched for sex, age and
to 17 years
74
exposure
general living conditions
Croatia Bogadi-Sare et
Benzene contaminated glues,
Median (range) = 5.9 (1.9-14.8) ppm Decreased mean Hb concentration and percentage of B-LC and
al. (1997, 2000)
cleaners and paints; co-exposed
increased MCV and band neutrophils in 49 exposed females
(area monitoring)
to 11-50 ppm toluene
compared to 27 unexposed controls
Miscellaneous Italy Vai et al. (1989)
There was a highly significant
>20 ppm Of 301 workers referred to an occupational health clinic with
uses of benzene- correlation between severity of
suspected benzene intoxication, 153 had transient and 39
based solvents bone marrow disease and current
progressive bone marrow abnormalities; 11 died from aplastic
or recent exposure
anaemia and 21 developed cancers of the blood and lymphatic
system
China Rothman et al.
No correlation between any
Median (range) current personal In 44 exposed workers compared to an equal number of controls
(1996a, 1996b)
exposure = 31 (1.6-328.5) ppm, matched for sex, age, cigarette and alcohol consumption, WBC, ALC, haematological parameter and
with an average duration of Plt, RBC and Htc levels were reduced and MCV values increased. In cumulative exposure
exposure of 6.3 years 11 workers exposed to a median (range) level
of 7.6 (1-20) ppm, only ALC was decreased
China Xia et al. (1995)
Mean (range) = 5.8 (0.7-139) ppm 26% of 326 exposed workers had leukopoenia (WBC count <4.5 x
(assessment method not specified) 109/L) compared to 8.9% of 236 non-exposed workers
Priority Existing Chemical Number 21
China Yin et al. (1987a)
Co-exposed to 6-7 ppm toluene
Mean (maximum) = 59.2 (210) in Decrease in ALC in 83 exposed women compared to 85
women and 47.9 (210) ppm in unexposed controls, but no differences between 61
men, for an average of 5 years exposed men and 44 unexposed controls
Table 11.1: Continued
Condition(s) observed Comments Reference
Industry Country Benzene exposure (TWA8)
Canada Khuder et al. (1999)
Petroleum Mean (range) = 0.81 (0.14-2.08) ppm In 105 exposed workers, levels of WBC, RBC, Hb, MCV and Plt were
Benzene
for an average of 10 years
refining generally in the low normal range. MCV and Plt values were
negatively correlated with duration of employment, but not with
individual benzene exposure
USA Median = 0.53 ppm Tsai et al. (1983)
All haematological parameters generally within normal limits in 303
workers followed from 1959-1980
UK Yardley-Jones et al.
In 66 exposed compared to 33 non-exposed workers, All absolute MCV values were
10 ppm
(1988)
within the normal clinical range
there was no difference in various unspecified
haematology and serum biochemistry values, except
for a small increase in MCV values in exposed workers
USA 11-1060 ppm for 3-5 years Greenburg et al.
Printing 130/332 exposed workers showed signs of intoxication, including No cases of relapse after
(1939)
anaemia, increased MCV, reduced Plt counts and/or reduced benzene use was discontinued
WBC counts
USA Median exposure estimated at Cody et al. (1993)
Rubber In 161 workers hired between 1946-49, there was a 10% decline Pliofilm cohort
30-54 ppm
manufacturing in WBC counts over the first 4 months of employment, but no (Section 11.6.1)
consistent changes in RBC levels
75
USA Mean estimated at 75 ppm during Kipen et al. (1988,
In a longitudinal study of 459 workers, WBC, RBC and Hb levels Pliofilm cohort
1940-48 and at 15-20 ppm during 1989)
decreased with total exposure between 1940-48, but showed no (Section 11.6.1)
1949-78 persistent trends over the ensuing 25 years
Range estimated at <5-34 ppm
USA Ward et al. (1996)
Haematological screening data for 657 workers exposed between Pliofilm cohort
1939 to 1975 showed a relationship (Section 11.6.1)
between benzene exposure and the risk of a low WBC or RBC
count which was stronger for WBC, with no evidence
for a threshold exposure level
USA Mean and range estimated at 100 Wilson (1942)
Following complaints of malaise, nausea, vomiting, and bleeding, Outbreak coincided with large
and 50-500 ppm respectively blood counts were done on 1104 workers. ALC was abnormally war orders for synthetic rubber
low in 83 of them and 25 had severely reduced WBC, RBC and Plt
counts. Of these, 9 were hospitalised, where aplastic anaemia
was diagnosed by bone marrow biopsy; 3 died.
USA 60-600 ppm Midzenski et al.
Ship repair No relationship between blood
9/15 workers exposed over several days from the
(1992)
changes and duration of
degassing of shipboard tanks developed abnormal WBC, ALC,
exposure
Hb, Plt and/or MCV values within 4 months. At 12 months, 7/15
still had one or more abnormal values.
Turkey 0-110 ppm (area monitoring) Aksoy et al. (1987)
Used thinners and solvents
Tyre cord Decreased WBC count in 9, decreased Plt count in 4 and
containing up to 6-8% benzene
manufacturing decreased WBC, RBC and Plt count in 1 of 231 exposed workers
* TWA8 = 8-h time-weighted average.
CBC = complete blood cell count; for other abbreviations, see text.
In 44 Chinese workers exposed to a median benzene concentration of 31 ppm, with
a range from 1.6-328.5 ppm, Rothman et al. (1996a, 1996b) found a decrease in
WBC, RBC and Htc, an increase in MCV and an inverse correlation between ALC
and benzene exposure. In a subgroup of these workers with a median exposure
level of 7.6 ppm (range: 1-20 ppm), the lowest exposure group examined, the only
haematological finding was a 16% decrease in ALC (1.6 x 109/L compared to 1.9 x
109/L in controls; p = 0.03). This study is small, but had a well-matched control
group, minimal exposure to other chemicals (toluene and xylenes) and a dose-
response relationship was established between ALC and benzene exposure as
measured by repeated personal monitoring as well as with benzene metabolites in
the urine.
Three other studies reported haematological effects in workers whose exposure was
stated to range from 1.9-14.8 (median: 5.9), <5-34 and 0.7-139 (mean: 5.8) ppm
respectively (Bogardi-are et al, 1997; Ward et al, 1996; Xia et al, 1995). However,
these studies assessed exposure by means of area monitoring, a job-exposure
matrix or unspecified methods and are therefore less suitable for dose-response
characterisation.
Repeated exposure at higher levels was usually associated with clear signs of BP in
some workers, with little or no relationship with cumulative exposure (Aksoy et al,
1971; Midzenski et al, 1992; Rothman et al, 1996a, 1996b; Vai et al, 1989).
Dosemeci et al. (1997) evaluated the statistical relationship between a clinical
diagnosis of BP and benzene exposure in a subgroup of 412 cases drawn from a
large Chinese cohort study (Hayes et al, 1997), which is described in detail in
Section 11.6.1. The cumulative incidence of BP (defined as (1) a WBC count <4 x
109/L or a WBC count <4.5 x 109/L and a Plt count <80 x 109/L over several
months, (2) occupational benzene exposure for 6 months and (3) exclusion of
other causes of abnormal blood counts) rose sharply with increasing estimated
intensity of benzene exposure over a period of 18 months prior to diagnosis, as
shown by the following relative risks (RRs):
Exposure <5 ppm 5-19 ppm 20-39 ppm 40 ppm
RR (95% CI)6 1.0 (reference level) 2.2 (1.7-2.9) 4.7 (3.4-6.5) 7.2 (5.3-9.8)
The clear trend with the level of exposure is noteworthy, even if the absolute
exposure levels may have been underestimated, as discussed in Section 11.6.1
below.
The risk of BP developing into cancer was assessed in a subgroup of 11,177
benzene-exposed workers from the same Chinese cohort, 103 of whom had BP as
defined above (Rothman et al, 1997). At follow-up 4-14 years after diagnosis, three
of the cases had developed acute non-lymphocytic leukaemia (ANLL), non-
Hodgkin's lymphoma (NHL) and myelodysplastic syndrome (MDS) respectively,
compared to 6 cases of cancer of the blood and lymphatic system (including 2 with
ANLL) and 1 case of MDS among the 11,074 workers without a diagnosis of BP
(Table 11.2)7. The corresponding RRs indicate that a diagnosis of BP is associated
6
Throughout this section, ranges in brackets immediately following a relative risk (RR), odds ratio
(OR), standardised mortality rate (SMR) or standardised incidence rate (SIR) represent the 95%
confidence interval (CI) of the statistic.
7
ANLL comprises all acute leukaemias other than acute lymphocytic leukaemia and can usually be
equated to AML. MDS is a term that encompasses a variety of preleukaemic disorders.
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76
with a 42-fold increase in the risk of pre-cancer or cancer of the blood and
lymphatic system and with a 71-fold increase in the risk for ANLL/MDS. The RRs
changed little upon adjustment for cumulative exposure, indicating that the elevated
cancer risk was not due to a higher cumulative exposure in the 103 BP cases.
Table 11.2: Benzene poisoning and subsequent risk of blood and lymphatic
system cancer and related disorders (Rothman et al, 1997)
Without
benzene With benzene
Parameter* poisoning poisoning
Person-years of follow-up 122,620 848
RR (95% CI) of all pre-cancer or cancer of the blood and
lymphatic system 1.0 42.3 (10.7-167.0)
RR (95% CI) of ANLL/MDS 1.0 70.6 (11.4-439.3)
RR (95% CI) of all pre-cancer or cancer of the blood and
lymphatic system, adjusted for cumulative benzene 1.0 47.4 (11.7-191.9)
exposure
RR (95% CI) of ANLL/MDS, adjusted for cumulative
benzene exposure 1.0 61.3 (9.8-384.3)
* ANLL = acute non-lymphocytic leukaemia; CI = confidence interval; MDS = myelodysplastic syndrome;
RR = relative risk.
Similarly, Vai et al. (1989) reported 28 cases of fatal blood cancer among 304
workers in Northern Italy who were hospitalised 15-35 years earlier with suspected
BP, representing a 13.3-fold increase over the incidence in the general population
in the region.
Public exposure
In the 1980s, the US Federal Department of Health and Human Services created a
National Exposure Registry to assess the health consequences to the general
population from long-term, low-level exposure to specific substances in the
environment. A Benzene Subregistry was established in 1991 based on a
population health survey in a community in Texas, USA, where tap water from the
public water system was known to have contained 66 礸/L benzene since 1
January 1979 (Burg & Gist, 1998). The survey included 1,143 persons who had
used contaminated water as the sole source of drinking, bathing and cooking for at
least 30 consecutive days. These persons were administered a questionnaire and
follow-up telephone interviews were conducted one and two years later. The
questions asked were similar to those used in the National Health Interview Survey
(NHIS) conducted every year in USA, except that the benzene questionnaire
contained a qualifier relating to professional rather than self diagnosis of ailments,
so as to minimise reporting bias. Findings were compared with concurrent NHIS
data subsets matched for demographic variables and current and ever smoking
rates. The initial response rate was 97%. There was a loss of 9% for each follow-up
from the previous data collection.
The outcome of anaemia and related blood disorders within the last 12 months was
reported in excess at all three data collections, with 40 observed vs. 14.1 expected
cases at baseline, 32 observed vs. 11.6 expected cases at one year (p <0.01), and 28
observed vs. 11.9 expected cases at two years. There was no difference in the
reporting of cancer.
Benzene 77
Conclusions
Several occupational surveys show that chronic exposure to benzene may lead to
bone marrow depression, with manifestations that range from small reductions in
blood count parameters to aplastic anaemia. The available data indicate that both
the incidence and severity of this effect is dose-related. In a small, but reliable
study, the only haematological effect in workers with a median (range) exposure of
7.6 (1-20) ppm (TWA8) was a modest reduction in ALC. As this was the lowest
exposure group examined, 7.6 ppm (TWA8) is currently considered the best
estimate for a LOAEL which may be close to the point of departure for the onset of
haematological effects (USEPA, 1998c). An appropriate NOAEL has not been
determined, but studies with various limitations indicate that it is likely to be >0.5
ppm (TWA8).
The only available epidemiological study in the general population found an excess
occurrence of anaemia and related disorders in a community whose tap water
contained 66 礸/L benzene.
There is some evidence that bone marrow depression is associated with a
substantially increased risk for ANLL/MDS.
11.4.5 Reproductive effects
Effects on fertility
Vara & Kinnunen (1946) reported a variety of gynaecological disorders in 12
female rubber workers who were exposed to unspecified levels of benzene on a
daily basis. All 12 women had menstruation disorders, with sparse bleeding being
the most common complaint. Although most of the women practised regular
unprotected intercourse, only two of them had conceived since they started working
and both pregnancies ended in spontaneous abortions (SAb) by the first trimester.
Five had ovarian hypoplasia. Other common findings included excessive bruising,
tiredness, dizziness, headaches and abnormal haematological findings, particularly
low WBC and Plt counts.
Menstruation abnormalities have also been reported in surveys of female workers
exposed to mixed aromatic hydrocarbons including benzene or to benzene,
petroleum and chlorinated hydrocarbons in Poland and Russia in the 1960s
(Michon, 1965; Mukhametova & Vozovaya, 1972; both as cited in ATSDR, 1997)
and in female workers at a large petrochemical company in China (Thurston et al,
2000). Huang (1991) reported menstruation disorders in 49% of 223 Chinese
leather footwear workers co-exposed to an average of 29 (range: 1-132) ppm
benzene and 19 (range: 1-136) ppm toluene compared to a prevalence of 16% in
unexposed controls (p <0.01). There is no information on the smoking habits of the
study population.
Benzene exposure as a risk factor for fecundability (time to pregnancy) was
assessed in a Norwegian case-control study in 558 female dental surgeons and 450
high school teachers with at least one child (Dahl et al, 1999). Forty percent of the
dentists reported daily exposure to a now discontinued disinfectant containing
0.25% v/v benzene. There was no difference in fecundability between dental
Priority Existing Chemical Number 21
78
surgeons exposed to benzene and the controls. Potential confounders were
considered, but the level of benzene exposure resulting from the disinfectant was
not assessed.
In males, De Celis et al. (2000) studied the sexual functioning and semen profile of
48 Mexican rubbers workers exposed to a mixture of benzene (10-15 ppm), ethyl
benzene (~50 ppm), toluene (~50 ppm) and xylenes (~12 ppm) for 2 years. Mean
sperm count and the mean percentage of motile and normal sperm forms were
reduced by 78, 62 and 24% respectively, compared to a group of 42 age-matched
controls. There was no correlation between smoking or alcohol intake and
alterations in the semen profile. Longer abstinence intervals may have contributed
to the reduced sperm concentration and motility in exposed workers as they also
had an increased prevalence of reduced libido.
Effects on pregnancy outcome
Huang (1991) investigated pregnancy outcome in 106 Chinese leather footwear
workers co-exposed to an average of 29 ppm (range: 1-132) ppm benzene and 19
(range: 1-136) ppm toluene and 209 unexposed controls. Exposure to benzene and
toluene was associated with an elevated incidence of SAb (5.8 vs. 2.4%; RR = 2.4;
p <0.01), whereas there was no difference in the incidence of preterm delivery or
stillbirth. There is no information on the smoking habits of the study population.
Lindbohm et al. (1991) used Finnish census data, hospital records and industry-
wide air monitoring results collected in 1975-82 to study the outcome of 11,570
pregnancies with potential paternal exposure to hazardous chemicals compared
with a control group of 87,616 unexposed pregnancies. The RR for SAb was
elevated for paternal exposure to solvents used in petroleum refineries, but did not
differ significantly from unity when analysed separately for exposure to benzene.
Although not quantified, benzene exposure levels were estimated to be low.
In a case-control study of female workers in the Finnish pharmaceutical industry
which included 44 cases of SAb and 130 matched controls, Taskinen et al. (1986)
found a non-significant association between abortion risk and benzene exposure
(OR = 2.4 (0.5-12.0)).
The effects of parental occupational exposures on foetal development were
investigated in an exploratory case-control study based on probability samples of
live births and foetal deaths obtained by the US National Natality and Fetal
Mortality survey conducted in 1980 among married women (Savitz et al, 1989).
The samples included case groups of stillbirths (2096 mothers, 3170 fathers),
preterm deliveries at <37 weeks of pregnancy (363 mothers, 552 fathers) and
small-for-gestational age (SGA) infants (218 mothers, 371 fathers). Control
pregnancies were drawn from the same survey. Occupational exposures within the
last 12 months were defined by industry of employment and relative levels of
exposure to individual agents estimated on the basis of a job-exposure linkage
system. In computing the OR, adjustments were made for known confounding
factors for each pregnancy outcome, such as child's race, receipt of prenatal care,
mother's age, number of previous miscarriages, previous induced abortions and
maternal smoking and alcohol consumption.
Overall, this study found a significantly elevated SGA risk in the offspring of
fathers exposed to benzene at work (OR = 1.5 (1.1-2.3)), with a strong dose-
response gradient. Benzene-exposed fathers of SGA infants included a large
percentage of engine mechanics and repairers, welders and flame cutters. Maternal
Benzene 79
benzene exposure showed a marginally significant association with stillbirths (OR
= 1.3 (1.0-1.8)), which was supported by the demonstration of a dose-response
gradient. In these mothers, benzene exposure was attributed mainly to work in the
textile industry, barbering and cosmetology, with smaller contributions from the
chemical, pharmaceutical and paint industries.
St點ker et al. (1994) evaluated the risk of SAb before 28 weeks among the spouses
of 1077 male workers at two organic chemical factories in France, on the basis of
exposures estimated by plant occupational physicians and questionnaires
administered to the men and their wives. Medical records of the women were not
examined. There was a total of 1739 pregnancies, of which 171 (9.8%) ended in
SAb. The abortion rate was 8.8% in the wives of unexposed workers. Workers
were divided into low (<5 ppm) and high (5 ppm) exposure categories depending
on their estimated past exposure to benzene. After adjustment for maternal tobacco
consumption, age and pregnancy order, the risk of SAb did not differ from unity in
either of the two exposure groups. Similar results were obtained in analyses of first
pregnancies only, and when pregnancy outcome was examined against a more
detailed exposure graduation.
A Finnish case-control study of 206 cases of SAb in laboratory workers and 329
individually matched controls identified 11 cases of benzene exposure in the SAb
group compared to 25 among the controls and concluded that benzene exposure
was not a significant risk factor (Taskinen et al, 1994).
In a Chinese study, the overall risk of SAb in 3070 non-smoking, primiparous
women employed at a large petrochemical complex and married to male workers at
the same facility was 8.8% in chemical compared to 2.2% in non-chemical workers
(Xu et al, 1998a). Benzene, toluene, xylenes and styrene exposure levels in 38
breathing zone samples collected throughout the complex averaged 0.86, 0.40, 0.50
and 0.03 ppm respectively. In analyses for exposure to specific chemicals during
the first trimester of pregnancy, the estimated ORs of SAb were significantly
elevated for benzene (2.5 (1.7-3.7)) and petrol (1.8 (1.1-2.9)).
Chen et al. (2000) conducted a prospective study of pregnant workers at a Chinese
petrochemical plant producing benzene, toluene, xylenes, styrene and phenol.
Compared with 459 mothers not exposed to organic solvents, there was a small
reduction in birth weight (?8 g; 95% CI = ?15 to ? g) among 366 mothers
exposed to 0.02-0.2 ppm benzene with or without other exposures.
Conclusions
There are several reports of menstruation disturbances in female workers and one
of reduced semen quality in male workers exposed to benzene.
The available studies of pregnancy outcome have produced mixed results with
regard to the risk for SAb. One study found an elevated SGA risk for fathers with
occupational exposure to benzene. In another study, there was a marginally
significant reduction in birth weight in infants whose mothers had been exposed to
low levels of benzene at work.
However, all of the available studies have one or more limitations, such as multiple
exposures, inadequate adjustment for other confounders and/or inadequately
quantified exposure to benzene as well as other chemicals. Therefore, there is at
present no convincing evidence from human studies that benzene may have adverse
effects on reproduction.
Priority Existing Chemical Number 21
80
11.4.6 Other health effects
Chronic tiredness and headache and large, spreading bruises on the arms and legs
have been described in a number of workers exposed to benzene air levels in the
order of 100-200 ppm (Helmer, 1944).
Yin et al. (1987a) conducted a survey of the prevalence of symptoms of
intoxication in Chinese factory workers exposed to high levels of benzene or
benzene and toluene for up to 40 years. There was a slight decrease in ALC in both
groups. Sore throat and episodes of nose bleeding were common in all exposed
workers and their frequency was related to benzene exposure levels.
In an uncontrolled case report, Davidoff et al. (1998) described a group of workers
who began complaining about petrol odour and symptoms of nausea, headache,
throat and eye irritation, and cough while tunnelling underneath a former service
station site. An air sample from the tunnel contained 60 ppm benzene. Eight out of
30 randomly selected workers subsequently investigated in detail reported the post-
incident onset of chemical hypersensitivities and other characteristics which,
according to the authors, fitted conservative criteria for the diagnosis of multiple
chemical sensitivities syndrome.
11.5 Genotoxic effects
Several occupational studies conducted over the past 30 years point to a link
between a number of unstable or stable, numerical or structural chromosome
aberrations and benzene exposure (ATSDR, 1997; IPCS, 1993). In most cases,
these studies were conducted in workers exposed to benzene levels >10 ppm.
However, Tompa et al. (1994) analysed whole blood metaphase spreads from
workers employed in an environment where improved working conditions over a 3-
year period reduced average peak exposures from 21 ppm in 1990 to 8.4 ppm in
1991 and 5.7 ppm in 1992. As shown in Figure 11.1, the reduction in benzene
levels was paralleled by a decrease in the frequency of chromosome aberrations,
but not in SCEs. These findings provide evidence of a direct relationship between
benzene exposure and the extent of chromosome damage, but do not establish a
threshold level for the effect.
Figure 11.1: Changes in the frequency of SCEs and chromosome aberrations
(excluding gaps) in workers exposed to progressively reduced benzene
levels (Tompa et al, 1994)
10
SCEs/cell
8
Frequency
C hro m o so m e
6
ab erra tio ns (%)
4
2
0
25 20 15 10 5 0
B enz en e concentration (ppm)
Benzene 81
Table 11.3 summarises a number of recent occupational studies which used
personal air monitoring to measure benzene exposure and modern cytogenetic
techniques such as polymerase chain reaction methods, 32P-postlabelling,
fluorescence in situ hybridization and alkaline single cell gel electrophoresis to
determine the genotoxic effects in various cell samples.
Table 11.3: Genotoxic effects in workers exposed to airborne benzene
Study population (number)
Effects and effect levels (TWA8)* Reference
Exposed Controls
Petrol station Matched for Excess of overall DNA damage and highly damaged Andreoli et
attendants (12) sex, age and cells in freshly isolated non-cycling peripheral blood al. (1997)
smoking LC in subjects exposed to a mean air level of 0.11
habits (12) ppm (range: 0.03-3.0 ppm) (Lagorio et al, 1997)
Petrol station Matched for No evidence of numerical aberrations involving Carere et al.
attendants (12) sex, age and chromosomes 7, 11, 18 or X in peripheral blood LC (1998)
smoking of subjects exposed to an average air level of 0.1
habits (12) ppm
Increase in kinetochore-positive MN in T-LC, but no Holz et al.
Styrene plant Matched for
changes in DNA adducts in MC or in DNA single (1995)
workers (25) sex and age
strand breaks, SCE or total MN in LC at average
(25)
exposure levels corresponding to 0.24 ppm benzene
and 0.31 ppm styrene (as well as toluene, xylenes
and ethylbenzene)
Coke gas plant Matched for No increases in the frequency of MN, MN harbouring Surrall閟 et
workers (56) age (28) whole chromosomes or acentric chromosomal al. (1997)
fragments or chromosome 9 numerical abnormalities
in LC and buccal cells at exposure levels from 0.5-
1.2 ppm
Coke gas plant Unmatched Small but statistically significant increase in Marcon et
workers (12) inhabitants of centromeric breakage of chromosomes 1 and 9 in al. (1999)
and oven neighbouring interphase LC in benzene workers exposed to a
operators (5) rural village geometric average of 1.3 ppm benzene, but not in
(8) coking oven workers exposed to a geometric
average of 1.0 ppm
Workers using Matched for In heterozygous individuals, the frequency of NN but Rothman et
benzene-based sex, age, not N?GPA mutants was doubled in peripheral RBC al. (1995,
solvents (24) smoking, and strongly correlated with lifetime cumulative 1996b)
drinking and benzene exposure, at a mean exposure level of 72
obesity (23) ppm (range: 2-301 ppm)
Workers using Matched for There was a dose-related increase in hyperdiploidy Smith et al.
benzene-based sex and age at chromosomes 8 and 21 and in hypodiploidy at (1998)
solvents (43) (44) chromosome 8 in LC of workers with a median
exposure level of 31 ppm (range not specified).
There was also a 15-fold increase in t(8;21) (27
versus 2% LC) and a doubling of t(8;?) and t(21;?) in
LC at exposures >31 ppm. All increases were
related to current but not to cumulative exposure
Increased frequency of hyperdiploidy at chromo- Zhang et al.
some 9, mainly trisomy, in LC at exposure levels (1996)
>31 ppm, which correlated with ALC decreases
Increased frequency of monosomy at chromosomes Zhang et al.
5 and 7, in trisomy and tetrasomy at chromosomes (1998)
1, 5 and 7, and a dose-dependent, up to 3.5-fold
increase in long arm deletions of chromosomes 5
and 7 in whole blood metaphase spreads, at a
median exposure level of 31 ppm (range: 2-329
ppm)
* ALC = absolute lymphocyte count RBC = red blood cells
GPA = glycophorin A SCE = sister chromatid exchange
LC = lymphocytes t(a;b) = translocations between chromosomes a and b
TWA8 = 8-h time-weighted average
MC = monocytes
MN = micronuclei ? = unidentified chromosome.
The studies of Andreoli et al. (1997) and Carere et al. (1998) of petrol station
attendants exposed to benzene concentrations that averaged around 0.1 ppm are
Priority Existing Chemical Number 21
82
difficult to interpret as there is no information on the nature and extent of co-
exposure to other chemicals in petrol or vehicle exhaust fumes, which would
include 1,3-butadiene and a number of genotoxic PAHs (IARC, 1999; IPCS, 1998).
Furthermore, Carere et al. (1998) investigated only one of the six chromosomes in
which aberrations have been found at high levels of benzene exposure.
Holz et al. (1995) reported kinetochore-positive (that is, whole chromosome) MN
in workers with an average exposure of 0.24 ppm benzene and 0.31 styrene.
However, styrene alone is known to cause chromosome damage in human
lymphocytes at low concentrations (IARC, 1994).
In coal gas by-product workers, Surrall閟 et al. (1997) found no chromosome
aberrations at benzene levels 1.2 ppm, whereas Marcon et al. (1999) found a small
increase in centromeric breakages in chromosomes 1 and 9 at 1.3 ppm, but not in
coke oven workers exposed to a slighter lower level averaging 1.0 ppm. However,
coke oven and coal gas by-product workers are co-exposed to numerous PAHs,
many of which have a variety of genotoxic effects at low concentrations (IPCS,
1998).
The main findings at exposure levels 31 ppm benzene were aneuploidy, long-arm
deletions and translocations involving chromosomes 1, 5, 7, 8, 9 and 21 and gene
duplication in nucleated RBC stem cells at the glycophorin A locus on
chromosome 4 (Rothman et al, 1995, 1996b; Smith et al, 1998; Zhang et al, 1996,
1998). The subjects of these studies were co-exposed to toluene and xylenes, which
may inhibit the metabolism of benzene, but have not been shown to cause
chromosome lesions that resemble the above (IPCS, 1997; McGregor, 1994).
As such, whereas studies using modern cytogenetic techniques have shown a clear
association between extensive chromosome damage and exposure to high benzene
levels, they have not contributed to the definition of a threshold level for genotoxic
effects in humans.
11.6 Carcinogenicity
11.6.1 Cohort studies
Cohort studies with poorly characterised benzene exposure levels
Table 11.4 summarises a number of occupational cohort studies with a combined
study population approaching 450,000 workers holding jobs with the potential for
exposure to benzene, mainly in the petroleum industry. They include the ongoing,
prospective Health Watch (1998) cohort study, which covers about 95% of the
Australian petroleum industry's 18,000 employees in refineries, natural gas plants,
distribution terminals and production sites. They also include two meta-analyses
based on a large number of petroleum industry cohorts (Raabe & Wong, 1995;
Wong & Raabe, 1996, 2000). The most important limitation of these studies and
meta-analyses is their lack of adequate data on benzene exposure levels.
Benzene 83
Table 11.4: Summary of cohort studies in workers exposed to poorly characterised benzene levels
Exposed population Controls Ratio (95% CI) Comments Reference
Health outcome*
Chemical industry
Any death rate
National population Decoufl?et al.
No difference
259 workers ever employed at a US benzene In 194 workers employed for 12 months,
(1983)
alkylation plant from 1947-60 and followed up SMR for CBLS = 3.77 (1.09-10.24)
for 17-30 years
All-cause mortality
Architects from same Olin & Ahlbom
RR = 1.14 (0.91-1.37)
822 chemists graduated from university in There were 10 cases of CBLS among the
All cancer mortality
school (1980)
RR = 2.54 (p <0.05)
Stockholm, Sweden, between 1930-50 and chemists compared to 0 among the
All CBLS
followed up till the end of 1974 architects; nine were organic chemists
RR = (p = 0.02)
Coke oven and coal gas by-product workers
Regional population Hurley et al.
Benzene breathing zone levels were
Leukaemia:
2708 men employed by British Steel
(1991)
SMR = 0.41 (0.05-1.47) reported to average 1.3 ppm in by-product
Corporation at 14 coke works in the UK in All workers
SMR = 0.98 (0.02-5.57) and 0.3 ppm in coke oven workers in the
1967 and followed up for 20 years By-product workers
SMR = 0.35 (0.01-1.92) 1980s
Coke oven workers
Regional population
3812 men employed by National Smokeless Leukaemia:
SMR = 0.42 (0.09-1.23)
Fuels Ltd at 13 coke works in the UK in 1967 All workers
SMR = 0.76 (0.02-4.29)
and followed up for 20 years By-product workers
84
SMR = 0.34 (0.00-1.86)
Coke oven workers
SMR = 0.58 (0.01-3.28)
Maintenance workers
National population Swaen et al.
SMR >1.00 (p< 0.05) Among 222 benzene plant workers, death
All-cause mortality, all
5659 coke oven workers employed for 6
(1991)
rates were similar to the expected figures
cancer, liver cancer, and
months from 1945-69 at a Dutch coke plant and
respiratory disease
followed up for 15-40 years
Footwear manufacturing
Paci et al.
National population Workers in some departments were
Male workers (n = 1008):
2013 men and women ever employed at an
SMR <1.00 (p <0.05) exposed to glues containing >70% benzene (1989)
GI disease and accidents
Italian shoe manufacturing plant from 1939-64
SMR = 15.66 (5.47-32.64)
Blood disease
and followed up for 20-45 years
All non-cancer blood disease cases were
SMR = 1.40 (1.09-1.81)
All cancer
aplastic anaemia
SMR = 2.40 (1.37-3.78)
Stomach cancer
SMR = 4.00 (1.46-8.70)
Leukaemia No relationship between leukaemia risk and
duration of exposure
Female workers (n = 1005):
No information on job categories, which
No difference
Any cause of death
likely may have explained negative findings
in female workers
Priority Existing Chemical Number 21
Table 11.4: Continued
Exposed population Controls Ratio (95% CI) Comments Reference
Health outcome*
Benzene
Highway maintenance workers
All-cause mortality and
Regional white Bender et al.
4849 men employed for at least 1 year SMR <1.00 (p <0.05) In workers with 30-39 years of
all cancer
population (1989)
between 1945-84 as highway maintenance employment, the SMR for leukaemia
workers by the Department of Transportation was 4.25 (1.71-8.76)
All CBLS
in Minnesota, USA SMR = 0.95 (0.66-1.33)
Leukaemia SMR = 1.07 (0.62-1.71) No observed deaths from melanoma
compared to 2.9 expected
Petrol and petroleum distribution
Male workers (n = 16,524): Lynge et al.
National population No information on employment status
18,969 men and women employed as petrol
All malignant neoplasms (1997)
of gainfully SIR = 1.1 (1.0-1.1) before or after the census date and
station attendants on the day of the 1970
Cancer of the nose
employed SIR = 3.1 (1.5-5.7) hence no adjustment for person-years
censuses in Denmark, Norway, Sweden and
Lung cancer SIR = 1.3 (1.1-1.4) at risk
Finland and followed up for deaths and
Non-Hodgkin's lymphoma SIR = 1.1 (0.8-1.5)
incident cancer cases for 15-20 years
Hodgkin's disease SIR = 1.0 (0.5-1.8)
Multiple myeloma SIR = 0.6 (0.3-1.1)
Leukaemia SIR = 0.9 (0.6-1.3)
Female workers (n = 2445):
85
All malignant neoplasms SIR = 1.0 (0.8-1.1)
Cancer of the nose SIR = 8.0 (1.0-28.9)
Non-Hodgkin's lymphoma SIR = 0.6 (0.0-2.0)
Hodgkin's disease SIR = IC
Multiple myeloma SIR = IC
Leukaemia SIR = 0.7 (0.1-2.4)
All-cause mortality, all
Regional Lagorio et al.
SMR <1.00 (p <0.05) Benzene exposure levels were reported
2665 petrol station workers in the Latium
cancer, and CV disease
population (1994a)
to be in the order of 0.2 ppm
(greater Rome) region in Italy in 1980 and
followed up for 10 years
All CBLS SMR = 0.40 (0.07-1.26)
All-cause mortality,
Regional Rushton
SMR <1.00 (p <0.05)
23,306 workers employed for 1 continuous
respiratory, liver and
populations (1993b)
year between 1950-75 at UK oil distribution
kidney disease, all cancer
centres and followed up for 15-40 years
and cancer of the
oesophagus, lung and
pleura
Leukaemia SMR = 1.08 (0.83-1.40)
Table 11.4: Continued
Controls Ratio (95% CI) Comments Reference
Exposed population Health outcome*
Petrol and petroleum distribution: Continued
All-cause mortality,
National population Wong et al.
SMR <1.00 (p <0.01)
18,135 US workers employed for 1 year
all cancer and circulatory, (1993)
at land-based petrol terminals or on marine
respiratory and liver disease
petrol tankers from 1946-1985 and followed
up for 5-55 years
Leukaemia SMR = 0.89 (0.59-1.29) Land-based workers
SMR = 0.70 (0.42-1.09) Marine workers
Lymphoma SMR = 0.75 (0.58-0.97) Land-based workers
SMR = 0.61 (0.43-0.83) Marine workers
Petroleum production, refining and distribution
All-cause mortality, all CV Consonni et al.
SMR <1.00 (p <0.05) Limited monitoring data indicate that a
1583 workers ever employed at an Italian refinery National population
disease, stroke, respiratory (1999)
substantial fraction of the workforce had
from 1949-82 and followed up for
disease, liver, and GI been exposed to benzene levels >1 ppm
10-42 years
disease
86
CBLS (all workers) SMR = 1.79 (1.00-2.95)
CBLS (employment >15 SMR = 2.71 (1.09-5.59)
years) Leukaemia SMR = 3.77 (1.01-9.65)
(employment >15 years)
CBLS (employment pre- SMR = 2.82 (1.13-5.81)
1961)
Lymphoma (employment SMR = 4.02 (1.08-10.28)
pre-1961)
All-cause mortality,
National population Health Watch
SMR <1.0 (p <0.05) Elevated incidence of leukaemia mainly
15,732 male workers employed for 5 years
ischaemic heart disease, (1998)
accounted for by refinery and terminal
in the Australian petroleum industry from
stroke, and respiratory, liver workers; no definite relationship with length
1981-96 and followed up for 5-15 years
and GI disease of employment
Bladder cancer SIR = 1.4 (1.0-1.9) Estimated long-term benzene exposure
Multiple myeloma SIR = 1.9 (1.0-3.3) levels were 5 ppm in all cases; estimated
Leukaemia SIR = 2.0 (1.3-2.9) cumulative exposures ranged from 0.005-
Lymphocytic leukaemia SIR = 2.0 (1.0-3.5) 50.9 ppm-years (Glass et al, 1998)
Myeloid leukaemia SIR = 2.2 (1.2-3.6)
Melanoma SIR = 1.6 (1.3-1.9) No excess mortality from melanoma (SMR
= 0.7 (0.4-1.4)
Priority Existing Chemical Number 21
Table 11.4: Continued
Controls Ratio (95% CI) Comments Reference
Exposed population Health outcome*
Benzene
Petroleum production, refining and distribution: Continued
National population J鋜vholm et al.
4319 Swedish refinery operators and All male workers (n = 4128):
(1997)
All-cause mortality, CV disease, SMR <1.00 (p <0.05)
distribution workers employed for 1 year
and lung cancer
between 1958-91 and followed up for
5-35 years
Refinery operators (n = 1339):
Leukaemia SIR = 3.6 (1.5-7.0)
Distribution workers (n = 1391):
All cancer and lung cancer SIR <1.00 (p <0.05)
Leukaemia SIR = IC (0-2.0)
Lewis et al.
National population There was an increase in multiple
Male workers (n = 26,322):
34,560 workers employed 1 year in refinery,
(2000)
myeloma (SMR = 1.94 (1.11-3.15)) in
All-cause mortality, endocrine, SMR <1.00 (p <0.05)
petrochemical, distribution, marketing,
marketing and distribution workers
circulatory, respiratory and GI
production, drilling and pipeline locations
disease, all cancer
throughout Canada from 1964-83 and
Leukaemia SMR = 0.89 (0.67-1.16)
followed up for 11-31 years
Aortic aneurysm SMR = 1.27 (1.04-1.53)
Female workers (n = 8238):
87
All-cause mortality, endocrine, SMR <1.00 (p <0.05)
circulatory, respiratory and GI
disease
Leukaemia SMR = 0.86 (0.32-1.88)
Nelson et al.
National population All-cause mortality, all cancer SMR <1.00 (p <0.05)
9187 male workers employed for 6 months
(1987)
and CV, respiratory and GI
at 10 US refineries from 1970-80 and
disease
followed up for 2-12 years
All CBLS SMR = 0.60 (0.34-0.97)
10/11 deaths from skin cancer were due to
Skin cancer SMR = 2.01(1.00-3.60)
melanoma
Pukkala (1998)
National population The breast cancer cases were
All workers:
9454 workers employed for 3 months in 3
concentrated among clerical workers
Kidney cancer SIR = 1.97 (1.29-2.88)
refineries, 1 petrochemical plant and the
(SIR = 1.70 (1.08-2.56)), particularly in the
Male workers (n = 7512):
head office of an oil company in Finland
head office (SIR = 2.29 (1.25-3.84)), and
Non-Hodgkin's lymphoma SIR = 2.01 (1.00-3.59)
from 1967-82 and followed up for 13-28 years
the SIRs did not differ from those found in
other studies of Finnish women in office
Female workers (n = 1942):
jobs
Breast cancer SIR = 1.50 (1.05-2.08)
Table 11.4: Continued
Exposed population Controls Ratio (95% CI) Comments Reference
Health outcome*
Petroleum production, refining and distribution: Continued
SMR <1.00 (p <0.05) The SMR for melanoma was not elevated Rushton
All-cause mortality, stroke
34,569 men employed at 8 UK refineries for 1 Regional populations
in workers first employed before 1955, but (1993a)
all heart, respiratory and
continuous year between 1950-75 and followed
reached 2.30 (1.05-4.37) and 4.67 (2.02-
liver disease, all cancer and
up for 15-40 years
9.20) in workers first employed between
cancer of the mouth,
1955-64 and after 1965 respectively. It
pharynx, lung and pleura
varied markedly between refinery locations
SMR = 1.20 (1.07-1.35) and was higher among office staff than in
Diseases of the arteries
SMR = 0.97 (0.76-1.24) workers employed outdoors.
Leukaemia
SMR = 1.78 (1.20-2.54)
Melanoma
UK national Thorpe (1974)
SMR = 0.77 (0.41-1.13)
All leukaemias
Workers representing 383,276 man-years of In a subgroup of workers exposed for 5
employment in 1962-71 at 8 European affiliates population years to streams containing 1% benzene,
of a US oil company the SMR for leukaemia was 1.21 (0.37-
Wong & Raabe
MSMR = 1.02 (0.93-1.11) Meta-analysis of leukaemia mortality by
All leukaemias
Meta-analysis of 19 cohorts comprising 208,741 Various national and
regional populations (1995); Raabe
MSMR = 1.16 (0.81-1.61) cell type; no data on other death rates
Acute lymphocytic
refinery, production, pipeline and distribution
& Wong (1996)
leukaemia
workers ever employed in USA and UK from
MSMR = 0.96 (0.81-1.13)
Acute myeloid leukaemia
1937-1989 and followed up for 13-50 years
88
MSMR = 0.84 (0.67-1.04)
Chronic lymphocytic
leukaemia
MSMR = 0.89 (0.68-1.15)
Chronic myeloid leukaemia
Various national and Wong & Raabe
MSMR = 0.90 (0.82-0.98)
Non-Hodgkin's lymphoma
Meta-analysis of 26 cohorts comprising
regional populations (2000)
more than 308,000 refinery, production and
distribution workers ever employed in
Australia, Canada, Finland, Italy, USA
and UK from 1937-1996
Printing
National population Paganini-Hill et
SMR = 3.03 Exposed to printing inks and solvents
Kidney cancer
1361 men ever employed as rotary press
al. (1980)
SMR = 2.05 containing benzene
Liver cirrhosis
workers in Los Angeles from 1949-65 and
SMR = 2.47 No analysis for statistical significance
Leukaemia
followed up till 1980
Tyre manufacturing
National population McMichael et
SMR <1.00 No exposure assessment, but `benzene
All-cause mortality
18,903 male workers employed for 10 years
al. (1976)
SMR = 1.48/1.16/1.19 was once the most widely used organic
Stomach/colon/prostate
at 4 tyre manufacturing plants in Ohio and
solvent in the industry'
cancer
Wisconsin, USA, from 1945-1964 and
SMR = 1.31 No analysis for statistical significance
CBLS
followed up for 10 years
Priority Existing Chemical Number 21
SMR = 1.30
Leukaemia
SMR = 1.58
Lymphocytic leukaemia
SMR = 1.29
Lymphoma
Table 11.4: Continued
Benzene
Exposed population Controls Ratio (95% CI) Comments Reference
Health outcome*
Vehicle mechanics
All-cause mortality and
335 predominantly black men employed for Regional population Hunting et al.
SMR <1.00 (p <0.05) Regular contact workers used petrol to
liver and GI disease (1995)
clean engine parts and wash hands or
1 year as vehicle maintenance workers in
CBLS (all workers) SMR = 3.63 (0.75-10.63) siphoned petrol by mouth
Washington, DC, from 1977-89 and
CBLS (regular contact SMR = 9.26 (1.12-33.43)
followed up for 3-15 years
workers)
Miscellaneous industries
All-cause mortality and
74,828 male and female workers employed 35,805 unexposed Yin et al.
No difference
all cancer deaths
from 1972-87 in the painting, printing, workers (1996)
Fatal CBLS
footwear and chemical industries in RR = (2.5-)
Fatal leukaemia
China and followed up for 1-15 years RR = 2.3 (1.1-5.0)
Fatal lymphoma RR = 4.5 (1.3-28.4)
89
* CBLS = cancer of the blood and lymphatic system; CV = cardiovascular; GI = gastrointestinal; GU = genitourinary.
IC = incalculable (no observed cases); MSRM = meta-SMR; SIR = standardised incidence ratio; SMR = standardised mortality
ratio; RR = relative risk; = indefinite (no cases in the unexposed group).
Cohort studies with detailed benzene exposure assessments
There are four occupational cohort studies in which the exposure to benzene has
been assessed in detail.
The Chinese cohort
The US National Cancer Institute and the Chinese Academy of Preventive
Medicine have collaborated to follow up on a large cohort study commenced in
1982 to assess the risks of specific bone marrow disorders in relationship to
occupational benzene exposure (Hayes et al, 1997). The final cohort comprises
74,828 male and female benzene-exposed workers employed from 1972 to 1987 in
672 factories in 12 cities in China and 35,805 unexposed workers. The subjects
were followed until the end of 1987, for an average of approximately 11 years. RRs
were determined for incident cancer of the blood and lymphatic system, NHL,
leukaemia, ANLL, a diagnosis of either ANLL or MDS, and leukaemia other than
ANLL, with stratification by age and sex. Smoking or other potential confounders
were not considered. The exposed workers held permanent jobs in the painting,
printing, footwear, rubber and chemical industries. Exposure levels were estimated
from available area monitoring data, detailed production and process information,
and employee records.
There were 58 specified cancers of the blood and lymphatic system and 18 other
bone marrow disorders (2 cases of agranulocytosis, 9 of aplastic anaemia and 7 of
MDS) in the cohort, compared to 13 and 0 respectively in the control group.
When the cohort was divided into three categories according to the estimated
average benzene exposure level, the RRs for all cancer of the blood and lymphatic
system and ANLL/MDS were elevated in all categories, with a positive trend for
increasing average exposure, as shown below:
Estimated average exposure:
Cancer type/R: <10 ppm 10-24 ppm >25 ppm Trend
Blood and
lymphatic system 2.2 (1.1-4.2) 3.1 (1.5-6.5) 2.8 (1.4-5.7) p = 0.003
ANLL/MDS 3.2 (1.0-10.1) 5.8 (1.8-18.8) 4.1 (1.2-13.2) p = 0.01
The RR for NHL was 4.7 (1.2-18.1) in workers exposed to 25 ppm, but was not
elevated in the lower average exposure categories.
When the cohort was divided into three categories according to the estimated
cumulative benzene exposure level, the RR for all cancer of the blood and
lymphatic system was elevated in all categories, whereas the RRs for leukaemia
and ANLL/MDS were elevated at cumulative exposures 40 ppm-years:
Estimated cumulative exposure
Trend
Cancer type/RR <40 ppm-years 40-99 ppm-years 100 ppm-years
Blood and
lymphatic system 2.2 (1.1-4.5) 2.9 (1.3-6.5) 2.7 (1.4-5.2) p = 0.004
Leukaemia 1.9 (0.8-4.7) 3.1 (1.2-8.0) 2.7 (1.2-6.0) p = 0.04
ANLL/MDS 2.7 (0.8-9.5) 6.0 (1.8-20.6) 4.4 (1.4-13.5) p = 0.01
The RR for NHL was not elevated in any of the three cumulative exposure
categories.
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Only NHL was linked to duration of exposure. None of the RRs were related to the
year of initial employment in the study factories. ANLL/MDS was linked to recent
exposure (<10 years prior to diagnosis), whereas NHL was linked to distant
exposure (10 years prior to diagnosis).
The authors concluded that the results suggest an association between benzene
exposure and a spectrum of blood cancers and related disorders, with an increase in
cancer risk at cumulative exposures <40 ppm-years and a tendency, although not
strong, for the risk to rise with increasing levels of exposure.
It should be noted that personal monitoring in a subset of the Chinese cohort
measured current exposure levels which were reported to be `much higher than
expected' compared to the estimates that were made in the course of the main study
(Rothman et al, 1995, 1996b). As such, the historical exposure levels used to
determine the dose-response relationship may have been grossly underestimated
(Budinsky et al, 1999; EPA, 1998a; Wong, 1999).
Overall mortality rates in the Chinese cohort have been reported by Yin et al.
(1996) and are summarised in Table 11.4. The average latency period of fatal
leukaemia in benzene-exposed workers was estimated at 11-12 years, with a range
from 10 months to 50 years (Yin et al, 1987b).
The CMA cohort
The Chemical Manufacturers Association (CMA) sponsored a study of 4602 male
chemical workers who were employed for 6 months from 1946-75 at 7 US plants
(Wong, 1987a, 1987b). Two comparison groups were used: the general US
population and 3074 unexposed male workers employed at the same plants at the
same time as the cohort. Smoking or other potential confounders were not
considered. The vital status of all subjects was followed up until the end of 1987
and the findings compared to average and peak exposures as determined from
available air monitoring data and employment records obtained from the
participating companies.
There were 19 deaths from cancer of the blood and lymphatic system in the
exposed workers compared to 3 in the unexposed group. In the exposed group, 7 of
the observed cases were diagnosed with leukaemia and the remaining 12 with
lymphoma. The subjects with leukaemia comprised 1 case with acute lymphatic
leukaemia (ALL), 2 with chronic lymphatic leukaemia (CLL), 1 with unspecified
lymphatic leukaemia, 2 with chronic myeloid leukaemia (CML) and 1 with
unspecified acute leukaemia. In the unexposed workers, all 3 cases were diagnosed
with lymphoma. The SMRs for all cancers of the blood and lymphatic
system/leukaemia reached 0.91/0.97, 1.47/0.78 and 1.75/2.76 for cumulative
exposures of <180, 180-719 or 720 ppm-months respectively, but none of the
ratios was significantly different from unity. The RRs for all cancers of the blood
and lymphatic system were 2.10, 2.95 and 3.93 respectively for the same
cumulative exposure groups, with p = 0.02 for trend. The RRs for leukaemia were
indefinite as there were no cases in the unexposed workers, with p = 0.01 for trend
with cumulative exposure. There was no correlation with peak levels or duration of
exposure.
Based on the RRs and their trend with cumulative exposure, the author concluded
that workers exposed to benzene exhibited a significant excess of deaths from
leukaemia as well as from the broader category of all cancers of the blood and
Benzene 91
lymphatic system when compared with workers who were not exposed to the
chemical.
Ireland et al. (1997) conducted an extended mortality study in production personnel
from one of the plants included in the CMA-sponsored study. The workers were
stratified into three categories based on cumulative exposure: <12 ppm-months (n =
666), 12-72 ppm-months (n = 378) and 72 ppm-months (n = 164). Compared to
the regional population, the SMR for leukaemia was 2.5 (0.3-8.9) in the lowest,
incalculable (0.0-5.9) in the middle, and 4.6 (0.9-13.4) in the highest exposure
category, with no clear dose-response relationship.
The Dow Chemical cohort
This cohort comprised 956 male chemical workers employed at a single site in
Michigan, USA, between 1940 and 1982. The workers were exposed to benzene in
chlorobenzene or alkylation plants which used benzene as a raw material, or in an
ethyl cellulose plant where benzene was used as a solvent (Bond et al, 1986; Ott et
al, 1978). They were followed up until the end of 1982. The average exposure
duration and length of follow-up were 7 and 26 years respectively. Each job entry
was assigned an exposure intensity level on the basis of job classification and
representative personal air monitoring data.
The analysis accounted for co-exposure to arsenic, asbestos or high levels of vinyl
chloride. Smoking or other potential confounders were not considered. There were
6 deaths from cancer of the blood and lymphatic system against 4.8 expected,
including 4 cases of myelogenous leukaemia against 0.9 expected, and 4 from skin
cancer (3 melanomas and 1 squamous cell carcinoma) against 0.9 expected, using
concurrent US white male mortality rates as reference values. The excess of
myelogenous leukaemia was statistically significant (p = 0.011; SMR and 95% CI
not stated) and the risk for skin cancer was significantly elevated (SMR = 4.41
(1.21-11.38)). There were no significant trends with either work area, cumulative
exposure or duration of exposure. Of the 6 cases of blood and lymphatic system
cancer, 4 had been exposed to <500 ppm-months and 2 to 1000 ppm-months. In
the case of myelogenous leukaemia, cumulative exposures varied from 18-4211
ppm-months. The 4 cases of skin cancer all occurred in workers with exposures
<500 ppm-months, but otherwise had no unusual or common characteristics.
The authors concluded that their study provided support for an association between
exposure to benzene and myelogenous leukaemia.
The Pliofilm cohort
An excess incidence of leukaemia in rubber workers at two Goodyear facilities in
Ohio, USA was reported in a preliminary paper by Infante et al. (1977) and in more
detail by Rinsky et al. (1981). Depending on its definition, this cohort comprises
1165-1212 male workers employed from 1936-75 in the manufacture of Pliofilm,
which is a material made from rubber hydrochloride (Paxton et al, 1994a; Rinsky et
al, 1987). The manufacturing process used large volumes of benzene as a solvent
and there was no exposure to other known carcinogenic substances. The last worker
joined the cohort in 1965 and the most recent follow-up was in 1987.
Excluding deaths before 1950, Rinsky et al. (1987) identified 15 deaths from
lymphatic and haematopoietic cancers versus 6.6 expected (SMR = 2.27 (1.27-
3.76)) and 9 deaths from leukaemia versus 2.7 expected (SMR = 3.37 (1.54-6.41)).
In a later analysis that included deaths between 1940-50, Paxton et al. (1994a)
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identified 21 deaths from lymphatic and haematopoietic cancers versus 9.51
expected (SMR = 2.21 (1.37-3.38)) and 14 deaths from leukaemia versus 3.89
expected (SMR = 3.60 (1.97-6.04)). Neither of these analyses considered smoking
or other potential confounders.
The individual exposure histories of the cohort members were reconstructed after
the plants closed in 1975, from fairly detailed monitoring and health surveillance
data and other information on record.
Based on unpublished exposure estimates, Rinsky et al. (1987) found SMRs for
leukaemia of 1.09 (0.12-3.94) at a cumulative exposure <40 ppm-years, 3.22 (0.36-
11.65) at 40-200 ppm-years, 11.86 (1.33-42.85) at 200-400 ppm-years and 66.37
(13.34-193.93) at >400 ppm-years.
Paxton et al. (1994a) recalculated the SMRs for a different set of cumulative
exposure categories and compared them with similar statistics derived from
independent, more detailed exposure estimates produced by Crump & Allen
(unpublished report prepared for the Occupational Safety and Health
Administration in 1984) and Paustenbach et al. (1992), as shown in Table 11.58.
The results reproduced in the table suggest a strong dose-response relationship of
risk increasing with cumulative exposure, no matter which estimate is used, and
indicate that there is a significantly elevated risk for leukaemia (according to 2 of
the 3 available exposure estimates) at a cumulative dose >50 ppm-years,
corresponding to a long-term average exposure of 1.25 ppm over 40 years.
Table 11.5: SMRs (95% CI) for leukaemia in the Pliofilm cohort, analysed by
cumulative exposure as estimated by Crump & Allen (1984, unpublished),
Paustenbach et al. (1992) and Rinsky et al. (1987)(from Paxton et al, 1994a)
Cumulative Exposure estimate
exposure
(ppm-years) Crump & Allen Paustenbach et al. Rinsky et al.
0-5 0.88 (0.02-4.89) 1.33 (0.03-7.43) 1.97 (0.41-5.76)
>5-50 3.25 (0.88-8.33) 1.79 (0.22-6.45) 2.29 (0.47-6.69)
6.93 (2.78-14.28)
>50-500 4.87 (1.79-10.63)* 2.80 (0.76-7.16)
10.34 (2.13-30.21) 11.86 (4.76-24.44)
>500 20.00 (0.51-111.4)
* p <0.05
p <0.01
As the SMR was not significantly different from unity at cumulative exposures 50
ppm-years for any of the three exposure estimates, the authors concluded that the
results of the analysis were consistent with a threshold model for benzene-induced
leukaemia. However, the power of the analysis was insufficient to support this
conclusion. The upper 95% confidence limits given in Table 11.5 range from 6.45-
8.33 in the >5-50 ppm-year exposure category and from 4.89-7.43 the 0-5 ppm-
year category. In either case, the upper limits are well above unity irrespective of
the exposure estimate used. Therefore, it cannot be excluded that a cumulative
exposure level 50 ppm-years is also associated with an excess mortality from
leukaemia.
8
The major distinction between the three exposure estimates is the disregard by Rinsky et al. (1987)
for the likely increase in exposure levels during and in the aftermath of World War II because of
wartime conditions and longer working hours. In addition, only Paustenbach et al. (1992) have given
consideration to the potential for dermal exposure.
Benzene 93
Wong (1995) reanalysed the findings of Paxton et al. (1994a) by cell type (AML
and multiple myeloma (MM)), using the Rinsky et al. (1987) exposure estimate
which in general is the lowest of the three. He found no relationship between
cumulative exposure and the risk of MM, whereas the SMR for AML showed a
clear dose response, as follows:
Cumulative exposure SMR (95% CI) Statistical significance
<200 ppm-years 0.91 (0.02-5.11) Not significant
200-400 ppm-years 27.21 (3.29-98.24) p <0.01
>400 ppm-years 98.37 (20.28-287.65) p <0.01
Total cohort 5.03 (1.84-10.97) p <0.01
The author concluded that there was no significant increase in the risk of AML for
cumulative exposure to benzene <200 ppm-years, above which the risk rose sharply
to a very substantial SMR of 98.37 for >400 ppm-years. However, as the 95%
upper confidence limit in the lowest exposure group was 5.11, an increase in
mortality from AML at a cumulative exposure <200 ppm-years cannot be ruled out.
In another re-analysis based on the three sets of exposure estimates referred to
above, Schnatter et al. (1996b) used the work history of each Pliofilm worker to
define each worker's maximally exposed job/department combination over time
and the long-term average benzene exposure level associated with the maximally
exposed job. They then determined the number of observed and expected cases of
leukaemia (all cell types) in subcategories of workers and person-years who were
always exposed at levels that did not exceed specific concentrations of benzene. As
shown in Table 11.6, this analysis showed that there were fewer observed than
expected deaths in all subcategories that were always exposed to benzene
concentrations 15 ppm, irrespective of the exposure estimate used. However,
because of the low number of expected cases, this finding could also be due to
chance.
Table 11.6: Observed and expected cases of leukaemia (all cell types) for
selected cut-off points for the average long-term exposure level in the
maximally exposed job (Schnatter et al, 1996b)
Long-term Exposure estimate
benzene
Crump & Allen Paustenbach et al. Rinsky et al.
exposure
(ppm) Observed Expected Observed Expected Observed Expected
1 0 0.53 0 0.07 1 1.53
5 0 1.01 0 0.10 1 1.72
10 0 1.04 0 0.11 1 2.00
15 0 1.28 0 0.15 1 2.00
20 2 1.92 0 0.21 3 2.30
25 2 2.13 1 0.80 7 2.92
30 3 2.35 1 0.90 7 3.24
40 5 2.73 1 1.33 10 4.04
50 5 2.98 3 1.96 14 4.79
100 8 3.98 5 3.55 14 4.87
200 9 4.20 14 4.70 14 4.87
260 14 4.87 14 4.87 14 4.87
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Conclusions
Cohort studies with poorly characterised benzene exposure levels
Several of the studies summarised in Table 11.4 have associated cancer of the
blood and lymphatic system (including but not limited to leukaemia) with the
obsolete practice of using benzene-containing adhesives, cleaners and solvents.
Some studies indicate a positive association with long-term employment at
petroleum refineries, in the chemical industry or in highway maintenance. There
was no excess mortality from leukaemia in three cohorts of coke plant workers.
The risk for malignant melanoma or skin cancer (mainly melanoma) was elevated
in three petroleum industry cohorts (Health Watch, 1998; Nelson et al, 1987;
Rushton, 1993a). The SIR for breast cancer was elevated in female workers in a
Finnish oil company cohort (Pukkala, 1998). However, the elevation was mainly
due to cases among clerical workers and similar in magnitude to that found in other
studies of Finnish women in office jobs.
Cohort studies with detailed benzene exposure assessments
There was an excess mortality from cancer of the blood and lymphatic system in all
four cohorts for which detailed benzene exposure assessments are available and a
significant trend with cumulative exposure in all but the smallest cohort (the Dow
Chemical cohort). As such, it is widely accepted that these studies provide
sufficient evidence of a clear dose-response relationship between benzene exposure
and the broad category of all cancers of the blood and lymphatic system (ATSDR,
1997; OECD, 2000; IARC, 1982a; IPCS, 1993; USEPA, 1998a). In terms of
specific cancer categories, the relationship is primarily due to the risk for AML
(ANLL).
In the CMA cohort, the SMR for leukaemia was elevated (2.6) in workers with a
cumulative exposure of 720 ppm-months (that is, 60 ppm-years), but it was not
significantly different from unity and therefore could have been due to chance. In a
subset of the CMA cohort, the SMR for leukaemia was 4.6 in workers with a
cumulative exposure of 72 ppm-months (6 ppm-years), but again did not differ
significantly from unity. There was no clear dose-response relationship in the Dow
Chemical cohort and there is doubt about the true exposures in the Chinese cohort.
As such, the Pliofilm cohort is the most suitable for the determination of the
carcinogenic potency of benzene. In addition, the Pliofilm cohort has the advantage
of limited if any co-exposure to other potentially carcinogenic compounds and a
very long follow-up period. However, it suffers from uncertainty about actual
exposure levels, particularly prior to 1950, which is important as there are no cases
of leukaemia in workers first employed after that year (USEPA, 1998a).
Based on an unpublished assessment of individual exposures in the Pliofilm cohort,
Rinsky et al. (1987) determined SMRs for leukaemia that increased exponentially
with cumulative exposure, starting from near unity at a cumulative exposure <40
ppm-years. More recent dose-response analyses that include other, more
comprehensive exposure assessments indicate that the risk for leukaemia is
significantly elevated at a cumulative exposure level above, but not below 50 ppm-
years, corresponding to an average exposure level of 1.25 ppm over 40 years
(Paxton, 1994b). Moreover, whatever exposure estimate was used, the number of
observed cases of leukaemia was consistently below the expected number in all
workers whose long-term exposure never exceeded 15 ppm (Schnatter et al,
1996b). However, because of the limited statistical power resulting from the size of
Benzene 95
the Pliofilm cohort, these results do not rule out the possibility of an increased risk
of leukaemia at exposure levels lower than those cited above.
In the Dow Chemical cohort, there was an association between benzene exposure
and skin cancer. However, all cases occurred in the lowest cumulative dose group
(<500 ppm-months) and there was no trend with either level or duration of
exposure.
11.6.2 Case-control studies
The case-control studies reviewed below have been divided by organ system. They
comprise studies based in a specific industry, such as petroleum refining, and
studies conducted in a community population. Limitations in statistical power and
study quality, particularly in relation to exposure assessment and/or control for
potential confounders, pervade all of the studies reviewed.
Cancer of the blood and lymphatic system
Industry-based studies
A study nested within a cohort of male workers at a large tyre manufacturing plant
in Ohio, USA included 11 cases of lymphocytic leukaemia and 1350 controls
(Checkoway et al, 1984). The OR for direct exposure through routine use or
handling of benzene or benzene-containing solutions was 4.50 (95% CI not stated),
but did not reach statistical significance (p = 0.22). The ORs for exposure to
acetone, carbon disulfide, carbon tetrachloride, ethyl acetate, hexane or methanol
ranged from 4.3-18 (95% CIs not stated) and were all statistically significant.
Austin et al. (1986) compared 14 cases of leukaemia in white male workers at a US
refinery, including 8 cases of AML, with 50 controls. Neither job category,
department nor length of employment was a significant risk factor.
In an exploratory study of cancer mortality at a transformer assembly facility in
Massachusetts, USA, where benzene was used for general cleaning purposes until
1950, benzene exposure was not a significant risk factor for leukaemia (OR = 1.4
(0.64-3.2)) (Greenland et al, 1994).
Sathiakumar et al. (1995) studied 69 workers with leukaemia, predominantly AML
or CLL (numbers not specified), and 284 controls who had worked for the same
US-based petroleum company for 1 year from 1976-90. Forty-four risk factors
tested for included site of work, involvement in production, job category, duration
and year of employment. The only risk factors identified were for AML and
included length of employment, with an OR = 8.7 (2.0-37.2) in workers employed
for >30 years (trend: p = 0.01), and upstream employment in crude oil production
or maintenance (OR = 3.2 (1.1-9.2)).
Schnatter et al. (1996a) compared 7 cases of NHL, 7 cases of MM and 55 controls
drawn from the cohort of Canadian petroleum distribution workers described by
Lewis et al. (2000). Tests included several measures for benzene exposure. The
only risk factors identified were a family history of cancer and cigarette smoking,
with cumulative benzene exposure showing no additional risk.
A study nested in the cohort of British petroleum distribution and marketing
workers described by Rushton (1993b) compared 91 cases of leukaemia,
predominantly ANLL (31) and CLL (31), with 364 controls (Rushton & Romaniuk,
1997). Risk factors tested for included cumulative, mean and maximum airborne
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and potential skin exposure to benzene, duration of employment, date of hire,
employment as driver, socio-economic status, and age at and years from start of
work. For ANLL, none of the ORs differed from unity. For CLL, the risk factors
identified included duration of employment, white-collar status and years of work,
but not exposure to benzene.
The case-control study nested within the cohort of Australian petroleum industry
workers currently comprises 63 cases with lympho-haematopoietic cancers, mainly
NHL, MM, AML and CLL, and 315 controls (Health Watch, 1998). In the analysis,
the OR was used to compare groups with different levels of exposure to various
potential causative agents, relative to the least exposed or baseline group.
Compared to the baseline of the rate in refineries, the OR was marginally elevated
for work in terminals (1.8 (1.0-3.5)). Length of employment and period of first
employment were not significant risk factors. Past exposure to benzene was ranked
on a scale from 1-5, depending on AIP jobcode, the company site where the job
was carried out and length of service in any job. When cases and controls were
compared to the highest benzene rank of any job ever held (ranks 4-5), the OR was
7.9 (1.6-39) times higher than for rank 1 (the baseline). When compared to the
benzene rank of the job held longest, the OR was 3.2 (1.1-9.4) times higher than
baseline for rank 3 and 6.6 (1.4-30) times higher for rank 4 (the highest rank in this
test). The authors concluded that a relatively higher exposure to benzene might be
the significant factor leading to an increased risk of leukaemia and MM in the
cohort study.
Nilsson et al. (1998) conducted a nested case-control study of Swedish seamen with
two study bases. These comprised a total of 92 men who were registered as seamen
at the national censuses in Sweden in 1960 and 1970 respectively and recorded in
the Swedish National Cancer Register with cancer of the blood and lymphatic
system from 1971-88. The controls were 291 age-matched men registered as
seamen at the same censuses. NHL (37) and leukaemia (30) accounted for most of
the cases. There were no increased risks for the 1960 cohort, in which few cases
were exposed to benzene or petrol. In the 1970 cohort, the OR was increased for
cancer of the blood and lymphatic system (OR = 2.6 (1.1-5.9)) and for NHL (OR =
3.3 (1.1-10.6)) in seamen who had worked on deck on chemical or petroleum
product tankers, but not on crude oil tankers.
Wong et al. (1999) studied 59 cases of leukaemia, including unspecified leukaemia
(35), AML (13) and MM (11), and 220 controls drawn from a US-based cohort
study of 18,135 petrol distribution workers (Wong et al, 1993). Test variables
included duration of employment, duration of exposure, job category, cumulative
exposure to hydrocarbons, cumulative frequency of peak exposure to hydrocarbons,
and year of first exposure. None of these was identified as a risk factor for any of
the study diagnoses.
In a study nested within the Pliofilm cohort described above, Finkelstein (2000)
examined the temporal variation of leukaemia risk following exposure to benzene.
Each leukaemia case was matched with 6-333 control subjects and the exposure of
cases and controls were then assessed according to Rinsky et al. (1987) and
compared at various times before the death of the case subject. As expected,
leukaemia risk was significantly associated with cumulative exposure (p = 0.024).
However, exposures incurred in the previous 10 years were found to account for
most of the risk and there was no significant difference in the benzene exposure of
cases and controls 15 or more years prior to the death of the case subject.
Benzene 97
Community-based studies
Exposure to benzene and/or toluene was investigated in 401 cases of various
serious blood disorders and 124 controls sampled from the same general hospital in
Lyon, France (Girard & Revol, 1970). The prevalence of exposure was
significantly higher among patients with acute leukaemia, CLL and aplastic
anaemia than in the comparison group. The majority of the exposed patients had
worked in small workshops where the main sources of exposure were reported to
be cleaning fluids and paint and glue thinners.
Ishimaru et al. (1971) interviewed 303 matched pairs of controls and cases of
leukaemia (not further specified) with onset from 1945-67 in Hiroshima or
Nagasaki in Japan. The OR was 2.5 (p <0.01) among those with a history of any of
11 occupations with the potential for frequent exposure to benzene or x-rays and
showed a positive trend with the length of time in those occupations.
Eighteen (36%) out of 50 working men with ANLL seen at a hospital in Lund,
Sweden, were occupationally exposed to petroleum products or vehicle exhaust
fumes through occupation as petrol stations attendants, drivers or operators of
excavators or power saws (Brandt et al, 1978). By comparison, similar exposure
patterns occurred in only 10% of three outpatient control groups (p = 0.0002),
including a group of male patients with CML or CLL (p = 0.006), or 10-11% of the
general male population in the region.
Linos et al. (1980) compared 138 cases of acute or chronic leukaemia (not further
specified) that occurred in residents in a county in Minnesota, USA between 1955-
74 with 276 controls, with regard to past occupational and chemical exposure. The
OR for exposure to benzene was not significantly elevated (3.34 (0.60-27.60)).
In a study of 131 cases of MM, 111 cases of CLL and 431 controls resident in a
rural woodland district in central Sweden, Flodin et al. (1987, 1988) observed an
association with occupational exposure to exhaust fumes from diesel and petrol
engines, including tractors and chainsaws. The OR was 2.1 (1.2-3.9) for MM and
2.2 (1.2-4.2) for CLL.
Another Swedish study of 125 cases of acute leukaemia (including 97 AML and 24
ALL cases) and an equal number of controls found a large excess risk for
professional painters exposed to solvents that would have contained benzene as an
impurity (OR = 13 (2-554) (Lindquist et al, 1987). There was also an excess risk
among professional drivers, with an OR = 3.0 (1.1-9.2). The OR reached 5.0 (95%
CI not stated; p <0.05) for those who had been drivers for >5 years in their lifetime
or >1 year during the 5-20-year period prior to diagnosis and remained after
adjustments for exposure to organic solvents, smoking and therapeutic x-ray
treatment (Lindquist et al, 1991).
A study of 475 cases of lymphoma, leukaemia and MM in white male residents in
Missouri, USA, and 1425 controls found an elevated risk of leukaemia in
mechanics (OR = 4.79 (1.42-16.18)) (Brownson & Reif, 1988).
Richardson et al. (1992) conducted an interview study of occupational risk factors
of acute leukaemia in French adults, based on 31 cases of ALL, 154 cases of AML
and 513 controls. A significant relationship was observed between AML and high
or medium exposure to benzene (OR = 3.6 (1.7-7.7)). For ALL and AML
combined, the OR for any exposure to benzene was 1.3 (0.8-2.3), whereas it was
2.8 (1.3-5.9) for high or medium exposure.
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98
In an interview study of 622 white males with NHL and 1245 controls drawn from
the general population in Iowa and Minnesota, USA during 1980-83, there were no
indications that industrial exposures were a major determinant for NHL (Blair et al,
1993). The OR for benzene exposure was close to unity, but did increase slightly
with intensity of exposure (lower intensity: OR = 1.1 (0.8-1.4); higher intensity:
OR = 1.5 (0.7-3.1)).
In a study of 86 cases of AML, CML or MDS in residents in Turin, Italy, there was
a marginally elevated risk of leukaemia/MDS in vehicle mechanics (OR = 2.7
(0.97-7.6)) and truck and other drivers (OR = 2.7 (0.8-9.6)), but no association with
exposure to benzene (Ciccone et al, 1993).
A French, hospital-based case-control study of 226 male cases of hairy cell
leukaemia and 425 matched controls found no association between occupational
exposure to benzene and this rare B-lymphoid chronic leukaemia (Clavel et al,
1996).
A recent review by Savitz & Andrews (1997) identified 12 additional community-
based case-control studies of benzene and cancer of the blood and lymphatic
system, none of which reported any association between the two.
Childhood leukaemia
Leukaemia is the most common cancer in children under the age of 15 (Shu, 1997).
A number of case-control studies have explored the potential relationship between
childhood leukaemia and parental exposure to agents that might be toxic to the
unborn or breast-fed baby and/or the germ cells of the parents.
Some of these studies have suggested a link between childhood leukaemia and pre-
conceptional occupational exposure of the father to solvents, petroleum products,
motor vehicle exhaust fumes, benzene, or plastic monomers or polymers (Buckley
et al, 1989; Fabia & Thuy, 1974; McKinney et al, 1991; Shu et al, 1999; Vianna et
al, 1984). Others have found a weak association with maternal employment in jobs
with the potential for exposure to various chemicals including benzene, petrol,
solvents and thinners, paints and/or plastic monomers or polymers (Shu et al, 1988,
1999; van Steensel-Moll et al, 1985).
A study of 123 cases of childhood leukaemia and an equal number of matched
controls found a significant, dose-related elevation in the risk of leukaemia for
children whose parents burned incense in the house during pregnancy or lactation
(Lowengart et al, 1987). Incense stick has been reported to emit the same quantity
of benzene in smoke as tobacco and herbal cigarettes (L鰂roth et al, 1991).
In a study of 97 cases of childhood leukaemia (78 of whom had ALL) and 259
matched controls from Denver, USA, Pearson et al. (2000) found an association
between childhood leukaemia and proximal high traffic streets with traffic counts
20,000 vehicles per day (OR = 8.28 (2.09-32.80)).
Skin cancer
In a study of 307 cases of non-melanoma skin cancer (basal and/or squamous cell
carcinoma) and 229 controls resident in Texas, USA, the most important risk
factors were red hair, fair skin, outdoor sun exposure, and a family history of skin
cancer (Gamble et al, 1996). Employment at any time in the petroleum industry
was associated with a slightly elevated risk of developing concurrent basal and
squamous cell carcinomas (OR = 2.10 (1.08-4.09)).
Benzene 99
In a Dutch study of 140 cases with non-metastasised melanoma and 181 controls
with other types of malignancy, increased risks were found for subjects ever
employed in the electronics, metal and transport and communication industries
(Nelemans et al, 1993). However, they were not statistically significant and there
were no trends for duration of employment or latency. Also, there was no increase
in risk for workers in the chemical industry.
The American Cancer Society enrolled 1.2 million randomly selected people in a
study of life style and environmental factors in relation to cancer mortality, 2780 of
whom had a history of or developed melanoma during the 6-year study follow-up
period (Pion et al, 1995). These cases were compared with controls selected from
the remaining people enrolled on a 1:3 basis and matched for age, sex, race, and
geographic location. In men, the risk of melanoma was elevated in high-paying
versus low-paying jobs (OR = 1.58; p <0.001) and in white-collar versus blue-
collar jobs (OR = 1.33; p <0.001), but unrelated to outdoor versus indoor
occupations. In women, the findings were inconclusive. The only specific work-
related risk factor was exposure to x-rays. Other large community-based studies in
Australia, Britain and Sweden came to similar results (Burnley, 1997; V錱er?et al,
1990).
Other cancers
G閞in et al. (1998) conducted a community-based case-control study of 19 specific
cancers excluding leukaemia in 3730 men and 533 controls aged 35-70 years and
resident in Montreal, Canada. Their exposure to various workplace chemicals
including benzene, toluene, xylenes and styrene was estimated through interviews
and from workplace records. There were 737 subjects, mainly mechanics, service
station attendants and shoe workers, who had been exposed to benzene, usually
with concomitant exposure to toluene and xylenes. However, there was no evidence
that the risks of common cancers such as those of the gastrointestinal tract, lungs,
prostate, bladder or kidney were related to exposure to any of the chemicals under
investigation. For NHL (215 cases) and melanoma (103 cases), the ORs for
benzene exposure were <1.00.
The industry-based study by Wong et al. (1999) mentioned above under cancer of
the blood and lymphatic system also included 12 cases of kidney cancer. There was
no difference between cases and controls with regard to duration of exposure or to
cumulative or peak exposures to hydrocarbons.
Petralia et al. (1999) studied the relationship between the risk of pre-menopausal
breast cancer and exposure to benzene or polycyclic aromatic hydrocarbons in 301
cases and 316 controls sampled from two counties in New York State between
1986-91. There were 55 breast cancer cases and 35 controls who had been exposed
to benzene, mainly through employment as laboratory technicians, painters,
sculptors, craft-artists, or assemblers in the motor vehicle industry. Following
adjustment for age, years of education, age at first birth, age at menarche, history of
benign breast disease, history of breast cancer in a first-degree relative, body mass
index, and months of lactation, four variables relating to benzene had ORs that
reached or approached statistical significance. These were duration of exposure 4
years (2.57 (1.23-4.73)); medium-to-high probability of exposure (1.95 (1.14-
3.33)); low average exposure intensity (2.36 (1.30-4.30)); and medium-to-high
cumulative exposure (1.93 (1.00-3.72)).
In Denmark, Hansen (2000) conducted a nationwide register-based case-control
study on primary breast cancer in men, which included 230 cases and 12,880
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100
controls. Allowing for a lag time 10 years and after adjustment for socio-
economic status, the OR was 2.5 (1.3-4.5) in all men with >3 months of
employment as car mechanic or petrol station worker and 5.4 (2.4-11.9) in men
who were <40 years old when first employed in those occupations. Exposure to
benzene was not assessed.
Conclusions
While the case-control studies reviewed above have limitations in statistical power
and study quality, there are several which indicate that occupation and/or benzene
exposure is associated with an increased risk of cancer of the blood and lymphatic
system, including, but not limited to AML and other leukaemias. Positively
identified risk factors include employment in upstream petroleum production, at
petroleum terminals, on deck on chemical or petroleum product tankers, and as a
mechanic, machinist, chemical worker, chemist, painter, driver or logger. The
studies by Health Watch (1998) and Richardson (1992) found that the risk was
significantly elevated at relatively high, but not at lower levels of exposure to
benzene.
There are some indications that parental exposure to benzene and in particular
maternal exposure during pregnancy may be linked to childhood leukaemia, but the
overall evidence for this association is limited at present. Other tentative findings
suggest a relationship between the risk of breast cancer and exposure of female
workers to benzene on the one hand and between male breast cancer and exposure
to petrol and vehicle exhaust on the other.
11.6.3 Ecological studies
Leukaemia and car traffic variables
Robinson (1982, 1991) found a strong relationship between leukaemia mortality
and vehicle usage (as monitored by the annual rate of vehicle fatalities) in
Australia, France, Germany, Italy, Japan, The Netherlands, UK and USA. In a
study of all incident childhood cancer in Denver, Colerado, USA, between 1976-
83, Savitz & Feingold (1989) found a statistically significant association between
traffic density at the place of residence at the time of diagnosis and the risk for all
leukaemia combined. In a sample of 22 British counties, Wolff (1992) found a
significant correlation coefficient between the incidence of AML, lymphoma, ALL,
CLL and low-grade NHL for the years 1984-88 and the number of cars per
household reported in the 1981 Great Britain Population Census.
Swaen & Slangen (1995) found a non-significant, inverse relationship between
leukaemia mortality and petrol consumption in 19 European countries, but a weak
positive association between the incidence of myeloid leukaemia and the
consumption of petrol per km2. However, both findings could be due to unrelated
factors such as changes in prognosis or country differences in leukaemia case
ascertainment. As such, the authors concluded that their study did not support an
association between petrol consumption and leukaemia incidence or mortality.
Nordlinder & J鋜vholm (1997) compared the 1975 car density in Swedish local
government areas with the 1975-1985 cumulative incidence of ALL, AML, CML
and NHL in persons under 25. None of these showed a significant correlation with
car density, although the combined group of areas with >5 cars/km2 had a higher
rate of AML than those with <5 cars/km2 (95% CI for the difference: 0.1-4.0
cases/106 person-years).
Benzene 101
Leukaemia and industry emission variables
There was an excess mortality rate between 1950-69 from childhood leukaemia and
young adult Hodgkin's disease and lymphoma among residents in the heavily
industrialised New Jersey-New York-Philadelphia Metropolitan Region compared
to USA as a whole (Greenberg et al, 1980). However, other early studies of
populations residing in the vicinity of petroleum refineries and chemical plants
have not suggested links with cancers of the blood and lymphatic system (Blot et
al, 1977; Hearey et al, 1980; Hoover et al, 1975; Kaldor et al, 1984).
A more recent study of an area within a radius of 3.0 km of a large petrochemical
plant in South Wales, UK, compared the 1974-91 incidence of leukaemia and
lymphoma with onset before age 25 among study area residents with those in the
regional population (Lyons et al, 1995). There were no statistically significant
differences, although the number of observed cases was higher than expected for all
disease types except myeloid leukaemia. Data from ambient monitoring for
benzene around the site showed monthly peak values varying from 4-16 ppb.
11.7 The Illawarra leukaemia cluster
The Illawarra leukaemia cluster refers to a group of 12 cases of leukaemia that
occurred in 1989-96 in three contiguous suburbs bordering the Port Kembla
steelworks near Wollongong, New South Wales (Westley-Wise et al, 1999). There
were 3 cases of AML, 3 of CML and 6 of ALL. All cases were under 44 years of
age at the time of diagnosis and nine were 20 years of age. Four attended the same
local high school in the late 1980s, three of them in the same school year. Using the
rest of the region as reference population, only 3.49 cases were expected,
corresponding to a SIR of 3.44 (1.42-6.92).
The regional health authority launched an investigation which examined a wide
range of possible explanations for the cluster, including benzene emissions from
the coking ovens and coal gas by-product plant at the steelworks. It was estimated
that ambient air levels of benzene had averaged up to 3 ppb since 1970, although
the mean levels measured in 1996 did not exceed 1 ppb within 1.6 km from the
plant. As this is less than one-thousandth of the level at which leukaemia risk has
been identified in occupational epidemiological studies, the authors concluded that
the cause of the cluster was uncertain, although an association with chemical
exposures could not be totally excluded. The odds that it was due to chance were
calculated at 1 in 4-8000 (Westley-Wise & Hogan, 1997).
11.8 Summary and conclusions
There is anecdotal evidence that acute exposure to benzene vapours causes
dizziness and other CNS effects at concentrations above 25 ppm and eye, mucous
membrane and skin irritation at levels above 30-60 ppm. Furthermore, aspiration of
liquid benzene has been observed to cause lung oedema and bleeding. Deaths from
cardio-respiratory arrest have occurred following short-term inhalation of 20,000
ppm benzene, or from ingestion of a single dose of 125 mg benzene per kg BW.
Several studies demonstrate that repeated exposure to benzene may induce bone
marrow depression, cause damage to genetic material and induce leukaemia,
specifically AML. Some studies also point to an association between benzene
exposure and the risk for lymphoma, specifically NHL and MM. For bone marrow
depression, the best estimate for a LOAEL is 7.6 ppm (TWA8), based on current
Priority Existing Chemical Number 21
102
data. An appropriate NOAEL has not been determined, although studies with
various limitations indicate that it is likely to be >0.5 ppm (TWA8). Dose-related
structural or numerical chromosome aberrations have been detected in peripheral
LC of workers exposed to benzene levels above 10 ppm (TWA8), but a threshold
level has not been identified. The risk of developing leukaemia increases with
exposure and has been shown to be significantly elevated above, but not below, a
cumulative exposure of 50 ppm-years, corresponding to an average occupational
exposure of 1.25 ppm (TWA8) over 40 years. However, this finding derives from a
single cohort study with insufficient statistical power to rule out the possibility of
some increase in leukaemia risk at lower exposures.
In addition, some studies suggest an association between repeated exposure to
benzene or benzene-containing products and several other adverse health effects,
including menstruation disorders, spontaneous abortions, melanoma and breast
cancer in adults and reduced birth weight and leukaemia in the children of exposed
parents. However, considering the multiple exposure circumstances in most studies
and the limited consistency of the findings reviewed above, the human database
does not in itself suffice to establish a causal relationship between these effects and
benzene exposure.
Benzene 103
12. Modes of Action
While a general overview of benzene metabolism has been presented in Section 9,
this section presents a review of the evidence for the molecular basis of the action
of benzene metabolites. Several reviews of benzene metabolism and the proposed
mechanisms of toxicity have been published (Ross, 1996; Snyder, 2000; Snyder et
al, 1993; Snyder & Hedli, 1996; Yardley-Jones et al, 1991).
Exposure to benzene can result in haematotoxicity, immunotoxicity and
carcinogenicity in humans and animals. Haematotoxicity resulting from chronic
benzene exposure can present as anaemia, aplastic anaemia, leukopenia,
lymphocytopenia, thrombocytopenia, or pancytopenia (Aksoy, 1989). The principal
carcinogenic response in humans to chronic benzene exposure is leukaemia while
other animals tend to produce solid tumours in specific organs. While the liver is
the initial site for the biotransformation of benzene, hepatotoxicity is not a
consequence of benzene exposure. However, a number of studies have shown that
for benzene to produce haematotoxicity in animals it must first be metabolised by
the liver (Andrews et al, 1977; Sammett et al, 1979). Subsequent accumulation of
the major hepatic metabolites, phenol, hydroquinone and catechol, occurs in the
bone marrow where they are known to persist for varying durations after exposure
to benzene ceases (Rickert et al, 1979). Longacre et al. (1981) observed that strains
of mice that exhibit greater sensitivity towards benzene accumulate more benzene
metabolites (water-soluble and covalently bound) in bone marrow compared to less
sensitive strains. However, administration of specific benzene metabolites to test
animals has failed to reproduce the characteristic toxicity of benzene although co-
administration of phenol and hydroquinone has been shown to mimic its
haematotoxic effects (Eastmond et al, 1987). These data suggest that phenolic
metabolites of benzene in combination and not the parent molecule are responsible
for the haematotoxicity of benzene. The data further suggest that subsequent
biotransformation of the hepatic metabolites to reactive intermediates is required
and that this occurs within the bone marrow and those animal organs exhibiting
solid tumours.
12.1 Activation of benzene metabolites
In order for the phenolic metabolites of benzene to exert their toxic effect on bone
marrow, they must undergo activation to their oxidised forms. Once activated, they
can participate in covalent binding reactions with macromolecules. Several studies
have identified the presence of peroxidase enzymes in bone marrow and other
tissues as the primary mechanism by which activation of benzene phenolic
metabolites is achieved (Eastmond et al, 1986; L関ay et al, 1993). The peroxidases
are a diverse class of enzymes that catalyse the general reaction:
Donor + H2O2 oxidised donor + 2H2O.
While peroxidases generally act to detoxify peroxides, including hydrogen
peroxide, that form within cells as a result of several metabolic reactions, a number
of specialised peroxidases with other functions have evolved. In particular, the
leukocytes of several species, including humans, have been shown to possess large
amounts of a specific form, myeloperoxidase (Bainton et al, 1971; Himmelhoch et
al, 1969). In concert with the leukocyte nicotinamide adenine dinucleotide
Priority Existing Chemical Number 21
104
phosphate (NADPH) oxidase system that causes hydrogen peroxide to be produced
(Patriarca et al, 1971), myeloperoxidase plays a crucial role in the host defence
system by producing a potent microbicidal oxidant that protects the host from
microorganisms. Immature leukocytes in the bone marrow generally have higher
levels of myeloperoxidase than circulating mature cells (Bainton et al, 1971).
Consequently, bone marrow has considerable capacity to metabolise suitable
electron donors including the benzene metabolites, phenol, hydroquinone, catechol
and 1,2,4-trihydroxybenzene, to reactive species.
12.1.1 Activation of phenol
Incubation of phenol with human leukocyte lysates, which contain
myeloperoxidase, have demonstrated the formation of reactive intermediates that
covalently bind to macromolecules in the presence of hydrogen peroxide as a co-
oxidant (Eastmond et al, 1986; Smith et al, 1989). Eastmond et al. (1986)
concluded that although 4,4'-biphenol and diphenoquinone were identifiable
reaction products derived from the oxidation of phenol, only 6% of the covalent
binding could be attributed to diphenoquinone with most of the covalent binding
observed due to other reactive species, possibly the phenoxy radical or oxidation
products of 2,2'-biphenol or 4,4'-biphenol. However, in the presence of
hydroquinone, phenol appears to undergo a recycling process such that the initial
phenoxy radical is reduced to phenol by transferring an electron to hydroquinone
(Smith et al, 1989), thus limiting the formation of biphenol derivatives.
12.1.2 Activation of hydroquinone and catechol
Under physiological conditions, hydroquinone, catechol and 1,2,4-
trihydroxybenzene can undergo autoxidation to their respective semiquinone and
quinone forms (Brunmark & Cadenas, 1989) or their oxidation can be facilitated by
the presence of a peroxidase and hydrogen peroxide (Sadler et al, 1988; Schlosser
et al, 1989; Smith et al, 1989). Quinones are chemically reactive species capable of
depleting intracellular glutathione, promoting lipid peroxidation and forming
covalent adducts with macromolecules (Bolton et al, 2000; Irons, 1985; Monks et
al, 1992). Several studies have shown that hydroquinone and catechol are readily
oxidised by human myeloperoxidase (Eastmond et al, 1986; Sadler, et al, 1988) and
it has been observed that the oxidation of hydroquinone to benzoquinone by
peroxidase enzymes is enhanced by the presence of excess phenol which acts as a
co-oxidant obviating the need for hydrogen peroxide to drive the reaction (Smith et
al, 1989; Subrahmanyam, et al, 1990). Hydroquinone was found to be metabolised
by activated human neutrophils to covalent-binding species and the amount of
binding could be increased by approximately 70% by the addition of phenol
(Eastmond et al, 1987). Subrahmanyam et al. (1990) reported that the presence of
phenol enhanced the covalent binding of [3H]-hydroquinone metabolites to
macromolecules of mouse blood and bone marrow, but not to the kidneys or liver.
It was further noted that hydroquinone enhanced binding of [3H]-phenol
metabolites in blood, bone marrow and the kidneys but inhibited binding in the
liver. In contrast, catechol did not enhance [3H]-hydroquinone metabolite binding.
Sadler et al. (1988) observed that the oxidation of catechol by human neutrophil
peroxidases (myeloperoxidase) resulted in the formation of 1,2-benzosemiquinone
and 1,2-benzoquinone. Bhat et al. (1988) found that the addition of [14C]-catechol
to rat or human bone marrow cells resulted in the formation of a glutathione-
conjugate and covalent binding of radiolabel to protein. Both conjugate formation
and the binding of radiolabel were substantially increased by the presence of
Benzene 105
hydrogen peroxide or phenol, however, protein binding could be markedly
decreased by the presence of exogenous glutathione (GSH) or hydroquinone.
12.1.3 Role of cyclooxygenase
In addition to activation by peroxidases, phenol and hydroquinones can be
activated by prostaglandin H synthase (cyclooxygenase), an enzyme with
oxygenase and endoperoxidase activity (Markey et al, 1987; Schlosser et al, 1989).
Acting as an endoperoxidase, the enzyme requires an oxidant as a co-substrate
which phenol or hydroquinones can replace (Markey et al, 1987). Prostaglandin H
synthase is present in a number of bone marrow-derived cells including
monocyte/macrophage populations and platelets and converts arachidonic acid to
several prostaglandins including prostaglandin E2 (PGE2). PGE2 plays a major role
in the inhibition of progenitor cell proliferation and differentiation (Gentile and
Pelus, 1987). In vitro, both phenol and hydroquinone are activated by cell lysates
containing prostaglandin H synthase or by the purified enzyme and in the presence
of arachidonic acid or hydrogen peroxide (Schlosser et al, 1989).
The role of prostaglandin H synthase activity has been demonstrated in a number of
mouse strains (B6C3F1, DBA/2 and C57BL/6) where it was shown that bone
marrow toxicity could be reduced by prior treatment of the animals with non-
steroidal anti-inflammatory drugs (aspirin, indomethacin or meclofenamate) that
inhibit prostaglandin H synthase activity (Gaido and Wierda, 1987; Kalf et al,
1989). Pirozzi et al. (1989) further demonstrated that benzene-induced bone
marrow depression and micronucleus formation in erythrocytes of C57B1/6 mice
could be prevented by the co-administration of indomethacin and that protection
was achieved at doses that did not inhibit cytochrome P450 or myeloperoxidase
activity.
The bio-activation of catechol by prostaglandin H synthase activity in rat bone
marrow appears to be limited as the addition of arachidonic acid provided only a
small but significant (p<0.05) increase in covalent binding which was of limited
duration (Bhat et al, 1988).
12.1.4 Formation of reactive oxygen species
In addition to the formation of semiquinone and quinone species, the oxidation of
hydroquinones results in the formation of reactive oxygen species. Initially,
molecular oxygen is reduced to superoxide anion which, by dismutation, is
converted to hydrogen peroxide (Figure 12.1). In the presence of transition metal
ions (for example, iron) the very reactive hydroxyl radical can form. These reactive
species can promote the oxidation of protein and DNA bases, induction of
chromosomal aberrations, lipid peroxidation and the modulation of cellular
functions.
While hydroquinone and its semiquinone radical can both reduce molecular oxygen
to superoxide, Sadler et al. (1988) found superoxide production by catechol to be
limited to the first one electron reduction step to 1,2-benzosemiquinone with
molecular oxygen being unable to effect the subsequent oxidation of the
semiquinone to the quinone form. In contrast, 1,2,4-benzenetriol undergoes rapid
autoxidation to yield hydrogen peroxide (Brunmark & Cadenas, 1988).
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Figure 12.1. Redox cycle of hydroquinone with formation of reactive oxygen
species and biological effects
NQO1
NADPH-Cytochrome
NADPH-Cytochrome
reductase
reductase or
Disproportionation
.
OH O O
Autoxidation
Autoxidation
/Peroxidase
/Peroxidase
Hydroquinone 1,4-Benzoquinone
.-
.-
OH OH O
O2 O
O
O2 2
2
Dismutation/
DNA adducts
Superoxide dismutase H2O2
DNA oxidation
3+
Fe
Protein oxidation
Lipid peroxidation
.
Modulation of cellular function
OH
The detoxification of quinones can be achieved by a two-electron reduction to their
fully reduced forms. Two enzymes involved in the reduction of quinones are
NADPH-cytochrome reductase and NAD(P)H:quinone oxidoreductase (NQO1;
DT-diaphorase; Lind et al, 1982). In the case of NADPH-cytochrome reductase,
reduction of the quinone to a semiquinone is achieved by a one-electron transfer to
give a semiquinone and a second electron is transferred to molecular oxygen to
yield the superoxide anion. The resulting semiquinone is then free to autoxidise to
the quinone producing more superoxide. However, it has been proposed that redox
cycling of the semiquinone could not be maintained by NADPH-cytochrome
reductase at physiological pH due to protonation of the semiquinone thus
minimising superoxide production (Boersma et al, 1994). In the case of NQO1,
reduction to the hydroquinone is achieved by a simultaneous two-electron transfer
to the quinone with no reduction of molecular oxygen. The redox cycle for
hydroquinone, the role of NADPH-cytochrome reductase and NQO1 and the
biological effects of these processes are illustrated in Figure 12.1.
In cells that possess both peroxidase and NQO1 activities, the ratio of the two
enzymes may determine the extent to which reactive metabolites form. Thus a high
intracellular myeloperoxidase/NQO1 ratio, such as occurs in human stroma and
CD34+ bone marrow progenitor cells, may result in a greater risk of benzene-
induced cellular toxicity (Ross et al, 1996b). Although characterisation of NQO1
activity in primary cultures of mouse bone marrow stromal cells was found to be
low, the enzyme was shown to be inducible and induction of the enzyme conferred
protection against hydroquinone-induced toxicity (Twerdok et al, 1992).
Conjugation reactions, for example with GSH, can enhance the ability of
hydroquinones to autoxidise. Glutathionyl hydroquinone, identified as a urinary
benzene metabolite (Nerland & Pierce, 1990), was found by Brunmark & Cadenas
(1988) to autoxidise at a rate 8-fold faster than hydroquinone. Rao (1996)
Benzene 107
concluded that, in vitro, glutathionyl hydroquinone acted as a potent pro-oxidant
based on its ability to degrade DNA.
Reactive oxygen species may also form due to the reduction of molecular oxygen
by the action of cytochromes P450. Johannson & Ingelman-Sundberg (1983)
observed that benzene could be directly oxidized to phenol by hydroxyl radicals
derived from the reduction of molecular oxygen by microsomal cytochrome P450
activity or reconstituted enzyme systems. Similarly, Kahn et al. (1990) detected the
presence of hydroxyl radicals during the NADPH-dependent metabolism of
benzene by rat bone marrow microsomal preparations.
12.2 Reactivity of benzene metabolites
Results derived from in vivo and in vitro studies indicate that a number of
mechanisms contribute to the cytotoxicity, genotoxicity and carcinogenicity of
benzene metabolites. Cytotoxicity can arise due to depletion of intracellular GSH
and changes in intracellular redox status (Ludewig et al, 1989; Rao & Snyder,
1995; Witz, 1985) and covalent binding of benzene metabolites to macromolecules
(Latriano et al, 1989; Lutz and Schlatter, 1977; Mazzullo et al, 1989; Snyder et al,
1987). Metabolites suspected of contributing to the genotoxicity and
carcinogenicity of benzene include benzene oxide, hydroquinone, catechol, 1,2,4-
trihydroxybenzene and trans,trans-muconaldehyde. The effects induced by these
metabolites comprise DNA base alterations, chromosome structural aberrations and
aneuploidy. However, the metabolite concentrations at which many of these effects
have been shown to occur in vitro are higher than those expected to occur in vivo.
12.2.1 Genotoxicity
Several studies have demonstrated the formation of DNA adducts after incubation
of benzene metabolites with purified DNA. Hydroquinone when incubated with
calf thymus DNA resulted in the formation of deoxycytidine (Pongracz et al, 1990),
deoxyadenosine (Pongracz & Bodell, 1991) and deoxyguanosine adducts (Jowa et
al, 1990). Gut et al. (1996) were able to demonstrate the formation of the N-7
guanine adduct on exposure of calf thymus DNA to benzene oxide under in vitro
conditions while Latriano et al. (1989) found trans,trans-muconaldehyde to form
adducts with deoxyguanosine. In addition to nuclear DNA, in vitro studies have
shown mitochondrial DNA, derived from bone marrow mitoplasts, to undergo
alkylation by benzene metabolites (Kalf et al, 1985; Snyder et al, 1987).
Under cellular conditions, a comparison of the ability of benzene metabolites to
induce DNA adduct formation in HL-60 cells, a promyelocytic leukemia cell line,
found hydroquinone to be 7-9 times more effective at inducing such adducts than
catechol or 1,2,4-trihydroxybenzene and that a correlation existed between adduct
formation and cytotoxicity. Co-incubation of hydroquinone with either catechol or
1,2,4-trihydroxybenzene produced a synergistic effect that was 3-6 times greater
than the added effects of each metabolite. It was further observed that DNA
adducts form in the presence of benzene metabolite mixtures which are not
observed when cells are incubated with the individual metabolites, leading the
authors to suggest that other processes leading to adduct formation may be
involved (L関ay & Bodell, 1992; L関ay et al, 1991). Chenna et al. (1995)
subsequently identified an enzyme with glycosylase activity that excises
deoxycytidine and deoxyadenosine adducts of benzoquinone from DNA.
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It is noteworthy that transfected HL-60 cells expressing a high level of NQO1
activity exhibited lower levels of DNA adduct formation when exposed to
hydroquinone compared to non-transfected HL60 cells which are deficient in
NQO1 activity. Similarly, C15 cells, a myeloperoxidase-deficient HL-60 subline,
produced lower levels of DNA adducts with hydroquinone compared to HL-60
cells which normally express high levels of myeloperoxidase (Wiemels et al, 1999).
The ability of hydroquinone species to induce mutations has been demonstrated by
Joseph et al. (1998). In a series of in vitro experiments, it was demonstrated that
sequence-specific frame shift mutations could be caused by hydroquinone, but not
semiquinone, benzoquinone or reactive oxygen species, in the supF tRNA gene. It
was further demonstrated that BALBc/3T3 cells undergo transformation by
hydroquinone (15 礛) and that the frequency of transformation could be increased
by a tumour promoter. Such initiated cells produced tumours with 100% frequency
when injected into severe combined immunodeficient (SCID) mice. Sakai et al.
(1995) previously had shown that benzoquinone caused initiation in a two-stage
model of carcinogenesis using BALB/3T3 cells.
Mueller et al. (1987) detected the alkylation product of benzene oxide, N-7-
phenylguanine, in the urine of rats exposed to benzene (500 ppm) for 8 h while
Norpoth et al. (1996) detected several benzene-derived urinary guanine adducts
following the administration of benzene to rats. However, it should be noted that
the presence of N-7-phenylguanine in the urine does not provide sufficient
evidence that the adduct is derived from DNA excision-repair activities. The
presence of benzene-induced DNA adducts has been detected in the tissues of rats
dosed with [14C]-benzene (Lutz and Schlatter, 1977; Mazzullo et al, 1989) although
the nature of the adducts was not investigated. However, Reddy et al. (1989b)
found only equivocal evidence for the in vivo formation of aromatic DNA adducts
in the bone marrow, liver, kidney and mammary gland of benzene-treated female
Sprague-Dawley rats. DNA isolated from Zymbal glands was found to contain 4
adducts per 109 DNA nucleotides, although the adducts did not correspond to major
adducts described in in vitro studies. Thus it was concluded that DNA-quinone
adduct formation in the rat is not extensive, possibly due to the efficient elimination
of quinones by other mechanisms. In addition to forming DNA adducts in the bone
marrow of experimental animals, benzene exposure produced DNA adducts in the
livers of male mice (Lutz and Schlatter, 1977); however, liver tumours were not
observed in 2-year carcinogenicity studies of these animals (NTP, 1986).
The mutation frequency of V75 Chinese hamster cells increased in a dose-
dependent manner after treatment for 1 h with benzoquinone, an effect that was
found to be independent of intracellular GSH status and observed at low (< 10 礛)
concentrations. The frequency of micronucleated cells was also increased by
benzoquinone but only at concentrations greater than 20 礛. In contrast,
benzoquinone did not induce sister chromatid exchanges at any concentration up to
100 礛 (Ludewig et al, 1989).
As described in Sections 10.6 and 11.5, several studies have demonstrated
chromosomal aberrations in experimental animals and humans following exposure
to benzene. While the administration of benzene to CD-1 mice resulted in
micronuclei formation, treatment with either phenol, hydroquinone or catechol
failed to induce micronuclei (Gad-el-Karim et al, 1985). Barale et al. (1990)
demonstrated, in vivo, a synergistic effect on micronuclei formation in CD-1 mice
bone marrow cells by the concurrent administration of hydroquinone and phenol.
Benzene 109
Lewis et al. (1988) reported that hydroquinone, under in vitro conditions, caused
DNA to form single- and double-strand breaks by a mechanism that was
independent of reactive oxygen species. In contrast, catechol did not induce DNA
damage. These investigators further observed that DNA could be degraded by
1,2,4-trihydroxybenzene, an effect inhibited by scavengers of reactive oxygen
species. When tested together in vitro, hydroquinone and catechol produced a
synergistic effect on micronuclei formation in human lymphocytes, possibly by
interfering with mitotic spindle function and disturbing chromosome segregation
(Robertson et al, 1991). Benzoquinone has also been reported to interfere with
microtubule assembly by blocking a thiol-sensitive binding site (Irons et al, 1981).
12.2.2 Oxidative stress
The formation of reactive oxygen species is a normal part of cellular biochemistry
and is considered to be an important component of intracellular signalling
processes, including mediating signal transduction within haematopoietic cells
initiated by growth factor signals (Sattler et al, 1999). However, exposure of
biological systems to excessive levels of reactive oxygen species results in the
induction of oxidative stress. Oxidative stress can induce oxidative modification of
DNA bases and chromosomal abnormalities, depletion of intracellular GSH,
changes in intracellular redox status, peroxidation of lipids, oxidation of proteins
and modulation of cellular functions. The role of oxidative stress in benzene-
mediated toxicity has been extensively reviewed by Subrahmanyam et al. (1991).
Rao & Snyder (1995) examined the effects of hydroquinone, benzoquinone and
1,2,4-trihydroxybenzene (50 礛) on several parameters of antioxidant defence
function of HL-60 cells. The three metabolites did not induce the cells to generate
superoxide anion or nitric oxide but did produce detectable levels of hydrogen
peroxide. Intracellular GSH levels were depleted by hydroquinone and 1,2,4-
trihydroxybenzene but not benzoquinone.
The presence of lipid peroxidation products was found to increase in rat tissues
following the administration of benzene (Khan et al, 1984) while urinary levels of
malondialdehyde, a biomarker of lipid peroxidation, were elevated in rats receiving
hydroquinone (Ekstr鰉 et al, 1988). The presence of intracellular peroxidation
products has been detected in HL60 cells following treatment with either 1 礛
benzoquinone or 10 礛 hydroquinone (Hiraku & Kawanishi, 1996). Several
studies have identified the presence of 8-hydroxydeoxyguanosine (8-OHdG) as a
sensitive biomarker of DNA damage due to oxidative stress (Kasai & Nishimura,
1984, 1986; Shigenaga et al, 1989). In two occupational studies in workers known
to have benzene exposure, a dose-response relationship was demonstrated between
the exposure level and urinary 8-OHdG levels (Lagorio et al, 1994b, Nilsson et al,
1996). However, the presence of 8-OHdG in the urine is not conclusive evidence of
DNA excision-repair activities in response to oxidative modification of DNA.
Benzoquinone species and trans,trans-muconaldehyde readily react with GSH
(Brunmark & Cadenas, 1988; Rao et al, 1982) which can lead to depletion of
intracellular GSH levels and changes in intracellular redox status. Treatment of
V79 Chinese hamster cells with benzoquinone for 1 h resulted in decreased GSH,
NADPH and nicotinamide adenine dinucleotide levels but only at cytotoxic
concentrations at or above 100 礛 (Ludewig et al, 1989). Ekstr鰉 et al. (1988)
found rat hepatic GSH levels to be depleted after administration of hydroquinone
by gavage while the administration of trans,trans-muconaldehyde to mice for 10 or
16 days resulted in decreased hepatic sulfhydryl levels (Witz et al, 1985).
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The growth of HL-60 cells was found to be stimulated by the presence of
hydroquinone within the range of 10-40 礛. Similarly, the incorporation of [3H]-
thymidine was enhanced by hydroquinone, benzoquinone or 1,2,4-benzenetriol.
However, the effects produced by the three metabolites could be eliminated if the
cells were pre-incubated with catalase, an antioxidant specific for hydrogen
peroxide. The effects of hydroquinone and benzoquinone could be mimicked by
reactive oxygen species produced by a xanthine/xanthine oxidase system. It was
further observed that while hydroquinone or benzoquinone did not reduce the cell
cycle time they did increase the number of cells entering into S-phase from G0/G1
phase (Wiemels & Smith, 1999). The role of reactive oxygen species, and in
particular hydrogen peroxide, has been further explored by Sattler et al. (1999).
These investigators found haemopoietic growth factors to induce increased levels
of reactive oxygen species in MO7e cells, a growth factor-dependent human
megakaryocytic cell line. Treatment of these cells with either growth factors or
hydrogen peroxide resulted in increased tyrosine phosphorylation of cellular
proteins, a key step in intracellular signalling processes.
12.2.3 Modulation of cellular function
The mature macrophage produces interleukin-1 (IL-1), a cytokine essential for stem
cell maturation. However, it has been observed that macrophages treated with
hydroquinone (10 礛) produce less IL-1 than control cells (Thomas et al, 1989).
This is due to the inhibition of calpain, a protease required for the conversion of
pre-IL-1 to its active form, by hydroquinone (Renz & Kalf, 1991; Kalf et al, 1996).
Treatment of isolated mouse bone marrow-derived macrophages with non-
cytotoxic doses of hydroquinone (10 礛) resulted in a 10 to 30% reduction in total
calpain activity (Miller et al, 1994). In contrast, the production of PGE2 by bone
marrow cells, in vivo, was enhanced by benzene exposure (Gaido & Wierda, 1987;
Kalf et al, 1989) although it is uncertain how the release of arachidonic acid, the
precursor of prostaglandins, from phospholipid stores is initiated under these
conditions. However, hydroquinone and catechol have been shown to regulate
protein kinase C (PKC) activity by producing a short term cytosol-to-membrane
translocation of PKC (Gopalakrishna et al, 1994), a key step in the mobilisation of
arachidonic acid. Da Silva et al. (1989) have further shown that benzene can
directly activate PKC. PGE2 has been identified as an inhibitor of
granulocyte/macrophage progenitor cell proliferation (Gentile & Pelus, 1987).
The growth of granulocyte/macrophage colonies was stimulated in a synergistic
manner by co-treatment of mouse bone marrow cells with low concentrations of
hydroquinone (10-8 to 10-5 M) and recombinant granulocyte/macrophage colony
stimulating factor (GM-CSF) compared to cells treated with GM-CSF alone. The
maximal response was achieved with 1 礛 hydroquinone but no effect was
observed when phenol, catechol or trans,trans-muconaldehyde were substituted for
hydroquinone (Irons et al, 1992). While treatment of HL-60 cells with
hydroquinone at concentrations between 10-40 礛 resulted in an increase in cell
proliferation, at a concentration greater than 50 礛 hydroquinone caused a
decrease in cell viability (Wiemels & Smith, 1999). In a further study, Wiemels et
al. (1999) demonstrated that 12 h after treatment with hydroquinone (50 礛)
approximately 40% of HL-60 cells were apoptotic as determined by the terminal
deoxynucleotidyl-transferase (TdT) assay. Apoptosis is a form of physiological cell
death characterised by altered cell morphology including condensation of the
cytoplasmic and nuclear compartments and internucleosomal DNA fragmentation.
Apoptosis has been observed to occur in a dose-dependent manner when HL-60
Benzene 111
cells are treated with hydroquinone and catechol (25 to 100 礛) but not by phenol.
Similarly, hydroquinone or catechol induces CD34+ human bone marrow
progenitor cells to undergo apoptosis (Moran et al, 1996). These reports support an
earlier study in which weak internucleosomal cleavage was observed in HL-60
cells following incubation for 4 h with 20 礛 hydroquinone and 5 礛
benzoquinone and pronounced cleavage observed at 50 礛 hydroquinone and 10
礛 benzoquinone using pulse-field gel electrophoresis (Hiraku and Kawanishi,
1996).
12.3 Critical biological effects
12.3.1 Bone marrow toxicity
The critical biological effect of benzene in all experimental species is bone marrow
toxicity characterised by a reduction in bone marrow cellularity. Bone marrow
consists of stromal cells (composed of macrophage and fibroblastoid cell
populations) along with stem and progenitor cell populations that form a complex
matrix within which are produced a number of essential regulatory growth factors.
Stromal cells regulate stem and progenitor cell proliferation, differentiation and
maturation by producing both inducers (colony stimulating factors (CSFs) and
interleukins, particularly IL-1) and inhibitors (PGE2) of cell growth. PGE2 inhibits
cell growth by suppressing the production of CSFs and IL-1. Benzene metabolites
appear to disrupt the balance of these regulatory factors by inhibiting production of
CSFs and IL-1 and increasing PGE2 production, although low levels of
hydroquinone can replace or augment, in vitro, the effects of growth factors
(Wiemels & Smith, 1999). Evidence to support this hypothesis has been provided
by experiments in which the co-administration of IL-1 abrogates the effects of
benzene treatment. Similarly, if non-steroidal anti-inflammatory agents, which
inhibit PGE2 production and the cyclooxygenase-dependent oxidation of phenol
and hydroquinone, are co-administered with benzene, haematotoxicity is not
observed. Although increased apoptosis has been observed by exposing bone
marrow cells to various benzene metabolites, these effects appear to occur only at
high metabolite concentrations.
12.3.2 Leukaemia
Leukaemia is the progressive proliferation of abnormal and usually monoclonal
leukocytes in hemopoietic tissues. Benzene-induced leukaemias are typically
myelogenous in nature rather than lymphocytic. Currently, the mechanism(s) by
which benzene induces leukaemia in susceptible individuals remains obscure.
Clinical studies of therapy-related myelodysplastic syndromes and acute myeloid
leukaemia have shown an increase in chromosomal aberrations particularly
aneuploidy, long-arm deletions and translocations involving chromosomes 5, 7 and
8 (Pedersen-Bjergaard et al, 1995). Individuals with chronic exposure to benzene
tend to exhibit similar changes in chromosomes 5 and 7 of peripheral blood
lymphocytes (Zhang et al, 1998).
Chromosomal aberrations involving chromosomes 5, 7 and 8 of various cell lines,
including blood CD34+ progenitor cells, have been reported to occur, in vitro, in
response to low-dose hydroquinone exposure (Smith et al, 2000; Stillman et al,
1997). In particular, CD34+ bone marrow cells were observed to lose chromosome
7 accompanied by selective deletion of the long-arm of chromosome 5 (5q31) but
no changes in chromosome 8 (Stillman et al, 2000). Stillman et al. (1999) have also
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reported that while catechol does not alter cellular cytogenetics, a dose-dependent
synergistic effect is observed between hydroquinone and catechol. The
combination of metabolites induces changes in chromosome 5 not seen with
hydroquinone alone, a result analogous to the synergistic effect on micronuclei
formation in human lymphocytes described by Robertson et al. (1991).
A study of patients with therapy-related AML identified a close correlation
between the use of drugs with DNA-topoisomerase inhibitor activity and
aberrations in chromosomes 5, 7 and 8 (Super et al, 1993). Topoisomerases are a
class of nuclear proteins (endonucleases) that convert one topological version of
DNA into another by catalyzing the breakage and reformation of DNA
phosphodiester linkages. They are involved in DNA replication and transcription,
DNA repair, chromosome segregation and maintain genomic stability. Due to the
sulfhydryl-dependent nature of topoisomerases and the ability of several benzene
metabolites to modify sulfhydryl groups, inhibition of topoisomerase activity by
benzene metabolites has been proposed as a mechanism for leukaemia formation.
Chen & Eastmond (1995) found no evidence for topoisomerase I inhibition by
phenol, catechol, hydroquinone, benzoquinone or 1,2,4-benzenetriol at
concentrations up to 1000 礛. Similarly, topoisomerase II activity was not
inhibited by benzene metabolites at concentrations less than 500 礛 with the
exception of 1,2,4-benzenetriol which was inhibitory at 250 礛. The activation of
phenol by a peroxidase and hydrogen peroxide system resulted in inhibition at 50
礛 and the products of this reaction, 2,2'-biphenol and 4,4'-biphenol were found
to be inhibitory at 500 礛, whereas the peroxidase activation products of these
compounds were inhibitory at 100 and 10 礛 respectively. However, Parke and
Williams (1953) failed to find any evidence for the in vivo formation of biphenol
products after benzene exposure and there is evidence that these metabolites do not
readily form in the presence of hydroquinone (Smith et al, 1989). In contrast, Hutt
and Kalf (1996) found topoisomerase II activity to be inhibited by hydroquinone or
benzoquinone at 6 and 3 礛 respectively.
In addition to modulation of topoisomerase activity, benzene metabolites can
modify other nuclear proteins including tubulin (Pfeiffer & Metzler, 1996) and
produce DNA-protein cross-links (Schoenfeld & Witz, 1999) which may contribute
to chromosomal aberrations and the development of leukaemia. It has been
postulated that chromosomal aberrations could result in inactivation of tumour
suppressor genes, such as p53, activation of proto-oncogenes and altered
expression of growth-factor and growth-factor receptor genes on the aberrant
chromosomes (Irons and Stillman, 1996; Smith, 1996). Similarly, the formation of
apurinic sites due to depurination by N-7 guanine adducts of benzene oxide (Gut et
al, 1996) could result in misreplication of DNA and contribute to the development
of leukaemia, as could oxidative DNA base lesions due to benzene-induced
oxidative stress.
12.3.3 Tumours in Zymbal, Harderian, lacrimal and mammary glands
In addition to haematopoietic abnormalities, rodents exposed to benzene develop
solid tumours in the Zymbal, Harderian, lacrimal and mammary glands, although
other organs and tissues may also be involved (Huff et al, 1989). The mechanisms
by which benzene induces tumours in these glands have not been extensively
investigated. Biochemical characterisation has revealed the presence of high levels
of peroxidase enzymes which can activate phenolic metabolites of benzene to
reactive species capable of modifying DNA and altering cellular functions as
described above. Humans lack an anatomical equivalent of the Zymbal gland and
Benzene 113
the human Harderian gland is only of rudimentary development and has not been
characterised with respect to peroxidase activity.
Studies by Low et al. (1989) indicate that neither benzene nor its metabolites
accumulate in the rat Zymbal gland, a sebaceous gland of the external ear duct of
rodents. However, examination of Zymbal gland tissue after oral administration of
benzene revealed phenol and hydroquinone to constitute 3% and 30% respectively
of unconjugated metabolites. Phenyl glucuronide accounted for 35% of conjugated
metabolites but phenylsulfate could not be detected. The absence of phenylsulfate
was attributed to a lack of sulfotransferase activity in this tissue. In contrast,
Osborne et al. (1980) found the Zymbal gland to exhibit a high level of peroxidase
activity indicating that activation of phenolic benzene metabolites could occur in
this organ. Reddy et al. (1989a) subsequently identified DNA adducts in excised
Zymbal glands after incubation with benzene or its metabolites. The combination
of low sulfotransferase and high peroxidase activity would appear to be conducive
to the formation of reactive metabolites in the Zymbal gland, thus facilitating
tumour formation.
Both lacrimal glands and the accessory lacrimal glands, the Harderian glands,
develop tumours in response to benzene exposure. Biochemical characterisation of
these glands has demonstrated the presence of high constitutive levels of
lactoperoxidase (Morrison & Allen, 1966), which can activate phenolic metabolites
of benzene to reactive species in the same manner as myeloperoxidase.
Mammary gland tumours have been observed in rodents in response to benzene
(Huff et al, 1989) and limited epidemiological evidence suggests an association
between exposure to benzene or benzene-containing products and mammary
tumours in humans (Hansen, 2000; Petralia et al, 1999; see Section 11.6.2). The
mechanism for the formation of these mammary tumours is uncertain. Reddy et al.
(1989b) failed to detect DNA adducts associated with the mammary gland of
female rats after 10 weeks of benzene exposure, suggesting an epigenetic
mechanism may be involved. However, as stated in Section 9, Low et al. (1989)
found the distribution of radiolabel in female rats (Sprague-Dawley) to vary
depending on the dose of [14C]-benzene administered. When comparing doses of
benzene at 0.15, 1.5 and 15 mg/kg bw, the highest dose resulted in a substantial
increase in the amount of radiolabel associated with the mammary gland and bone
marrow compared to other tissues at the lesser doses. Mammary tissue is richly
perfused with blood and has a high fat content which allows for the accumulation
of benzene metabolites. It also contains lactoperoxidase which has been shown to
metabolise phenolic compounds to reactive species (Monzani et al, 1997).
Consequently, benzene metabolites may become activated within mammary tissue
resulting in altered cellular function and carcinogenesis.
12.4 Interindividual variations in susceptibility
12.4.1 Gender effects
While several studies have reported gender-dependent differences in the
metabolism and/or toxicity of benzene in mice, there are no reliable data to indicate
that there are gender differences in humans with respect to either the metabolism of
benzene or susceptibility to benzene toxicity.
Male Swiss (CD-1) mice exposed to benzene exhibited more severe benzene-
related toxicity, including genotoxic effects, than females (Meyne and Legator,
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1980; Ward et al, 1985). Similarly, suppression of bone marrow cellularity in male
DBA/2 mice was greater than females after exposure to benzene (Luke et al,
1988a). Corti and Snyder (1996) found, using Swiss Webster mice exposed to
benzene (10 ppm) for 6 h over 10 days, that the number of erythoid colony forming
units (CFU-E) had decreased in the bone marrow of adult-exposed males, in utero-
exposed males and foetal male livers compared to female adults and foetuses. It
was further shown by Corti and Snyder (1998), in vitro, that isolated CFU-E
derived from male mice were more susceptible to individual benzene metabolites
then female isolates.
A marked gender-related difference was observed in the hepatic glutathione-S-
transferase (GST) activity of CD-1 mice with the isoform exhibiting
approximately 25% greater activity towards trans,trans-muconaldehyde in the
females compared to males (Goon et al, 1993). Investigations of gender-related
differences in benzene metabolism by mouse bone marrow have not, as yet, been
undertaken. Hu et al. (1993) observed that microsomes prepared from the kidneys
(but not livers) of male mice (C3H/HeJ) possessed CYP2E1 activity up to 50-fold
higher for acetaminophen metabolism compared to female mice. It was further
observed that the administration of testosterone to female mice increased the
CYP2E1 activity in the kidneys of females. Supporting evidence for the role of
metabolic gender-differences was provided by Kenyon et al. (1995) who found that
male mice (B6C3F1) excreted more hydroquinone glucuronide when dosed with
phenol compared to female mice. In a subsequent study, Kenyon et al. (1998)
found bone marrow levels of phenol and hydroquinone to be higher in male mice
(B6C3F1) compared to female mice after exposure to benzene.
Attempts to demonstrate gender differences in benzene metabolism in humans by
comparing urinary metabolites (trans,trans-muconic acid and phenylmercapturic
acid) to benzene exposure levels have produced negative results (Inoue et al, 1989;
Inoue, 2000).
12.4.2 Genetic polymorphisms
It has been observed that different strains of male mice (DBA/2, C57B1/B6 and
B6C3F1) exhibit differing sensitivities to benzene when exposed under identical
conditions (Luke et al, 1988b; Pirozzi et al, 1989) and that the metabolic profile of
urinary benzene metabolites is strain-dependent (Longacre et al, 1981). These data
suggest that individual responses to benzene may be genetically determined.
Johnson & Lucier (1992) concluded from an analysis of trans,trans-muconic acid
biomarker assays in humans that genetic variability may account, in part, for the
variance between benzene exposure and urinary trans,trans-muconic acid
concentrations. Subsequently, it has been postulated that the presence of genetically
determined differences in enzyme expression or activity, genetic polymorphisms,
may partially account for the toxicity associated with benzene exposure (Aksoy,
1985; Moran et al, 1999; Rothman et al, 1997). Studies of cases involving familial
susceptibility to benzene (Aksoy, 1985) tend to support this view. Genetic
differences involved in the metabolism of benzene can modify its rate of
metabolism, the profile of metabolites produced and metabolite
activation/detoxification pathways. Such changes have been quantified by analysis
of the urinary metabolites of benzene, phenylmercapturic acid and trans,trans-
muconic acid (Rossi et al, 1999).
Benzene 115
CYP2E1
The metabolism of benzene by hepatic CYP2E1 is the critical first step in the
development of benzene toxicity as the enzyme is responsible for the formation of
phenol and its secondary metabolism to hydroquinone (Guengerich et al, 1991).
Genetic polymorphisms associated with CYP2E1 from different racial groups have
been identified, with frequencies ranging from 2-27% (Kato et al, 1992) and
changes in transcriptional activity of the enzyme in response to mutations have
been described (Hayashi et al, 1991). Seaton et al. (1994) observed that the
CYP2E1 activity of microsomes prepared from the livers of trauma victims varied
13-fold with respect to benzene metabolism. However, as DNA analysis was not
undertaken, it is not known if the differences were genetically determined.
Rothman et al. (1997) showed in a study of 50 workers exposed to benzene that
CYP2E1 genetic polymorphisms were not associated with benzene toxicity. In
another study of 59 workers exposed to benzene, although considerable variation in
urinary metabolite markers was observed, the subjects did not exhibit
polymorphisms associated with CYP2E1 (Rossi et al, 1999).
A cross-species analysis of the expression of CYP2E1 in the bone marrow of mice,
rats and rabbits and human CD34+ stem cells found the enzyme to be present in all
species tested. While the intra- and interspecies variability between mice and rats
was small with relatively low enzyme activities, rabbits exhibited enzyme activities
an order of magnitude greater (Bernauer et al, 2000).
Glutathione-S-transferase
The enzymatic conjugation of GSH to a number of benzene metabolites,
particularly benzene oxide, trans,trans-muconaldehyde and quinones, occurs via
the action of glutathione-S-transferase (GST) (Goon et al, 1993b; Jerina et al,
1968). It has been postulated that GST genetic polymorphisms are positively
correlated with increased risk of oxidative stress (Hayes & Strange, 1995) and
cancer (Strange et al, 1998). Xu et al. (1998b) found a significant association (p
<0.05) between benzene exposure (0.71 ppm TWA), sister chromatid exchanges
and the GSTT1 genotype in a study of 23 workers. Hsieh et al. (1999) examined the
role of GST polymorphism in workers exposed to benzene and found that those
with the GSTT1 and GSTM1 variants of the enzyme, which exhibit reduced
enzymatic activity, were more likely (p = 0.046) to have reduced white blood cell
counts on exposure to high levels of benzene.
Epoxide hydrolase
Epoxide hydrolase, which converts benzene oxide to benzene dihydrodiol, has the
potential to regulate the formation of trans,trans-muconaldehyde. Analysis of 40
transplant-quality human liver samples for interindividual variation in epoxide
hydrolase activity revealed an approximately 8-fold difference in enzymatic
activity and microsomal epoxide hydrolase protein levels were highly correlated
with that activity. In contrast, neither enzymatic activity nor microsomal epoxide
hydrolase protein levels correlated with microsomal epoxide hydrolase RNA levels
which varied by 49-fold. Polymorphisms in amino acid loci of epoxide hydrolase
accounted, in part, for the differences in enzyme activity (Hassett et al, 1997).
NAD(P)H:quinone oxidoreductase (NQO1)
NQO1 catalyzes the two-electron reduction of quinones to their corresponding
hydroquinone form (Lind et al, 1982). Twerdok et al. (1992) reported considerable
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strain differences in the basal and inducible levels of NQO1 between C57B1/6 and
DBA/2-derived mouse bone marrow stromal cells. The basal and maximal
inducible activity of NQO1 in C57B1/6-derived stromal cells was approximately 3-
and 5-fold greater respectively than that of DBA/2-derived cells.
Traver et al. (1992) identified a point mutation in the human NQO1 gene (609CT)
that results in loss of enzymatic activity in the protein. Thus individuals
homozygous for the mutation possess no NQO1 activity, while heterozygous
individuals exhibit reduced enzymatic activity. It has been estimated, using a
reference population, that the frequency of the mutation is 13% (Rosvold et al,
1995). Analysis of several ethnic groups has shown that homozygous individuals
range between 5-22% and heterozygous individuals from 34-52% of the population
(Kelsey et al, 1997). The study of Rothman et al. (1997) demonstrated a correlation
between NQO1 genetic polymorphism and benzene toxicity among 50 workers
exposed to benzene. Rossi et al. (1999) identified a high frequency of NQO1
genetic polymorphism (42.7% reduced activity and 8.3% no activity) amongst 59
workers exposed to benzene and urinary excretion of S-phenylmercapturic acid was
significantly lower in individuals lacking NQO1 activity. An increased prevalence
of the 609CT mutation has been found in a study of 104 patients diagnosed with
myeloid leukemias (Larson et al, 1999). However, a study of a group of six related
individuals predisposed to cancer showed that the NQO1 609CT transversion did
not correlate with NQO1 activity in heterozygous individuals, suggesting that either
the 609CT transversion has no effect on NQO1 activity or that post-transcriptional
regulation alters the activity of the modified enzyme (Kuehl et al, 1995).
Further investigations, in vitro, have found NQO1 to be inducible in wild-type
(C/C) human bone marrow cells on exposure to the benzene metabolites
hydroquinone and catechol. In contrast, cells homozygous for the 609CT mutation
(T/T) did not express NQO1 in response to hydroquinone treatment whereas
heterozygous cells (C/T) exhibited intermediate induction (Moran et al, 1999).
12.4.3 Environmental influences
In addition to genetic influences, the susceptibility of an individual to benzene
toxicity may also be influenced by environmental or lifestyle factors. Generally, the
role of environmental factors in modifying benzene toxicity have not been
adequately studied. Reviews of environmental influences on solvent toxicity,
including benzene, have been published (Medinsky et al, 1994; Sato, 1991).
Alcohol
As discussed in Section 9, CYP2E1 is the initial enzyme responsible for the
metabolism of benzene to phenolic metabolites. Studies have shown a number of
substances including alcohol (ethanol) to induce hepatic CYP2E1 activity
(Johansson & Ingelman-Sundberg, 1988; Koop et al, 1989). Alcohol consumption
by rats and rabbits resulted in increased microsomal metabolism of benzene
(Johansson & Ingelman-Sundberg, 1988; Nakajima et al, 1985) and increased
benzene-mediated myelotoxicity in rats (Nakajima et al, 1985). Consequently,
alcohol consumption by individuals exposed to benzene may result in enhanced
metabolite formation and increased risk of myelotoxicity.
Toluene
Toluene acts as a substrate for CYP2E1 (Nakajima et al, 1992) and thus, in the
presence of benzene, can act as an inhibitor of benzene metabolism. Andrews et al.
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(1977) demonstrated the inhibition of benzene metabolism by the co-administration
of toluene to male Swiss mice. Urinary benzene metabolites were significantly
decreased (p <0.01) and the amount of exhaled benzene increased in toluene- and
benzene-treated animals compared to control benzene-treated animals. While the
tissue concentration of benzene did not alter with toluene treatment, the
concentration of total benzene metabolites was significantly reduced (p <0.05) in
various tissues including blood and bone marrow. Inoue et al. (1989) showed that
workers exposed concurrently to benzene and toluene produced significantly less (p
<0.01) urinary trans,trans-muconic acid compared to workers exposed only to
benzene. However, in a study in which urinary phenylmercapturic acid was used as
a biomarker for workers exposed to benzene, no correlation with toluene exposure
was found (Inoue et al, 2000).
Non-steroidal anti-inflammatory drugs
Cyclooxygenase activity within bone marrow contributes to benzene-mediated
bone marrow toxicity by participating in the oxidation of phenolic metabolites to
reactive species and by the conversion of macrophage-derived arachidonic acid to
PGE2, an inhibitor of stem cell proliferation. Non-steroidal anti-inflammatory drugs
(NSAIDs) such as aspirin and indomethacin are potent inhibitors of
cyclooxygenase activity (Randall et al, 1980; Roth et al, 1975). The administration
of NSAIDs, prior to benzene exposure, has been shown to diminish the bone
marrow toxicity associated with benzene in mice (Kalf et al, 1989; Pirozzi et al,
1989). The routine use of NSAIDs may confer some protection from the effects of
benzene exposure.
12.5 Summary
Exposure to benzene can result in bone marrow toxicity in several species in
addition to leukaemia in humans and solid tumours in other animal species. In
order for bone marrow toxicity to occur, benzene must first be metabolised by the
liver to intermediate metabolites. These metabolites become localised within the
bone marrow where they undergo activation by peroxidase enzymes, particularly
myeloperoxidase which is found in large amounts in bone marrow, and, to a lesser
extent, by cyclooxygenase. While individual benzene metabolites appear not to
induce bone marrow toxicity, the combination of phenol and hydroquinone have
been shown to induce the same effects on bone marrow as benzene. This effect
appears to be due to the ability of phenol to act as a co-oxidant in the activation of
hydroquinone to the semiquinone and benzoquinone by myeloperoxidase.
Subsequent changes in cellular function result in altered growth factor production
with inhibition of bone marrow stem cell proliferation, differentiation and
maturation. The oxidation of hydroquinone also results in the formation of reactive
oxygen species. Damage to cells by these species can result from DNA adduct
formation, DNA base modification, chromosomal aberrations and changes to
intracellular redox status, particularly depletion of glutathione and oxidation of
protein sulfhydryl groups. Damaged cells not deleted by apoptosis and which
possess activated oncogenes or damaged tumour suppressor genes may begin to
proliferate as clonal lines, which may result in leukaemia in humans or solid
tumours in animals.
While a number of gender-related differences have been described in the response
of rodents to benzene exposure, there is no evidence for such differences in the
response of humans. However, humans do exhibit differences in the expression and
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activity of several enzymes involved in the metabolism of benzene, the most
notable of which occurs with NQO1, an enzyme which is responsible for
converting quinones to their corresponding hydroquinones and affords protection
against quinone-adduct and reactive oxygen species formation within cells. Thus
the expression of genetic polymorphisms may modulate the sensitivity of an
individual or ethnic group to the effects of benzene exposure.
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13. Health Hazard Assessment
This section compares and integrates key data on animal toxicity and human effects
in order to characterise the potential adverse human health effects of benzene and
their dose-response relationships. The critical studies have been described in
Sections 10-11. In integrating their findings, consideration has been given to
quality of data, strength of evidence and consistency of outcomes.
13.1 Acute effects
13.1.1 CNS effects
In animals and humans, acute exposure to benzene has dose-dependent CNS
depressant or anaesthetic effects which have a rapid onset of action and are
reversible upon cessation of exposure (unless fatal), with limited evidence of
neurobehavioural stimulation at sub-anaesthetic doses.
In mice, there are clinical signs of CNS depression at exposure levels 1000 ppm
benzene.
In humans, clinical signs include generalised symptoms such as dizziness,
headache and vertigo at levels of 250-3000 ppm, leading to drowsiness, tremor,
delirium and loss of consciousness at 700-3000 ppm, whereas exposure to 25 ppm
benzene for 8 h is not associated with any adverse signs or symptoms.
13.1.2 Skin, eye and respiratory tract irritation
Limited, but consistent animal data show that undiluted benzene is irritating to the
skin and eye. Benzene vapours have also been reported to cause lacrimation in rats.
In humans, aspiration of liquid benzene has been observed to cause pulmonary
oedema and bleeding. Furthermore, human case reports show that benzene vapours
may induce skin, eye and/or respiratory tract lesions that vary from slight to severe
irritation, depending on the vapour concentration. As such, benzene can be
characterised as irritating to the skin, eyes and respiratory tract. However, there are
no reports of skin, eye or respiratory tract irritation in humans exposed to benzene
vapour levels <33 ppm (TWA8).
13.2 Repeated dose effects (other than carcinogenicity)
13.2.1 CNS effects
Repeated exposure to benzene has been shown to affect the dopaminergic system in
both mice and rats and one study found a reduction in brain weight in mice exposed
to high doses (350 mg/kg/day) for 30 days. Although a variety of neurological
effects have been attributed to repeated occupational exposure to benzene, these
were predominantly recorded in studies that did not include an unexposed control
group. In the only available human study with an unexposed control group, there
was a dose-dependent increase in the prevalence of dizziness and headache within a
dose range that averaged 59 ppm benzene. As such, it would appear that any CNS
effects in humans from long-term exposure to benzene are likely to be similar to
those resulting from acute exposures and occur at exposure levels that are higher
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than those associated with other human health effects (such as bone marrow
depression).
13.2.2 Immunosuppression
Effects suggestive of an impairment of the ability of LC to respond to antigenic and
mitogenic stimuli with rapid proliferation have been consistently observed in
subacute oral and inhalation studies in mice and have also been found in a subacute
inhalation study in rats. The corresponding NOAEL/LOAEL values are 0.44/10
ppm in mice and 200/400 ppm in rats. These were established in studies in which
blood cells from animals exposed in vivo were tested in various in vitro systems.
There are no reports of similar findings in humans, although a reduction in the
number of LC in peripheral blood is common in benzene-induced bone marrow
depression. Changes in the blood level of some immunoglobulin classes have been
reported in workers exposed to 3-57 ppm benzene, but this finding has not been
confirmed in other studies.
In mice and rats, the LOAEL for immunosuppresion is similar to that for bone
marrow depression. Furthermore, whereas there is no evidence that benzene
compromises LC function in humans, benzene is an established cause of reduced
LC counts. Therefore, it is appropriate to characterise immunosuppression as a sign
of LC toxicity that is an aspect of, and included in, the wider effect of bone marrow
depression discussed below.
13.2.3 Bone marrow depression
Bone marrow depression (haematotoxicity, `benzene poisoning') from exposure to
benzene has been reported in all species examined, including mice, rats, guinea
pigs, rabbits, pigs and humans. Its main manifestation is a reduction in the number
of one or more of the formed elements of the blood (LC, Plt, RBC, WBC) and/or in
Hb, and/or an increase or decrease in RBC size (MCV). The mechanistic studies
discussed in Section 12 indicate that the toxicity of benzene to haematopoietic cells
in the bone marrow is due to several of its metabolites that are formed in situ in
relatively high concentrations and act in an additive or synergistic manner to
disrupt a range of mechanisms that regulate blood cell formation. Further support
for this notion is provided by the order of susceptibility of mice and rats to benzene
haematotoxicity (male mice > female mice > rats), which parallels the rate of
formation and tissue concentrations of reactive benzene metabolites.
In animals exposed to inhalation of benzene, abnormal blood counts and
morphological abnormalities in blood forming organs have been found at exposure
levels 10 ppm in mice (including mouse foetuses exposed in utero) and 100 ppm
in rats. These effects were observed even at the lowest dose tested in all long-term
studies. Therefore, a NOAEL cannot be established.
In humans, several occupational studies indicate that the incidence and severity of
bone marrow depression is related to recent or current exposure to benzene. It is not
possible to estimate the average latency period from the available human data;
however, animal studies indicate that abnormal blood counts may develop in less
than a month. As described in Section 11.4.4, a LOAEL for haematological effects
in humans has been determined in a study in 44 Chinese workers with long-term
exposure to benzene, in which the only haematological abnormality in the lowest
exposure group (n = 11; median exposure (TWA8) = 7.6 ppm; range 1-20 ppm) was
a modest decrease (16%) in ALC (Rothman et al, 1996a, 1996b). The limitations of
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this study include a relatively wide exposure range and a small number of subjects
of an ethnic group that may express genetic polymorphisms modulating sensitivity
to the effects of benzene exposure. On the other hand, the study had a well-matched
control group, minimal exposure to other chemicals (toluene and xylenes) and a
dose-response relationship was established between ALC and benzene exposure as
measured by repeated personal monitoring as well as with benzene metabolites in
the urine. Furthermore, the prevalence of polymorphisms known to increase the
susceptibility to benzene-induced bone marrow suppression (the GSTT1 and NQO1
(609CT) genotypes; see Section 12.4.2) is 3-5 times higher among Chinese than
among Caucasians (Kelsey et al, 1997; Xu et al, 1998). Therefore, a LOAEL
determined in Chinese subjects should also be valid for Caucasians. For these
reasons, based on current human data, 7.6 ppm (TWA8) is considered the best
estimate for a LOAEL which may be close to the point of departure for the onset of
haematological effects. The available human data are insufficient to establish an
appropriate NOAEL, but studies with various limitations indicate that it is likely to
be >0.5 ppm (TWA8).
The only epidemiological study in the general population found an excess
occurrence of anaemia and related disorders in a community whose tap water
contained 66 礸/L benzene. However, as the equivalent dose in a 60-kg person
with a daily water consumption of 2 L is <2.2 礸/kg/day or 450 times lower than
the only oral NOAEL for haematotoxicity recorded in animal studies (1 mg/kg/day;
Wolf et al, 1956), this finding may well have been heavily influenced by bias
arising from public awareness of the pollution of the water with benzene and the
health effects of the chemical.
In conclusion, there is a substantial body of animal, human and mechanistic data
which supports the association between benzene exposure and bone marrow
depression and indicates that this is a result of cytotoxicity and, therefore, a
threshold effect. The available studies are insufficient to draw firm conclusions
about the inhalation NOAEL, although human observations suggest that it is >0.5
ppm. The lowest inhalation LOAEL observed in animals (mice) is 10 ppm, which
is comparable to the best estimate for a human LOAEL (7.6 ppm).
13.2.4 Fertility effects
A single oral dose of benzene has been shown to induce chromosome aberrations
and have cytotoxic effects in mouse spermatogonia at high doses (220 and 880
mg/kg respectively). There is also evidence of degenerative changes in the testes
(atrophy) and ovaries (atrophy or cystic lesions) of mice exposed to repeated
inhalation or oral administration of high doses of benzene (300 ppm for 6 h/day and
25-50 mg/kg/day respectively). At these dose levels, there was evidence of
concomitant haematotoxicity, but no mortality or other findings that would suffice
to characterise the effects on the gonads as secondary to generalised toxicity.
Consistent with metabolic differences, benzene did not induce testicular or ovarian
toxicity at similar exposure levels in rats. There were no fertility-related effects in
female rats exposed to 300 ppm benzene for 6 h/day for 10 weeks prior to mating
and on GD 0-20. Another study found that female rats exposed to 200 ppm benzene
for 24 h/day produced no litters, but did not determine the cause of this.
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In humans, there are several reports of menstruation disturbances in female and one
of reduced semen quality in male workers exposed to benzene. However, the
studies have several limitations and do not provide convincing evidence that
benzene may have adverse effects on human fertility.
Based on a 13-week study in mice, the inhalation NOAEL for degenerative lesions
in the testis and ovaries is 30 ppm, with a LOAEL of 300 ppm (Ward et al, 1985).
Based on ovarian atrophy in a 2-year oral study in mice, the LOAEL is 25
mg/kg/day; a NOAEL was not determined (NTP, 1986). These effect levels are
either higher than or similar to those at which there is also clear evidence of bone
marrow depression.
13.2.5 Developmental effects
Based on the weight of evidence from a number of developmental toxicity studies
in mice, rats and rabbits, benzene can be characterised as foetotoxic, but not
teratogenic (see Section 10.5.2). The foetal effects observed in the absence of signs
of maternal toxicity were a small reduction in foetal BW and an increase in the
incidence of delayed ossification and other minor skeletal abnormalities. There is
also limited evidence of a reduction in the number of stem cells in the blood
forming tissues of mouse foetuses exposed in utero to benzene levels similar to
those known to cause bone marrow depression in adult animals (10-20 ppm).
Studies of pregnancy outcome in humans have produced mixed results with regard
to the risk for SAb. One study found an elevated SGA risk for fathers with
occupational exposure to benzene. In another study, there was a marginally
significant reduction in birth weight in infants whose mothers had been exposed to
low levels of benzene at work. However, the studies have several limitations and do
not provide convincing evidence that benzene may have foetotoxic effects in
humans. There are no studies of the effect of maternal benzene exposure on the
blood forming tissues of human foetuses.
In conclusion, animal and in vitro data indicate that benzene and/or its metabolites
may inhibit normal foetal growth, skeletal development and possibly blood cell
production. The available epidemiological data are insufficient to draw conclusions
about the likelihood that benzene may have similar effects in humans.
Based on adequately reported studies in the rat, the inhalation NOAEL for foetal
effects in the absence of maternal toxicity is 40 ppm, with a LOAEL of 100 ppm
(Coate et al, 1984; Green et al, 1978). In other studies in the rat, 100 ppm is also
the LOAEL for bone marrow depression.
13.2.6 Other non-neoplastic effects
Other non-neoplastic effects are inadequately documented to determine their
significance for health hazard assessment.
13.3 Genotoxicity
The genotoxicity of benzene has been investigated extensively in a broad spectrum
of in vitro and in vivo systems. Overall, the results are consistent with the
conclusion that several benzene metabolites (particularly cathechol, hydroquinone
and quinone) can induce a variety of lesions in genetic material, which range from
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DNA base alterations and single strand breaks to structural and numerical
chromosome aberrations. Chromosome aberrations have also been identified in
peripheral blood cells of workers exposed to benzene, generally at exposure levels
>10 ppm. Specifically, recent studies found an increase in the frequency of
aneuploidy, long-arm deletions and translocations involving chromosomes 1, 5, 7,
8, 9 and 21 (see Table 11.3). As discussed below, these findings suggest that
benzene exposure can lead to chromosome lesions which are similar to the specific
abnormalities that are the hallmark of human leukaemia. However, there is no
indication that an increase in the occurrence of such lesions in non-neoplastic
peripheral blood cells is associated with any adverse health effects per se.
Therefore, it is appropriate to characterise genotoxicity as a mode of action that is
an aspect of, and included in, the wider effect of carcinogenicity addressed below.
13.4 Carcinogenicity
13.4.1 Leukaemia
In several of the occupational cohort studies reviewed in Section 11.6.1, past
employment in an industry or job category with the potential for exposure to
benzene was associated with a significant increase in the risk for cancer of the
blood and lymphatic system and/or leukaemia. In addition, there was a significant
trend with cumulative exposure, that is, a clear dose-time-response relationship in
three out of four studies in which detailed exposure assessments were made. The
strength of the association ranged from weak in the majority of cohorts to strong
(SMR = 10-20) in Pliofilm workers with a cumulative exposure in excess of 500
ppm-years (Table 11.4; Table 11.5). With regard to leukaemia type, AML (ANLL)
was found to account for most of the risk elevation and there was no evidence of a
statistically significant dose-time-response relationship for CML, ALL or CLL in
any of the cohorts. Several case-control studies also identified prior exposure to
benzene or benzene-containing substances as a significant risk factor for a variety
of lympho-haematopoietic cancers, including but not limited to acute leukaemia
(see Section 11.6.2). As such, it is universally agreed that occupational exposure to
benzene may induce leukaemia, specifically AML (ANLL). In the largest cohort
studied to date, the latency period from first exposure to clinical diagnosis was
estimated at 11-12 years, with a range from 10 months to 50 years (Yin et al,
1987b).
Human leukaemias are clonal diseases generally characterised by a large variety of
acquired chromosome aberrations (including translocations, insertions, deletions
and inversions) in individual bone marrow cells in the haematopoietic stem and
progenitor cell compartment (Gilliland, 1998; Irons & Stillman, 1996).
As described in Section 12, although the mechanism of carcinogenesis of benzene
is unknown, several benzene metabolites have been shown to cause DNA damage,
including base alterations, chromosome structural abnormalities and aneuploidy.
In patients with AML secondary to treatment with alkylating agents or radiation (s-
AML), there is a recurrent pattern of cytogenetic abnormalities involving loss of all
or part of chromosomes 5 and 7. Furthermore, s-AML is generally preceded by a
period of preleukaemia (also known as MDS) characterised by a persistent bone
marrow dysplasia, which is believed to provide a microenvironment that increases
the susceptibility of stem and progenitor cells to chromosome damage and/or
enhances the survival and proliferation of cells with genetic abnormalities. The
pattern of cytogenetic abnormalities involving chromosomes 5 and 7 is also
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observed in studies of leukaemia patients occupationally exposed to benzene or
benzene-containing substances. It has therefore been speculated that benzene-
induced leukaemia is the result of a series of both epigenetic events that affect the
microenvironment and genetic events that lead to the activation of oncogenes
and/or the loss of tumour suppressor genes (Irons & Stillman, 1996) and, therefore,
is a threshold rather than a non-threshold effect (CONCAWE, 1996). There is little
documentation on the association between non-neoplastic bone marrow lesions
such as MDS and leukaemia in benzene-exposed subjects. Of 18 incident cases of
bone marrow disorders in the large cohort of benzene-exposed Chinese workers
described in Section 11.6.1, 11 had bone marrow depression whereas 7 had MDS.
Furthermore, in the same cohort, a diagnosis of bone marrow depression (`benzene
poisoning') was associated with a 71-fold increase in the risk for ANLL/MDS
which could not be attributed to cumulative benzene exposure. However, although
these findings are consistent with the hypothesis that non-neoplastic bone marrow
lesions precede frank leukaemia in some benzene-exposed subjects, they do not
suffice to prove that the pathogenesis of benzene-induced leukaemia involves an
epigenetic step.
As discussed in Section 11.6.1, only the Pliofilm cohort is suitable for the
determination of the carcinogenic potency of benzene. In this cohort, the SMR for
leukaemia was significantly elevated at cumulative exposures >50 ppm-years for
two of the three available exposure estimates (Table 11.5), equivalent to a long-
term exposure level of >1.25 ppm benzene over a working life of 40 years.
However, these findings derive from a single study with insufficient statistical
power to rule out the possibility of some increase in the SMR at lower exposures.
No observational studies were found which have examined the relationship
between leukaemia incidence or mortality and the exposure of individual adults or
children to non-occupational benzene levels.
13.4.2 Solid tumours
Lymphoma
Lymphomas are solid malignant tumours of lymphocytic origin. They include NHL
and MM which are monoclonal and Hodgkin's disease, which may be either
monoclonal or of mixed cellularity (Freedman & Nadler, 1998; Longo, 1998).
In mice, the incidence of lymphoma was elevated in several studies conducted in
strains where this is a common spontaneous tumour.
In humans, some of the occupational cohort studies summarised in Table 11.4 link
past employment in job categories with the potential for benzene exposure with a
significant or marginally significant increase in the risk for all lymphoma (in Italian
refinery workers employed prior to 1961 and Chinese workers in the painting,
printing, footwear and chemical industries), NHL (in Finnish petroleum industry
workers and Chinese workers in the painting, printing, footwear and chemical
industries) or MM (in Australian petroleum industry workers). The strength of the
association was weak in Australian and Finnish petroleum industry workers,
intermediate in Italian refinery workers employed prior to 1961 and highest (RR =
4.7 for NHL) in Chinese workers with assessed (and probably underestimated)
exposure levels 25 ppm benzene. However, a dose-time-response relationship has
not been demonstrated. Some of the case-control studies reviewed in Section 11.6.2
also suggest an association between prior exposure to benzene or benzene-
containing substances and the risk of NHL or MM.
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Although it cannot be excluded that there is an association between benzene
exposure and the risk for lymphoma, specifically NHL and MM, the evidence is not
as conclusive as it is for leukaemia.
Mammary cancer
In female mice, there was a statistically significant, dose-related increase in the
incidence of mammary gland carcinomas at dose levels 50 mg/kg/day in two oral
carcinogenicity studies. The incidence was not increased in female rats dosed orally
with up to 500 mg/kg/day for 2 years, or in a number of inhalation studies in mice
and rats exposed to up to 300 ppm benzene for 2 years or longer.
In humans, the SIR for breast cancer was elevated in a cohort study including 1942
female workers in a Finnish petroleum company; however, the elevation was
mainly due to cases among clerical workers and similar in magnitude to that found
in other studies of Finnish women in office jobs. In addition, there is a single, but
well controlled case-control study showing that the risk for breast cancer in women
is weakly associated with duration of benzene exposure, probability of exposure
and a crude estimate of cumulative exposure to the chemical. There was also a
marginally elevated risk associated with employment as a car mechanic or petrol
station worker in a case-control study of primary breast cancer in men. These
findings are insufficient to determine the likelihood of a causal relationship
between benzene exposure and breast cancer in humans, although it cannot be
excluded.
Skin cancer
There was an increased incidence of epithelial (non-melanoma) skin tumours in
male rats in two 2-year oral bioassays, but only at very high dose levels (200-500
mg/kg/day) that may have exceeded the maximum tolerated dose. Similar tumours
were not seen in female rats, or in any of several carcinogenicity studies in the
mouse.
In humans, the risk for melanoma or skin cancer (mainly melanoma) was elevated
in three petroleum industry cohorts (Table 11.4). In addition, ever employment in
the petroleum industry was a marginally significant risk factor for concurrent basal
and squamous cell carcinoma in one of the case-control studies reviewed in Section
11.6.2. The risk for skin cancer (mainly melanoma) was also elevated in the Dow
Chemical cohort, but there was no trend with either level or duration of exposure to
benzene. As such, although these studies suggest that there may be an elevated risk
for skin cancer among workers in the petroleum and chemical industries, there is no
indication that this can be attributed to exposure to benzene.
13.5 Summary and conclusions
Human case reports indicate that acute exposure to benzene vapours can cause
CNS depression and skin, eye and respiratory tract irritation. With regard to
chronic exposure, it is well documented through numerous epidemiological studies
that the principal human health hazards are bone marrow depression and
leukaemia, particularly AML (ANLL). There is also some evidence of an
association between chronic benzene exposure and the risk for lymphoma,
specifically NHL and MM. At present, leukaemia and lymphoma must be
considered non-threshold effects caused by exposure to a genotoxic carcinogen.
With regard to bone marrow depression, it is reasonable to assume that this is a
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threshold effect. Based on current human data, 7.6 ppm (TWA8) is the best estimate
of a LOAEL which may be close to the point of departure for the onset of
haematological effects. An appropriate NOAEL has not been established; however,
occupational studies with various limitations indicate that it is likely to be >0.5
ppm. Finally, it cannot be excluded that repeated exposure to benzene may be
weakly associated with reproductive effects and mammary cancer in humans.
No data from human studies were found to indicate that children are more
susceptible to benzene toxicity than adults or that benzene affects human males and
females differently. As discussed in Section 12.4.3, experimental data indicate that
alcohol consumption may increase the risk of adverse health effects from chronic
exposure to benzene.
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14. Classification for Occupational
Health and Safety
This section discusses the classification of the health effects of benzene according
to the NOHSC Approved Criteria for Classifying Hazardous Substances (the
Approved Criteria) (NOHSC, 1999a) or, in the case of physicochemical hazards,
the Australian Dangerous Goods (ADG) Code (FORS, 1998). The Approved
Criteria are cited in the NOHSC National Model Regulations for the Control of
Workplace Hazardous Substances (NOHSC, 1994c) and provide the mandatory
criteria for determining whether a workplace chemical is hazardous.
Where adequate human data were unavailable, the classification for health hazards
has been based on experimental studies (animal and in vitro tests). In extrapolating
results from experimental studies to humans, consideration was given to relevant
issues such as quality of data, weight of evidence, metabolic and mechanistic
profiles, inter- and intra-species variability and relevance of exposure levels.
Benzene is currently listed in the NOHSC List of Designated Hazardous
Substances (NOHSC, 1999b) with the following classification: `Flammable';
`Carcinogen, Category 1' and `Toxic: Danger of serious damage to health by
prolonged exposure through inhalation, in contact with skin and if swallowed'.
14.1 Physicochemical hazards
Benzene meets the criteria of the ADG Code for classification as a flammable
liquid, as it gives off flammable vapours at - 11癈 and an atmosphere containing
1.4-7.9% v/v benzene is explosive (Table 5.1). Benzene is not chemically reactive
under normal ambient conditions.
Classification. Benzene is already classified as `Flammable'.
14.2 Health hazards
14.2.1 Acute toxicity
The available human data on the acute toxicity of benzene are anecdotal in nature.
As shown in Table 10.1, the 4-h inhalation LC50 in the rat is 13,700 ppm (43.8
mg/L). The oral LD50 values determined in the rat are inconsistent (810, 5600 and
9900 mg/kg). However, as the oral LD50 in the mouse is 4700-6500 mg/kg, the
weight of evidence suggests that benzene has a low acute oral toxicity. The dermal
LD50 in the rabbit is >8200 mg/kg.
Single exposure to benzene has been associated with CNS stimulation or
depression in both animals and humans and with male germ cell toxicity in mice.
However, observations indicate that these effects are reversible after a recovery
period ranging from a few hours for CNS effects to several weeks for germ cell
damage.
Classification. Benzene does not meet the Approved Criteria for classification for
acute lethal effects or non-lethal irreversible effects after a single exposure.
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14.2.2 Irritant and corrosive effects
Liquid benzene has been shown to cause skin and eye irritation in rabbits. Benzene
vapours have been reported to cause eye irritation in humans and rats at
concentrations 33 and 10 ppm respectively. In humans, vapour levels >60 ppm
have been associated with irritation of the skin, including second degree burns, and
of the mucous membranes of the nose, mouth, throat and lower airways, including
signs of serious respiratory system effects such as dyspnoea, laryngitis, tracheitis,
bronchitis and pulmonary haemorrhage.
Classification. Based on animal tests and practical observation in humans, benzene
meets the Approved Criteria for classification as `Irritating to skin' (risk phrase
R38), `Irritating to eyes' (R36) and `Irritating to the respiratory system' (R37).
14.2.3 Sensitising effects
There are no animal studies or human case reports of skin or respiratory
sensitisation to benzene.
14.2.4 Effects from repeated or prolonged exposure
According to the Approved Criteria, a substance is classified as hazardous when
serious damage (clear functional disturbances or morphological changes which
have toxicological significance) is likely to be caused by repeated or prolonged
exposure by an appropriate route. In this context, haematological disturbances are
considered to be particularly important if the evidence suggests that they are due to
decreased bone marrow production of blood cells.
There is a substantial body of human evidence that repeated occupational exposure
to benzene vapours at 7.6 ppm (0.024 mg/L) can cause bone marrow depression.
This is usually a reversible condition, but may progress to aplastic anaemia or
cancer (AML). Toxic effects on the blood and blood forming organs have also been
found consistently in rats exposed to inhalation of benzene at concentrations 100
ppm (0.32 mg/L) for 6 h/day for 5 days/week, in mice exposed to inhalation of
benzene at concentrations 10 ppm (0.032 mg/L) for 6 h/day for 5 days/week, and
in rats and mice exposed to orally administered benzene at dose levels 25
mg/kg/day, in studies of a duration of 90 days (13 weeks) or longer.
There are no human or animal studies of the haematological effects of dermal
exposure to benzene. However, as benzene is absorbed through the skin in humans,
it is likely that bone marrow toxicity may also be caused by repeated or prolonged
exposure by the dermal route.
Classification. Benzene meets the Approved Criteria for causing serious damage to
health by repeated or prolonged exposure and is already classified as `Toxic:
Danger of serious damage to health by prolonged exposure by inhalation, in contact
with skin and if swallowed' (R48/23/24/25).
Benzene 129
14.2.5 Reproductive effects
Effects on fertility
The available human case reports and studies have several limitations and do not
prove a causal relationship between benzene exposure and fertility effects in
humans.
In a study of male mice, a single oral dose of 880-6160 mg/kg benzene had no
effect on body or testis weight, but was toxic to differentiating spermatogonia.
There is also evidence of degenerative changes in the testes (atrophy) and ovaries
(atrophy or cystic lesions) of mice exposed to repeated inhalation or oral
administration of high doses of benzene (300 ppm for 6 h/day and 25-50 mg/kg/day
respectively). At these dose levels, there was concomitant haematotoxicity, but no
mortality or other findings that would suffice to characterise the effects on the
gonads as secondary to generalised toxicity.
Benzene did not induce testicular or ovarian toxicity at similar exposure levels in
rats. There were no fertility-related effects in female rats exposed to 300 ppm
benzene for 6 h/day for 10 weeks prior to mating and on GD 0-20. Another study
found that female rats exposed to 200 ppm benzene for 24 h/day produced no
litters, but did not determine the cause of this.
As such, benzene may have a toxic effect on the testes and ovaries in mice, but
these effects were demonstrated only at high doses of doubtful relevance for
humans. The available data on reproductive capacity in rats are limited and
inconclusive.
Classification. The available evidence is insufficient to classify benzene as toxic to
fertility under the Approved Criteria.
Developmental effects
The available human studies have several limitations and do not prove a causal
relationship between benzene exposure and developmental toxicity in humans.
The available developmental toxicity studies in mice, rats and rabbits are
summarised in Table 10.2 in Section 10.5.2. Based on the weight of evidence from
these studies, benzene is foetotoxic, but not teratogenic. Foetotoxic effects were
mainly found at dose levels associated with maternal toxicity. However, some
studies in mice and rats found a small reduction in foetal BW or an increase in the
incidence of delayed ossification and other minor skeletal abnormalities at dose
levels at which no maternal effects were reported. These minor growth disturbances
were found in the foetuses of dams exposed to ingestion or inhalation of benzene at
high doses of doubtful relevance for humans (800-1300 mg/kg/day by mouth or
100-500 ppm by inhalation).
In two small studies, inhalation exposure of pregnant mice to 10-20 ppm benzene
on GD 6-15 resulted in toxic effects on blood cells in haematopoietic tissue in the
liver, bone marrow, or spleen of the offspring exposed in utero. These effects
occurred in the absence of other signs of developmental toxicity and were
consistent with lesions induced by benzene in the same tissue type in adult mice at
similar levels of exposure. However, the studies comprised an insufficient number
of animals to be entirely convincing.
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Classification. The available evidence is insufficient to classify benzene as a
developmental toxicant under the Approved Criteria.
Effects on lactation
Benzene has been found in human breast milk. In the rat, one study found small
changes in body and organ weights in the offspring of rats exposed to inhalation of
benzene during pregnancy and lactation, but did not establish whether these effects
were lactational or the result of exposure in utero.
Classification. The available evidence is insufficient to classify benzene for effects
on lactation.
14.2.6 Mutagenic effects
The Approved Criteria defines a mutation as a permanent change in the amount or
structure of the genetic material in an organism, resulting in a change of the
phenotypic characteristics of the organism.
To be classified in Category 1 (Substances known to be mutagenic to humans) or
Category 2 (Substances which should be regarded as if they are mutagenic to
humans), a substance must be known or strongly presumed to cause heritable
mutations in humans, that is, changes to the genetic material that occur in germ
cells and can be transmitted to the offspring. If a substance has only been shown to
induce mutations in somatic cells, it is classified in Category 3.
Benzene and/or its metabolites, particularly catechol, hydroquinone and quinone,
have been shown to cause DNA damage in mammalian in vitro systems as
determined by sensitive test methods. Furthermore, benzene has been shown to be
genotoxic to somatic cells in a broad spectrum of in vivo models in which the
chemical was administered to rodents by inhalation, oral gavage or parenteral
injection. These include tests for SCE and MN induction in peripheral blood cells,
bone marrow cells, foetal liver cells, lung fibroblasts and Zymbal gland cells; gene
mutations in LC, lung and spleen cells; chromosome aberrations in LC, bone
marrow cells and spleen cells; and DNA adducts in nucleated blood and bone
marrow cells. Chromosome aberrations have also been identified in peripheral
blood cells of workers exposed to benzene, generally at exposure levels >10 ppm.
Published documentation on mammalian germ cells appears to be limited to two
studies in the male mouse. Span?et al. (1989) found that a single oral dose of 880
mg/kg benzene caused a dose-dependent reduction in the relative cell count in the
primary spermatocyte and spermatid fractions, indicating that benzene and/or its
metabolites have the potential to reach the germ cells (see Section 10.5.1). Ciranni
et al. (1991) subsequently showed that a single oral dose of 220 mg/kg benzene
induced chromatid aberrations in differentiating spermatogonia in a dose-dependent
manner (see Section 10.6 and Figure 10.1). However, no evidence could be found
in the open literature that these results have been replicated by other laboratories or
are supported by findings in other appropriate tests. As such, the experimental data
available at present do not satisfactorily demonstrate heritable genetic damage.
Classification. Based on the above, benzene meets the Approved Criteria for
classification as a mutagenic substance in Category 3 (R40: `Possible risk of
irreversible effects').
Benzene 131
14.2.7 Carcinogenicity
The Approved Criteria provides for the classification of carcinogenic substances
into three categories. Category 1 includes substances known to be carcinogenic to
humans, whereas Categories 2 and 3 in general are used where there is more or less
convincing evidence from appropriate long-term animal experiments indicating that
human exposure to the chemical may result in the development of cancer.
A substance is included in Category 1 if there is sufficient evidence from
epidemiological studies to establish a causal association between human exposure
and the development of cancer. The existence of a causal relationship would be any
of the following:
an increased incidence of one or more cancer types in an exposed population
?br>
compared with a non-exposed population;
evidence of dose-time-response relationships, that is, an increased cancer
?br>
incidence associated with higher exposure levels or with increasing exposure
duration;
an association between exposure and increased risk observed in more than one
?br>
study;
demonstration of a decline in risk after reduction of exposure; and
?br>
specificity of any association, defined as an increased occurrence at one target
?br>
organ or of one morphological type.
For benzene, the strongest evidence is provided by the finding of an excess
mortality from cancer of the blood and lymphatic system and a significant trend
with cumulative benzene exposure in the Chinese, CMA and Pliofilm cohorts
described in Section 11.6.1 (Hayes et al, 1997; Paxton et al, 1994a; Wong et al,
1987b). Further evidence is provided by two case-control studies which found a
significantly elevated risk for blood and lymphatic system cancer at relatively high,
but not at lower levels of exposure to benzene (Health Watch, 1998; Richardson et
al, 1992). Finally, the increase in AML risk with cumulative exposure in the
Pliofilm cohort is evidence of cell type specificity of the association between
benzene exposure and human cancer (Wong, 1995).
Classification. Benzene meets the Approved Criteria for classification as a
carcinogenic substance in Category 1 and is already classified as such and assigned
risk phrase R45: `May cause cancer'.
14.3 Summary
Benzene is currently listed in the NOHSC List of Designated Hazardous
Substances (NOHSC, 1999b) with the following classification: `Flammable';
`Carcinogen, Category 1' and `Toxic: Danger of serious damage to health by
prolonged exposure through inhalation, in contact with skin and if swallowed'.
Based on the information available at this time, benzene also meets the Approved
Criteria for classification as `Irritating to eyes, respiratory system and skin'
(R36/37/38) and as a mutagenic substance in Category 3 (R40: `Possible risks of
irreversible effects').
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15. Environmental Exposure
In this section, environmental benzene levels and major sources of entry will be
discussed separately for the outdoor and indoor environment. Given the brief
residence time of benzene in surface water and soil, the main emphasis is on
benzene in the atmosphere.
Benzene will be released through many different activities in both a point source
and diffuse manner. As such, outdoor air levels have been considered under several
different scenarios for point source releases, whereas diffuse releases are addressed
in the context of estimating a predicted environmental concentration (PEC) in air
for urban environments.
Air monitoring data exist for several areas within Australia, both for urban and
point source releases. While monitored point source releases are discussed in their
relevant sections, they cannot be compared directly to predicted levels, as these are
determined for points at 100 m from the point source, while the monitoring data are
from a range of distances.
With regard to the indoor environment, there is documentation from studies
conducted in Australia and New Zealand of the concentration of benzene in motor
vehicles. However, there are few Australian measurements of benzene levels in
indoor air in homes and non-residential buildings. In consequence, these have been
assessed on the basis of both Australian and overseas studies and the estimated
concentration of benzene in air in a model Australian urban environment.
The environmental concentration estimates developed in this section must be
interpreted cautiously as they have been derived by the application of numerous
assumptions and approximations to inherently uncertain databases such as the NPI.
15.1 Point source releases to air
This section will consider several different industries. The primary end use of
benzene is as a component of petrol (Section 7) and as such the petroleum industry
is of major importance when assessing this chemical. Additionally, other specific
industries have been identified as releasing significant quantities of benzene,
including but not limited to the steel, aluminium and chemical industries.
15.1.1 Petroleum industry
Section 7.2.1 provides a brief overview of the refining process. More detailed
information is available from the AIP website (AIP, 2000).
Petroleum refineries
Benzene emissions from petroleum refineries can be grouped into five main
categories, namely process vents, storage tanks, equipment leaks, transfer
operations, and wastewater collection and treatment. USEPA (1998b) provides
techniques for estimating emissions of benzene through leak emissions from
refineries, which essentially consist of multiplying equipment counts, equipment
leak factors and the benzene concentration in each process. While data exist on the
concentration of benzene in various refinery streams, no information is available on
Benzene 133
equipment counts and leak factors. Furthermore, leak factors are estimations in
themselves so the final result would need to be treated with caution. As such, the
USEPA method has been disregarded for the purposes of this assessment.
The Technical Guidance Document (TGD) (EC, 1996) may be used to estimate
releases. However, production of benzene per se is not the objective of the refinery.
It is to produce marketable petrochemical products, of which benzene is a
component in various grades. As such, it is difficult to apply the correct scenario
from TGD. Nevertheless, if a refinery is considered an operation that produces
substances (other than intermediates) in dedicated equipment (category 1b), TGD
indicates that 0.01% of available benzene will be emitted during the refining
processes (based on the vapour pressure of benzene at 25癈).
AIP (1997) provides data on refinery capacity for the eight Australian refineries.
For the purposes of this assessment, data from these refineries have been averaged
to create a `model refinery' with a refining capacity of 3871 kt crude oil per annum.
Benzene is expected to be available for emission during distillation activities,
catalytic reforming and catalytic cracking. In order to determine the quantity of
benzene available for release, the annual quantity of material passed through each
of the processing stages has been averaged and multiplied by the maximum
expected percentage of benzene at each stage (0.1% for crude oil undergoing
distillation, 2% for material undergoing catalytic cracking and 8% for material
undergoing catalytic reforming, as discussed in Section 7.2.1). It was assumed that
refining operations are conducted on 300 days per annum. The release estimate of
0.01% was applied to the annual amount of benzene available for emission and
converted to an expected daily release.
The following results were obtained for the `model' refinery:
Total Benzene in Benzene in Total Benzene Benzene
benzene in catalytic catalytic re- benzene release release
crude oil cracking forming production per year per day
refined (kt/y) (kt/y) (kt/y) (kg) (kg)
(kt/y)
3.9 22.4 72.7 99 9900 33
The Australian refineries have provided estimates of their benzene emissions from
1 July 1999 to 30 June 2000 to NPI and these appear similar to values reported for
the previous year.
Table 15.1 shows that reported releases (average of 43 kg per day) are comparable
with those estimated above (33 kg per day). When benzene production is calculated
based on a benzene concentration of 0.1%, 2% and 8% in crude distillation,
catalytic cracking and catalytic reforming processes respectively, the release
percentages of benzene from Australian refineries range from 0.006 to 0.039%,
with an average release of 0.016%. This compares with 0.01% used for the model
refinery. These data suggest that the model underestimates releases. Therefore,
when determining predicted concentrations in air, reported release figures will be
used.
The PEC in air will be determined following the procedure in TGD (EC, 1996).
Estimates are at 100 m from the point source and are derived as follows: PECair
(mg/m3) = emission x Cstdair, where emission = emission rate to air (kg/d) and
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Cstdair = standard concentration in air at source strength of 1 kg/d = 2.78 x 10-4
mg/m3.
Following this calculation, the atmospheric PECs for all eight Australian refineries
range from 1.6-5.5 ppb at 100 m from the point source (Table 15.1).
Table 15.1: Release of benzene from Australian petroleum refineries and
predicted environmental concentrations in air at 100 m from the source
Benzene
Benzene
Benzene
production PECair
release
release
(mg/m3)
(kt/y) Release (%)
(kg/day)
(kg/y)* PECair (ppb)
State Refinery
NSW Shell 11000 30 91 0.01 0.008 2.6
Caltex 18000 49 131 0.01 0.014 4.2
QLD BP 18000 49 59 0.03 0.014 4.2
Caltex 5600 15 108 0.01 0.004 1.3
SA Mobil 10000 27 82 0.01 0.008 2.4
VIC Mobil 7000 19 120 0.01 0.005 1.7
Shell 15000 41 129 0.01 0.011 3.5
WA BP 19000 49 71 0.03 0.014 4.2
* As reported to NPI. N.B. BP from Western Australia is for the 1998-1999 reporting period as later
results are not yet available.
In their review of studies of hazardous air pollutants performed in Australia and
New Zealand, the Victorian EPA summarised measurements near two oil refineries
at Lytton, Brisbane in 1992 (EPA Victoria, 1999). The mean of half-hour average
measurements is stated as 0.0168 mg/m3, or 5.2 ppb, which is within the range of
the above estimated atmospheric concentrations. The highest 20 half-hour averages
ranged from 0.108-1.365 mg/m3 (or 33.5-423 ppb).
Petrol terminals
Once refined, petroleum product is transferred to the Terminals in the capital cities
via pipelines, while it is shipped to Coastal Bulk Plants. The product is transferred
by road to small inland bulk plants, and this is from the main terminals. Emissions
reported to NPI during 1999-2000 have been recorded as fugitive emissions and
tend to have been estimated rather than measured. However, the emission
estimation techniques used have been stated as acceptable in the NPI database and
these figures will be used to predict concentrations in air at points 100 m from the
terminal sites.
When interrogating the NPI database, emissions were only considered for those
sites readily identified as terminals, of which there were 28 (WA data not
provided). Emissions per annum ranged from 18,000 kg from the largest terminal
to 250 kg from the smallest. The average emissions from the terminals were 2706
kg per annum (with only eight of the terminals actually reporting emissions higher
than this). To ensure conservatism in the assessment, two scenarios will be
considered, one using the average of the full sample size (including the highest
emitting terminal), and one for the highest emitting terminal. The same calculation
is used as described above and it is assumed emissions occur over 365 days per
annum. The resulting PECs in the atmosphere are shown in Table 15.2.
Benzene 135
Table 15.2: Predicted environmental concentrations in air at 100 m from
Australian terminals
PECair (mg/m3)
Terminal Release (kg/y) Release (kg/day) PECair (ppb)
Largest terminal 18,000 49.3 0.014 4.2
Average terminal 2,706 7.4 0.002 0.6
15.1.2 Steel and associated industries
Coke making operations
Coal is converted to coke in coking ovens. Benzene is contained in coke oven gas
and, as such, may be emitted during charging of coke in ovens. Coke ovens are
arranged in batteries, with operating processes as described in Section 7.2.2.
Of the two steelworks in Australia, the Port Kembla coke ovens are significantly
larger. Data provided by the applicants show that in the order of 2700 kt/y of coke
were produced at Port Kembla in 1994-1996, whereas at the Whyalla plant in the
order of 891 kt (dry weight) coal was processed during 1999.
NPI data for 1999-2000 are available for both steel works. Port Kembla reported
release of benzene to the atmosphere of 99,000 kg. This was a combination of
stack emissions (24,000 kg determined through direct measurement) and fugitive
emissions (75,000 kg determined through engineering calculations). Whyalla
reported release of benzene to the atmosphere of 24,000 kg, a combination of stack
emissions (1,100 kg determined through direct measurement) and fugitive
emissions (23,000 kg determined through engineering calculations).
The PECair is calculated following the methodology described above. It was
determined based on atmospheric release as reported by the Port Kembla
steelworks for the 1999-2000 NPI reporting period. Based on this, 99,000 kg
benzene will be expected to be released in a year. For 365 days of operation per
annum, this equates to a daily release of 271 kg. Applying the formula described
above, the PECair at 100 m from the coke ovens is 0.076 mg/m3, or 23.3 ppb.
Coal gas by-product plants
A second benzene production site at an integrated steelworks is the by-product
plant where BTX and coal tar are recovered from coke oven gasses as described in
Section 7.2.2.
The USEPA (1998b) summary of benzene emission factors for furnace and foundry
coke by-product recovery plants, covers all aspects including naphthalene
separation; tar interception, dewatering, decantation and storage; light oil storage;
flushing liquor circulation tank; and wash oil decanter and circulation tank. While it
is expected foundry coke is used in the coking operations at Port Kembla and
Whyalla, as a worst case it will be assumed that furnace coke is used. Emission
factors are provided for both controlled and uncontrolled circumstances. As the
level of control is uncertain, both scenarios are considered. Table 15.3 provides
details (with all emission factors combined to provide a total emission factor). As
described above, the Port Kembla steelworks produces in the order of 2700 kt of
coke per annum. This is assumed to be the input for the determination of benzene
release from the by-product plant.
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Table 15.3: Estimated benzene emissions from a coal gas by-product plant
Controlled Uncontrolled
Emission factor 14.7 g/t 343.1 g/t
Benzene emission per annum 40 t 927 t
Benzene emission per day 133 kg 3090 kg
PECair* 11 ppb 270 ppb
* Follows methodology described above and is for points 100 m from the point source.
BHP has provided emission estimates and monitoring data from their gas
processing plant at Port Kembla. Annual benzene emissions were estimated at 443 t
in 1995, but are predicted to fall to 70 t once an ongoing project to control tank
vent releases to air has been completed. The monitoring data show an average
concentration of 174 ppb next to the plant, decreasing to 58 ppb at 200 m and
suggest a concentration at 100 m from the plant to be in the order of 120 ppb.
These estimates and monitoring data are within the range expressed above (Table
15.3).
In addition, ambient air benzene monitoring results are available from
measurements taken from September 1996-January 1997 at several points around
the by-product plant at the Port Kembla steelworks (Westley-Wise et al, 1999).
Highest average concentrations of 1.08 ppb were found closest to the plant (26
samples at 1.1 km). At 1.2 km, averages were significantly less at 0.42 ppb, but
higher again at 1.4 and 1.6 km (0.66 and 0.67 respectively). Control sites situated at
3.8, 5.5 and 12 km from the steelworks showed mean benzene levels of 0.68, 0.73
and 0.28 ppb respectively. These readings suggest that at distances of >1 km from
the point source, levels may be expected to be close to background readings.
Coal tar distillation
Tar produced at the coal gas by-product plants at Port Kembla and Whyalla is
shipped to Koppers in Newcastle for processing, as described in Section 7.2.2.
Koppers has provided information showing that they receive tar in the order of
96,000 t/y from Port Kembla and 27,000 t/y from Whyalla, containing 0.107% and
0.157% benzene respectively. This equates to 145 t/y of benzene.
Koppers states that the only source of benzene emission to air is from the fume
scrubbing systems' stacks. Koppers operates under a NSW EPA licence requiring
the concentrations of emissions from all fume systems to be analysed each year.
Annual releases of benzene from these stacks were provided for the last five years.
As only concentrations were reported, stack velocities of 1 m/s and operating
temperatures of 300C were assumed to calculate mass emissions of benzene per
annum.
15.1.3 Aluminium industry
Aluminium is produced from bauxite, from which alumina (aluminium oxide) is
extracted by a refining process, followed by the electrolytic reduction of the oxide
to the metal in aluminium smelters.
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Alumina refining
Alumina refining involves four basic stages: (1) digestion of bauxite in hot caustic
soda; (2) removal of residues from the liquor stream; (3) precipitation of alumina
hydrate from the clarified liquor; and (4) calcination of the precipitate to produce
anhydrous aluminium oxide.
Benzene emissions from the alumina refinery at Kwinana reported to NPI are the
result of `liquor burning' processes which treat the liquor residues referred to above
(Alcoa, 2000). This is presumably due to thermal degradation of organic impurities
in the bauxite. Liquor treatment processes differ from plant to plant mainly due to
bauxite quality differences. There are six alumina refineries in Australia, two of
which have liquor burning facilities. Kwinana has the oldest liquor burning plant
and does not have volatile organic chemicals (VOC) reduction equipment fitted,
hence the reported benzene emissions. The other refinery with liquor burning
facilities at Wagerup, Western Australia has a catalytic thermal oxidiser which
removes most VOCs from the off-gas. As a result, the levels of benzene emission
do not trigger NPI reporting.
Currently, the largest refinery in Australia, QAL in Gladstone, does not have liquor
burning facilities. It is reasonable to assume that new technology when put in place
will have VOC reduction equipment. So in determining a PEC in air, the Kwinana
plant will be used as the model.
Benzene emissions reported for Kwinana were 21,000 kg during the first year of
reporting to the NPI. The site produced 1900 kt of alumina indicating benzene
emissions are around 0.001% of alumina production. Emissions were determined
through a mixture of direct measurement (at the air stack) and engineering controls
to estimate fugitive emissions and are considered reliable.
Applying the above calculation to determine a PECair at points 100 m from the
point source and assuming operation on 300 days per annum, the concentration is
estimated to be 0.019 mg/m3, or 6.1 ppb.
Aluminium smelting
Metallic aluminium is produced from alumina by electrolysis. During the process,
oxygen is deposited on and consumes the cell's carbon anodes, which are made
from coal tar pitch and petroleum coke.
Benzene is not a component of coal tar pitch or petroleum coke, but could be
released as part of the VOCs produced during smelting operations. However, it
currently appears that no estimation techniques are available to predict emissions of
VOCs. None of the six aluminium smelters provided releases of benzene (or
VOCs) in their NPI reports. Because data were provided on other releases, it is
likely that benzene was produced in quantities <10 t/y, which does not trigger
reporting. Due to a lack of information, no meaningful estimations can be made
with regard to benzene emissions from aluminium smelting plants.
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15.1.4 Chemical industry
Bulk benzene storage
Locally produced BTX and imported benzene are stored in bulk at the Terminals Pty
Ltd bulk storage facility, Coode Island - Melbourne, then distributed to the major end
user of benzene feedstock, Huntsman Chemical Company in Melbourne. Emission
levels sourced from the NPI database for the reporting period July 1999 to June 2000
indicated that 8.2 t of benzene were released by this facility.
Butadiene rubber manufacture
Qenos' Altona facility uses about 40 t of benzene per annum as a solvent
component in the manufacture of butadiene rubber. The butadiene is polymerised
in an enclosed system, as briefly described in Section 7.2.3. The benzene is a minor
component in the cyclohexane based solvent and is not consumed during the
reaction. Instead, the solvent is removed from the rubber-solvent solution by steam
stripping, condensed, purified and recycled. No data are available to confidently
predict emissions of benzene during rubber manufacture.
USEPA (1998b) does not provide any in-depth discussion on the emissions of
benzene when used as a solvent as this use is expected to be eliminated in the next
few years, although process vents, dryer vents and building ventilation systems are
identified as emission points. However, TGD (EC, 1996) may be used to estimate
emissions. Based on its vapour pressure, TGD predicts that 0.01% of benzene will
be emitted to the atmosphere when used for chemical synthesis in a continuous
process. With 40 t per annum, this corresponds to an annual release of 4 kg, with a
daily release over 300 days of 0.013 kg, resulting in a predicted concentration in air
at points 100 m from the point source of 0.004 礸/m3, or 0.001 ppb.
Releases to water can also be predicted. Based on the solubility of benzene, TGD
estimates that 0.05% will be released with wastewater. This equates to 20 kg per
annum, or 0.07 kg per day.
Styrene manufacture
The Huntsman plant in Melbourne converts in the order of 80 kt benzene per
annum to ethyl benzene for processing into styrene (see Section 7.2.3).
USEPA (1998b) has provided emission factors based on a controlled 300 kt/y
capacity integrated ethyl benzene/styrene plant (Table 15.4). Major process
emission sources are the alkylation reactor area vents, atmospheric and pressure
column vents, vacuum column vents and the hydrogen separation vent. These
emission factors will be used for this assessment, although actual emission factors
may vary with throughput and control measures.
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Table 15.4: Benzene emission factors during manufacture of styrene and
phenol in a controlled 300 kt/y capacity model plant (USEPA, 1998b)
Plant Product Source Emission factor (kg/t)*
Styrene plant Ethyl benzene Alkylation reactor vent 0.0003
Benzene drying column 0.012-0.48
Polyethylbenzene recovery column 0.002-0.005
Benzene-toluene vacuum vent 0.03-1.2
Styrene Hydrogen separation vent 0.00003-0.0012
Total 0.04433-1.6865
Phenol plant Cumene Benzene drying column 0.001
Catalyst mix tank scrubber vent 0.00795
Wash decant system vent 0.000392
8.5 x 10-4
Benzene recovery column
5.82 x 10-5
Phenol Cumene oxidation
Total 0.01025
* These emissions do not consider equipment leaks and fugitive emissions through storage and
handling.
As mentioned above, in the order of 80 kt per annum benzene is used in the
manufacture of styrene. By weight, benzene accounts for around 74% of styrene,
that is, around 28 kt per annum ethylene is required for styrene manufacture. This
indicates an annual capacity through the plant of 108 kt of materials. Applying the
above emission factors to an environment where control technology is in place,
between 4.8 and 182 tonnes per annum benzene would be emitted.
Annual benzene emissions from the Huntsman plant are reported to have fallen
from 70 t in 1996 to 7 t in 1998 following the installation of a vapour recovery
system to control emissions from tanks in the styrene plant (Huntsman, 1999).
These emissions are within the range estimated above. Therefore, as estimated
emissions from the phenol plant are much smaller (see below), the PECair will be
calculated from the most recent Huntsman emission data, that is, 7 t/y. Assuming
365 days per annum of manufacture, this equates to 19.2 kg per day, corresponding
to a PECair at 100 m from the styrene plant of 0.0054 mg/m3, or 1.6 ppb.
Phenol manufacture
Huntsman uses up to 15 kt benzene per annum in the production of cumene
(isopropyl benzene), which is then split to phenol and acetone ( Section 7.2.3).
USEPA (1998b) provides emission factors for cumene and phenol production.
Major process emission sources are process vents, equipment leaks, storage vessels,
wastewater collection and treatment systems and product loading and transport
operations. These emission factors are presented in Table 15.4.
As mentioned above, up to 15 kt per annum benzene is used in the phenol
manufacture. By weight, benzene accounts for around 65% of cumene, meaning
around 8 kt per annum propylene is required for the cumene manufacture. This
indicates an annual capacity through the plant of 23 kt of materials. Applying the
above emission factors, in an environment where control technology is in place,
235 kg per annum of benzene can be expected to be emitted. Assuming
manufacture on 365 days per annum, this equates to 0.64 kg per day, corresponding
to an estimated air concentration at 100 m from the plant of 0.16 礸/m3, or 0.06
ppb.
Priority Existing Chemical Number 21
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Australian monitoring data
In their review of studies of hazardous air pollutants performed in Australia and
New Zealand, the Victorian EPA summarises measurements taken from the Altona
chemical complex in 1995 (EPA Victoria, 1999). Benzene-emitting industries in
the area include a petroleum refinery, a petroleum terminal and the Qenos and
Huntsman chemical plants. The summarised results for 3-min average
measurements show an average of 2.7 ppb with a maximum 3-min average of 39
ppb. The maximum hourly average is given as 30 ppb. Measurements from four
other locations show averages of 0.7 (0.2-2.5); 0.7 (0.2-1.2); 0.9 (0.3-1.6); and 0.7
(0.3-1.6) ppb (timing not specified).
Unpublished data from the Victorian EPA show benzene concentrations from 0.3-
8.1 ppb in 58 air samples collected within 400-2200 m from the Huntsman facility
in April-June 1997. In samples collected with a wind switch directional sampling
system on four separate days at a point 600 m from the plant, benzene levels ranged
from 1.5-6.4 ppb during downwind periods, with upwind (background)
concentrations ranging from 0.5-4.2 ppb.
These monitored results are higher than those estimated above for butadiene rubber
and phenol manufacture, but are within the range estimated for other benzene-
emitting industries in the area.
15.1.5 Fossil fuel burning for power generation
The greatest sources of fossil fuels for electricity generation are black coal, brown
coal and natural gas (NPI, 1999d). Electricity generation in Australia for 1996/97
saw 26% come from burning of brown coal and 58.5% from black coal (ESAA,
1999).
The combustion processes in fossil fuel power generation lead to the coincidental
production of a number of NPI category 1 substances, including benzene.
Generally, this coincidental production will be below NPI threshold levels.
However, in the NPI emission estimation technique manual for fossil fuel
electricity power generation, some emission data are available (NPI, 1999d). This
manual provides an emission factor for benzene of 6.5 x 10-4 kg/t coal burnt for
electricity generation.
On this basis, the NPI has estimated emissions for the largest Australian power
station sites utilising black and brown coals. The largest Australian power stations
utilising black coal are Eraring and Bayswater in New South Wales. These power
stations use 5-6 million t of coal per annum. In estimating the emissions, a
conservative assumption of 10 million t per year black coal was adopted, providing
a maximum site emission estimation of 6.5 t benzene (NPI, 1999d). For brown
coal, the largest single facility is Loy Yang Power, located in Victoria. This site
uses an average of around 20 million t of brown coal per annum. The total
emissions estimated by NPI assumed consumption of 25 million t brown coal per
annum, resulting in an estimated emission of 16.3 t benzene (NPI, 1999d).
Table 15.5 shows the estimated concentrations assuming emissions occur on 365
days of the year and applying the usual formula to determine a local PECair at
points 100 m from the above model power plants.
Benzene 141
Table 15.5: Predicted environmental concentrations of benzene in air at 100
m from fossil fuel power generation plants
PEC
Coal Benzene Daily PEC
(mg/m3) (ppb)
Fuel type consumption (kt/y) emitted (kg/y) release (kg)
Brown coal 25,000 16,300 45 0.013 3.9
Black coal 10,000 6500 18 0.005 1.6
15.1.6 Other point sources
Landfills
USEPA (1998b) provides an emission estimation technique for determining
benzene emissions from municipal solid waste landfills. The rate of benzene
emissions from a landfill is governed by gas production and transport mechanisms.
Production mechanisms for benzene will include biological decomposition or
chemical reaction. Transport mechanisms include transportation of benzene in its
vapour phase to the surface of the landfill, through the air boundary layer above the
landfill and into the atmosphere.
Uncontrolled benzene emissions from a landfill may be estimated by determining
the uncontrolled methane generation rate, using this to determine the uncontrolled
benzene emission rate and finally, using this to calculate the uncontrolled benzene
mass emission rate.
The uncontrolled methane volumetric generation rate may be estimated for
individual landfills by using a theoretical first-order kinetic model of methane
production (developed by USEPA), from the equation QCH4 = L0R(e-kc-e-kt), where
QCH4 = methane volumetric generation rate at time T, m3/y; L0 = methane
generation potential, m3 methane per t refuse; R = average annual acceptance rate
of degradable refuse during active life (t/y); k = methane generation rate constant,
yr-1; c = time since landfill closure (0 for active landfill); and t = time since initial
refuse placement (years). Default values for L0 and k are provided by USEPA. An
L0 value of 125 m3/t refuse is stated as appropriate for most landfills. Values for k
depend on moisture levels, with higher values (a suggested value is given of 0.05/y)
appropriate for areas with normal or above normal precipitation. For landfills with
drier waste, a k value of 0.02/y is more appropriate. For the US, an average k value
is 0.04/yr. This will be used as a default value.
Information from the Australian Waste Data Base (EA, 1999a) provides average
waste generation per person for selected states. The highest waste producing state
was Western Australia with an average of 1.61 kg/person/day municipal waste
generated over the 1995-1997 period. This compared to 1.12 kg/person/day over a
six-year period (1990/91-1995/96) in New South Wales, and 1.07 kg/person/day
over a 4-year period (1992/93-1995/96) in Victoria. Only municipal wastes have
been considered as they are expected to be highest in degradable material.
For a worst case `model' landfill, it will be assumed the landfill services a
population of 150,000 and disposal is at a rate of 1.6 kg per person per day, 365
days of the year, giving an annual waste input into the landfill of around 88,000 t
municipal waste. The landfill will be assumed to have commenced operation 10
years ago and still be in operation.
Applying these inputs to the above formula, the methane volumetric generation rate
can be estimated to be 3,630,000 m3 per annum.
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Based on the methane volumetric generation rate, a volumetric emission rate for
benzene can now be estimated using the equation QBZ = 2QCH4 x CBZ/(1 x 106),
where QBZ = benzene volumetric emission rate (m3/y); QCH4 = methane volumetric
emission rate (m3/y); and CBZ = benzene concentration in landfill gas in ppm
(USEPA, 1998b).
This model assumes that approximately 50% of landfill gas is methane. USEPA
provides emission concentrations of benzene based on a landfill site's history of co-
disposal with hazardous wastes. Their analysis indicates that benzene emissions
vary with the amount of hazardous waste co-disposed and provides the following
emission concentrations:
Type of waste disposed Emission concentration (ppm)
Municipal waste co-disposed with hazardous waste 24.99
Municipal waste, unknown history of co-disposal 2.25
with hazardous waste
Municipal waste only 0.37
With the exception of incinerators for hospital waste, there are no incinerator
facilities in Australia for disposing of hazardous or municipal waste, so the main
route for disposal of hazardous waste is to landfill. For this assessment, as a worst
case, it is assumed that municipal waste is co-disposed with hazardous waste. Thus,
a benzene emission concentration of 24.99 ppm will be used.
Applying this to the benzene volumetric emission formula above, the `model'
landfill is estimated to produce 181 m3 benzene per annum. Based on this, the
uncontrolled emission rate of benzene in kg/y can be estimated by the equation IBZ
= QBZ x 78.11/(8.205 x 10-5 m3.atm/(mol.癒))(1000 g)(273 + T), where IBZ =
uncontrolled benzene mass emission rate, kg/y; QBZ = benzene volumetric emission
rate, m3/y; T = temperature of landfill gas (癈) with a default value of 25癈; and
78.11 = molecular weight of benzene (USEPA, 1998b). This gives an estimated
annual emission of benzene from the `model' landfill of 580 kg per annum.
Assuming emission over 365 days per annum, and applying the formula to
determine a PECair, then at points 100 m from the landfill, the concentration of
benzene in air can be expected to be 4.4 x 10-4 mg/m3 or 0.14 ppb. As very little
hazardous waste is likely to be co-disposed in Australia, this is very much a worst-
case estimate.
Monitoring undertaken at the Castlereagh Waste Management Centre revealed
mean benzene concentrations of 0.4-1.5 ppb at 7 sampling areas. The minimum
reading was 0.3 ppb with a maximum level of 2.3 ppb detected (Dean et al, 1996).
These readings are higher than the PEC determined above. However, these
measurements fall within the expected urban background concentration levels for
benzene (Section 15.2.2).
Waste incinerators
In the absence of data on benzene emissions from waste incinerators such as those
used for hospitals and of relevant emission estimation techniques, meaningful
calculations cannot be performed.
15.1.7 Summary
Table 15.6 summarises the predicted environmental concentrations of benzene in
air at points 100 m from the point sources discussed above.
Benzene 143
Benzene release from point sources is highest for coal gas by-product and coke
oven plants. Coal tar distilleries and petroleum and alumina refineries may also be
expected to show significant levels of benzene in surrounding air.
Table 15.6: Summary of predicted environmental concentrations of benzene
in air at 100m from various point sources
PEC (mg/m3)
Point source PEC (ppb)
Petroleum industry
0.004-0.014 1.3-4.2
?refineries
0.002 (average) 0.6 (average)
?terminals
0.014 (maximum) 4.2 (maximum)
Steel and associated industries
0.076 23.3
?Coal coking
0.04-0.86 11-270
?Coke gas processing
0.025 7.7
?Coal tar distillation
Aluminium industry 0.019 6.1
Chemical industry
4 x 10-6 0.001
?Butadiene rubber manufacture
0.0054 1.6
?Styrene manufacture
1.6 x 10-4 0.06
?Phenol manufacture
Fossil fuel burning for power generation 0.005-0.013 1.6-3.9
4.4 x 10-4
Landfills 0.14
15.2 Diffuse releases to urban air
15.2.1 Emissions estimation
Within an urban environment, there will be many sources contributing to benzene
levels in the atmosphere. These include point source releases as well as diffuse
emissions from cars, service stations, solid fuel burning and lawn mowing.
Monitoring data for various Australian cities is considered further below. To
represent other urban areas of Australia, concentrations will be modelled based
upon releases to the atmospheric air column above an Australian model city located
inland, with a population of 300,000, at a population density corresponding to
Australia's largest city, Sydney.
To determine the land area the urban centre will cover, population density is
required. The New South Wales EPA provides a 1996 population for Sydney of
around 3,820,000 people. The Sydney area covers 1548 km2 (EPA New South
Wales, 1999), giving a population density approaching 2500 people/km2. The
method for determining the volume of atmospheric air columns is described in
Connell & Hawker (1986). With a population of 300,000 , the urban centre used for
this calculation would cover a land area of 120 km2, with an atmospheric air
column volume of 7.38 x 1011 m3.
Priority Existing Chemical Number 21
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Service stations
According to AIP (2000), there are 8233 service stations in Australia. The model
population of the model urban environment is around 2% of the Australian total.
Assuming a pro rata allocation for service stations, this equates to around 165
service stations in the urban centre.
The NPI draft emission estimation technique manual has been used to estimate
benzene emissions from service stations in the urban area (NPI, 1999c). This
document provides emission rates for various stages including underground tank
filling, tank breathing and emptying, vehicle refuelling and spillage. Different
emission rates are suggested for tank filling and vehicle refuelling depending on
methods and technology. Based on the NPI manual, this assessment will use the
emission rate for submerged filling of 880 mg/L throughput and assume that
displacement losses during refuelling are uncontrolled giving an emission rate of
1320 mg/L. These emission factors are for total emissions of VOCs and result in
the estimation of aggregated emissions from service stations in the model urban
centre shown in Table 15.7.
Table 15.7: Estimated emission of volatile organic chemicals (VOC) from
service stations
Emission source Emission factor (mg/L) Throughput (ML/y) VOC emissions (kg/y)
Underground tank filling 880
Tank breathing/emptying 120
Vehicle refuelling 1320
Spillage 80
Total 2400 360 864,000
NPI speciation data for VOCs emitted at service stations show benzene to be 0.9%
by weight of petrol vapour. Therefore, of these emissions, 7776 kg per annum will
be emitted as benzene.
Petrol engine exhaust
Benzene in petrol engine exhaust emissions is a combination of unburned benzene
originally present in fuel and benzene produced as a result of incomplete
combustion of other petrol components. Non-benzene aromatics in fuels can cause
around 70-80% of the exhaust benzene formed and some also forms from engine
combustion of non-aromatic fuel hydrocarbons (USEPA, 1993). As such, vehicles
using benzene-free fuel such as LPG and diesel may still release benzene in exhaust
emissions.
The quantity of benzene in exhaust varies depending on control technology and
fuel composition. A catalytic converter is a device that uses a catalyst such as
platinum and palladium to more fully complete the burning or oxidation of the fuel
as it leaves the engine. These unburned exhaust emissions comprise hydrocarbons
including benzene (in the form of unburned petrol), carbon monoxide (formed by
the combustion of fuel) and nitrogen oxides (created when the heat in the engine
forces nitrogen in the air to combine with oxygen). The catalyst helps to convert
carbon monoxide into carbon dioxide. It also converts the hydrocarbons into carbon
dioxide and water and the nitrogen oxides back into nitrogen and oxygen.
Benzene 145
Based on the 1996 census, Canberra, which has a population similar to the model
urban centre, has 118,700 households and 188,900 registered motor vehicles
(predominantly passenger vehicles, but includes light commercial vehicles). These
figures will be assumed for the model urban environment. Data collected by the
Australian Bureau of Statistics in 1995 indicate an average distance travelled of
15,200 km per annum (including vehicles which did not travel any distance). Duffy
et al. (1999) provide measurements of benzene emissions from Australian cars and
state that pre-1986 cars have an average emission of 132 mg/km, while post-1985
cars average 41 mg/km benzene emission.
The Motor Vehicle Census for Australia (ABS, 2000a) was used to determine the
number of vehicles expected to have control technology (catalytic converters) to
those that do not. This census gives data up to the end of October 1999, and lists
vehicles by fuel type, vehicle type and age. The data were divided into various age
classes with any vehicle in or before the 1983-1986 age group being assumed to not
have control technology.
Considering figures for petrol driven passenger motor vehicles and light
commercial vehicles (these two vehicle types accounted for around 92% of the
vehicle fleet), it was determined that in the order of 35.3% of the vehicles in the
model urban centre would not have control technology (that is, we assume they will
produce emissions in line with pre-1986 cars given above). The following
emissions were calculated:
Catalytic Total km/y Emissions (kg/y)
No. of vehicles
converters
1.86 x 109
Yes 122,218 76,166
9
No 66,682 1.01x 10 133,790
Total 209,956
Under the Fuel Quality Standards Act 2000, the Commonwealth Government is
establishing national standards prescribing a range of characteristics for petrol and
diesel. Federal Cabinet has agreed that there will be a maximum benzene
concentration in petrol of 1% v/v from January 1 2006. Modelling, based on an
earlier proposal to reduce benzene content to 1% by 2005, predicted this would
lower total benzene emissions (evaporative + exhaust) by 29% in the year 2010
(Environment Australia, 2000). Reducing the benzene content of petrol by two-
thirds does not equate to a similar reduction in total benzene emissions because
benzene exhaust emissions are to a large extent independent of benzene levels in
petrol.
Lawn mowing
It is assumed for worst case purposes that all dwellings have lawns. NPI has an
emission estimation technique manual for aggregated emissions from domestic
lawn mowing (NPI, 1999a). This document provides averages for percentages of 2-
stroke and 4-stroke machines and mowing times per annum per household
depending on fuel type. Estimated emissions of benzene are provided for each fuel
type. Based on 118,700 households, the following emissions of benzene from
domestic lawn mowing can be estimated following the NPI guidelines. As for
petrol engine exhaust above, the anticipated lowering of benzene in fuel to 1% will
lead to expected reductions in benzene emissions.
Priority Existing Chemical Number 21
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Petrol Per cent of No. of Mowing Emission Emission
Engine
type mowers mowers time (h/y) factor (g/h) (kg/y)
type
2-stroke Leaded 22 26,114 443,938 17 5330
Unleaded 27 32,049 512,784 17 8720
4-stroke Leaded 18 21,366 384,588 2.3 885
Unleaded 26 30,862 462,930 2.3 1065
Total 16,000
Industry benzene emissions
The model urban centre will be assumed to have benzene emitting industries such
as a power generator and a petrol terminal. According to the estimated releases
shown in Tables 15.2 and 15.6, these sources would provide an average yearly
emission of around 30 t, based on the highest values. While this obviously depends
on industry type and control factors, it will be used for this assessment as a worst
case assumption.
Domestic solid fuel burning
While estimation techniques have been developed (NPI, 1999b), as yet no survey
data appear available to determine quantities of wood burnt in different heater types
or consumption of timber for heating purposes. UK data indicate that the
combustion of fuels contributes around 2% of total benzene emissions (Wadge &
Salisbury, 1997). This will be assumed to hold for the current calculation. Total
annual emissions from other uses estimated above amount to around 273 tonnes,
indicating a further 5580 kg are released through domestic solid fuel burning.
15.2.2 Predicted environmental concentration in urban air
The calculated daily releases within the model urban centre are summarised in
Table 15.8.
Table 15.8: Predicted daily releases of benzene within a model urban centre
Approximate annual Average daily Average daily
Emission source emission (kg) release (kg) release (%)
Service stations 7800 21 2.9
Vehicle exhaust 209,956 575 78
Lawn mowers 16,000 44 6
Industry 30,000 82 11.1
Domestic solid fuel burning 5600 15 2
Total 269,356 737 100
The atmospheric component for the model urban centre is defined as 7.38 x 1011
m3. With 737 kg entering the atmosphere daily, this equates to a concentration of 1
礸/m3, or 0.31 ppb. This applies to a ground area of 120 km2, with a population
density of 2500 people/km2.
This calculation only provides a daily contribution to the atmosphere and does not
account for breakdown and dispersion of benzene or accumulation in the
atmosphere through release occurring every day. Assuming an atmospheric half-
life of 8 days (Section 8.2.1) and no dispersion from the atmospheric column above
the urban centre to the surrounding atmosphere, the concentration of benzene in the
atmosphere is calculated to stabilise at around 3.4 ppb. This may be considered an
Benzene 147
overestimation, as dispersion from the atmospheric column above the urban centre
will occur. However, for the purposes of this assessment it will be used as a worst
case average urban atmospheric PEC.
As explained above, under the Fuel Quality Standards Act 2000, the maximum
benzene concentration in petrol will be lowered to 1% from January 1 2006. This
will lead to a significant reduction in benzene emissions, due to lower emissions
from vehicles and lawn mowers and reduced releases from petroleum refineries and
terminals, which will affect the PEC calculation for benzene in urban air.
Australian monitoring data
Table 15.9: Reported concentrations of benzene in urban air in Australia
(from EPA Victoria (1999) and DEP Western Australia (2000))
Concentration (ppb)
Location and period* Average Maximum
Adelaide, Edwardstown (industrial) 1994 19 77
Adelaide, North Terrace (CBD) 1994 8 26
Brisbane, 3 residential areas 0.62 1.67
0.502 1.41
0.328 0.78
Goat Island, NSW, downwind of refinery 1979 2.6 No data
Latrobe Valley, VIC 1987/88 (summer) ~1 No data
Melbourne, Altona 1991 7.9 20
Melbourne, CBD 1983/841 22.3 37.8
Melbourne, CBD 1990 15.7 19.8
Melbourne, CBD 1991 (?) ~16 No data
Perth and Kwinana, urban background 1993/94 1.63 No data
Perth, Darling Scarp 1993/94 0.45 No data
Perth, Gooseberry Hill 1997/98 0.15 0.21
Perth, Kwinana, plume 1993/94 4.7 No data
Perth, metropolitan area 1997/98 1.44 17.6
Perth, North Fremantle 1997/98 0.37 0.54
Perth, smog 1993/94 1.9 No data
Sydney, Cahill Tunnel (peak hour) 1991 (?) 7-38 38
Sydney, George Street, summer 1994 4.1 5.2
Sydney, George Street, winter 1994 7.6 9.5
Sydney, near point sources 1992 (summer) 2.5 6.8
Sydney, suburban 1995:
0.4 No data
?Castlereagh Llandilo Road
0.5 No data
?Castlereagh Northern Road
4.72 No data
?Earlwood
1.63 No data
?Lidcombe
0.90 No data
?North Ryde
2.40 No data
?Randwick
1.29 No data
?Rozelle
4.90 No data
?Westmead
*Results may not be comparable because of differences in sampling and analytical
methodology
1
CSIRO, 1995
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The Victorian EPA has undertaken a review of monitoring studies performed in
Australia and New Zealand on hazardous air pollutants, which was published in
1999 (EPA Victoria, 1999). In addition to this, a recent document provides
monitoring for various air toxics including benzene in Perth (DEP Western
Australia, 2000). The studies outlined in these documents are summarised in Table
15.9. All figures have been converted to ppb.
Comparison of modelled urban atmospheric PEC to monitored data
The level of 3.5 ppb for a model urban centre derived above is within the range of
results reported through monitoring studies in Australian urban centres.
15.3 Indoor air concentrations
15.3.1 Homes
In general, benzene concentrations in the home are higher than the corresponding
outdoor level. Table 15.10 summarises the results of several studies comparing
average airborne concentrations of benzene in homes with corresponding outdoor
levels.
Table 15.10: Summary of studies comparing average airborne concentrations
of benzene in homes with corresponding outdoor levels
Benzene (ppb)
Region
or area
Location Indoors Outdoors Ratio Reference
Alaska, USA Remote 6.2 2.5 2.5 Goldstein et al. (1992), as cited
in Wallace (1996)
Antwerp, Belgium, Urban 9.4 4.4 2.1 Cocheo et al. (2000)
Arizona, USA State-wide 0.5 0.4 1.3 Robertson et al. (1999)
Athens, Greece Suburban 10.1 20.7 0.5 Cocheo et al. (2000)
Bristol, England Urban 2.5 1.6 1.6 Brown & Crump (1996)
State-wide 3.1 1.8 1.7 Wallace (1996)
California, Maryland
and New Jersey, USA
California, USA Rural 1.1 0.4 2.8 Sheldon et al. (1991), as cited in
Wallace (1996)
Copenhagen, Denmark Urban 4.5 3.1 1.5 Cocheo et al. (2000)
Erfurt, Germany Urban 1.2 0.9 1.4 Schneider et al. (1999)
Hamilton, Canada Urban 1.7 1.2 1.4 HAQI (1997)
Hannover, Germany Urban 1.0 2.9 0.3 Levsen et al. (1996)
Semi-rural 0.7 0.3 2.3
Hertfordshire, England Semi-rural 3.7 2.2 1.7 Brown & Crump (1996)
Huddersfield, England Suburban 0.5 0.4 1.4 Kingham et al. (2000)
Melbourne, Australia Suburban 1.0 0.6 1.7 Brown (2000)
Mumbai, India Urban 11.6 13.5 0.9 Srivastava et al. (2000)
Munich, Germany Urban 0.8 0.8 1.0 Gebef黦i et al. (1995)
Murcia, Spain Urban 12.3 11.7 1.1 Cocheo et al. (2000)
Nancy, France Urban 3.3 1.4 2.4 Gonzalez-Flesca et al. (1999)
Padua, Italy Urban 7.0 8.0 0.9 Cocheo et al. (2000)
Rouen, France Urban 9.5 4.7 2.0 Cocheo et al. (2000)
Rotterdam, Holland Urban 2.0 0.9 2.2 Lebret et al. (1986)
Windsor, Canada Urban 1.0 0.8 1.3 Bell et al. (1994)
The predominant finding of higher benzene levels indoors than outdoors is
attributed to specific sources located within or in the immediate vicinity of the
Benzene 149
home and/or the inability of these emissions to escape (Wallace, 1989). These
include environmental tobacco smoke (ETS), heating and cooking systems,
cooking fumes, evaporation from products and materials used in the home, and
drift of vapours from attached garages or external sources of benzene.
Longitudinal studies of individual homes have shown that contributions from
domestic sources are overlaid on those from outdoor air, which generally account
for most of the seasonal and diurnal variations in indoor benzene levels (Gebef黦i
et al, 1995; Lioy et al, 1991; Thomas et al, 1993). However, indoor air levels also
depend on the proximity to road traffic and the degree of ventilation, which in turn
is dependent on diurnal, seasonal and climatic conditions (Levsen et al, 1996; Gilli
et al, 1996; Cocheo et al, 2000). Ambient air concentrations are lowest during the
night. However, if houses are closed up at night, either for safety reasons or in
colder climates, especially during winter, benzene levels acquired during the day
are unable to escape. Therefore, the total exposure over 24 h is increased relative to
outdoor levels. During summer, and in warmer climates, when ventilation is
greater, indoor concentrations are similar to outdoor concentrations.
In addition to ventilation patterns, the types of furnishing materials may influence
the amount of benzene retained in the home. A study of benzene exposure in
European cities found that, while urban pollution levels increased from north to
south, the ratio of indoor to outdoor air levels were lower in southern European
urban areas than in the north (Cocheo et al, 2000). One explanation proposed by the
authors is that volatile organic pollutants, including benzene, from both indoor and
outdoor sources may be trapped in absorbent fabrics and other materials, resulting
in higher residual levels in houses that have more carpets, wood, linoleum and soft
furnishings, as do houses in cold climates.
In the absence of localised sources inside the home (such as proximity to an
attached garage, room with smokers), there are no significant differences in
benzene concentrations between kitchens, living rooms and bedrooms, height
above floor level, or older versus newer apartments (Schneider et al, 1999).
Approximately 85% of ETS comprises sidestream smoke emitted by the
smouldering end of a cigarette (cigar or pipe, as the case may be), with lesser
contributions from the mainstream smoke that active smokers directly inhale and
exhale. The emission factor for sidestream smoke is in the range of 300-500 礸
benzene per cigarette, with little variability between brands (Daisey et al, 1998;
Miller et al, 1998). In two studies conducted in 200-300 homes with and without
smokers in Germany and USA respectively, the average increase in benzene levels
in homes with one or more smokers was 4.0 礸/m3 or 1.2 ppb (Wallace, 1996).
Surprisingly, an international study of exposure to tobacco smoke reported that
fixed-site measurements in an unspecified number of homes in Sydney found
slightly higher indoor air concentrations of benzene (median: 1.1 ppb) in non-
smoking houses than in those where cigarettes, pipes or cigars were smoked within
the communal areas (median: 0.9 ppb) (Phillips et al, 1998).
Herbal cigarettes, marijuana, incense sticks and mosquito coils produce benzene
emissions similar to cigarettes, about 0.4-0.5 mg/g material burnt (L鰂roth et al,
1991). However, the frequency of burning such articles is much less than for
tobacco cigarettes and their contribution to indoor benzene levels is expected to be
minimal.
Combustion of wood produces approximately 400 mg benzene for every kg dry
wood burned or 114 礸 benzene per kJ heat produced compared to 9 礸/kJ for
Priority Existing Chemical Number 21
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kerosene and 2 礸/kJ for LPG. Per-meal emissions from unflued cookstoves, such
as a caravan or enclosed barbecue, are estimated to be 36 礸.h/m3 (LPG), 124-268
礸.h/m3 (kerosene), 316 礸.h/m3 (charcoal) and 1220 礸.h/m3 (wood) (Zhang &
Smith, 1996). In actively burning fires, most of the combustion products go up the
chimney. However, even well constructed open fireplaces are subject to downdrafts
and smoke drift, especially when the fire is low. In addition, high outdoor benzene
levels in smoke produced by wood fires can re-enter homes, particularly in areas
subject to temperature inversions during winter.
Volatile emissions from cooking oils have been studied by Pellizzari et al. (1995)
and Shields et al. (1995) who found that emissions of benzene in wok cooking
vapours were higher from unrefined rapeseed oil than from peanut, soybean and
canola oils (2.4 compared to 0.2, 0.5 and 0.7 ng/mL respectively in one
experiment). Wok cooking is generally carried out at very high temperatures (275-
280癈). Reducing the temperature of cooking from 275癈 to 185癈 reduced
benzene emissions by sevenfold (Shields et al, 1995). However, given the average
use of cooking oil in the home (about 50 mL per day), this source would not
contribute measurably to benzene levels in the indoor atmosphere.
Some petroleum-based domestic products such as oil-based paints, particleboard
and adhesives may contain very low concentrations of benzene as an impurity. The
contribution to indoor air levels of benzene from these sources has not been
measured, but is expected to be low. In New Zealand, Stevenson & Narsey (1999)
found that redecorating activities increased the indoor concentrations of toluene
and xylenes, but not benzene. Brown (2000) did not identify significant sources of
benzene release in new and renovated buildings in Melbourne.
Indoor air levels of benzene are significantly increased in houses with an attached
garage (Brown, 2000; Gebef黦i et al, 1995; Levsen et al, 1996; Thomas et al,
1993). Sources of benzene in garages include vapours from cars and lawn mowers
and stored petrol or other solvents. In New Zealand, the highest indoor air level for
any site investigated (16.6 ppb or 20 times typical ambient air levels) was in a
home with smoker occupants and an internal double garage housing two cars
(Stevenson & Narsey, 1999). Sampling of 52 private flats in Munich revealed one
unusually high indoor concentration (>31 ppb, or >37 times the outdoor
concentration) which was attributed to infiltration from a garage (Gebef黦i et al,
1995). Benzene concentrations in four attached garages in the USA ranged from 1-
61 ppb; the mass transfer from sources in the garage to living areas in three of these
homes ranged from 730-26,000 礸/h (Thomas et al, 1993). In Alaska, where petrol
contains 5% benzene compared to 1.5% in other US states, garages were found to
have benzene air levels ranging from 19-350 ppb (Gordian & Guay, 1995).
Removal of a car, lawn mower, petrol canister and solvents from a garage in
Hannover, Germany, reduced the benzene concentration in the garage from 25 ppb
to 0.4 ppb (Levsen et al, 1996).
The measured indoor air levels shown in Table 15.10 refer to one Australian and a
number of overseas localities which are difficult to compare, let alone extrapolate
to the Australian continent as a whole, because of differences in a number of
factors such as ambient benzene levels, climate, construction methods, heating
systems, ventilation practices, smoking occupancy and the prevalence of homes
with attached garages. It is nonetheless reasonable to assume that the average
indoor to outdoor ratio in urban environments in Australia is close to the median of
the available Australian and overseas data excluding remote, rural and semi-rural
regions and areas, or 1.4 (range: 0.3-2.4).
Benzene 151
The PECair in the model Australian urban environment described in section 15.2.2
is 3.4 ppb. Therefore, the estimated indoor air level taken forward for public
exposure assessment is 1.4 x 3.5 = 4.8 ppb.
15.3.2 Non-residential buildings
Measurements of benzene in offices, shops, classrooms, hotels, bars, restaurants,
theatres and other non-residential indoor environments are limited compared to
homes. Available literature data giving indoor to outdoor concentration ratios are
presented in Table 15.11. The highest ratios were due to specific sources such as
petrol vapours and engine exhaust at a motocross event or tobacco smoke in bingo
halls and taverns. Of these, emissions from indoor use of motor vehicles are not
expected to contribute measurably to average indoor air levels of benzene, whereas
tobacco smoke may have a significant impact, depending on smoking policies and
occupancy, volume of space, rate of ventilation, heating, air-conditioning and air
cleaning systems.
Table 15.11: Benzene air concentrations in non-residential buildings
Ppb
Location Building or venue Indoors Outdoors Ratio Reference
California, USA Portable classrooms 0.5-0.6 0.5-0.6 1 SUSD (1999)
Manila, Philippines Office 0.4 1.1 0.4 Reverente et al.
(1996)
Restaurant 5.3 14 0.4
Shopping centre 1.2 3.9 0.3
Melbourne, Australia Gymnasium 0.6-1.9 0.8 0.8-2.4 Brown (2000)
Mumbai, India Offices, smoking 15.1 9.3 1.6 Srivastava et al.
(2000)
Research library 10.7 11.4 0.9
Sydney, Australia 209-334 2.3* 90-150
Entertainment centre Angove et al.
(motocross event) (2000)
Washington DC, USA Library of Congress 2.1 1.9 1.1 NIOSH (1996)
Windsor, Canada Offices, non-smoking 1.0 0.8 1.3 Bell et al. (1994)
Hotel rooms 1.2 0.8 1.5
Bingo halls 6.4 0.8 8.0
Taverns 10.7 0.8 13
* Sample taken inside building prior to the motocross event.
Other Australian data include a study conducted in Hobart, Tasmania, which found
indoor air levels of benzene ranging from 0.9-7.8 ppb in eleven office buildings in
the central business district (Mesaros, 1998). However, these buildings were
selected for investigation because a very high number of their occupants suffered
from typical sick building syndrome symptoms.
In the absence of sufficiently representative measured data, it is reasonable to
assume that the concentration of airborne benzene in non-residential buildings in
Australia is similar to the estimated indoor air concentration in Australian homes,
except in restaurants, bars and the like with high levels of ETS.
As benzene and nicotine are both found in the vapour phase of cigarette emissions,
nicotine concentrations can be used as an indicator of relative benzene exposures.
A recent review of ETS exposure quoted typical nicotine air levels of 1-3 礸/m3 in
residences, 3-8 礸/m3 in restaurants, and 10-40 礸/m3 in bars (Hammond, 1999).
As such, the additive effect of ETS in restaurants and bars where smoking is
Priority Existing Chemical Number 21
152
permitted could be higher than in the homes of smokers by a factor of 2.7 (8/3) and
13 (40/3) respectively. The indoor air concentration of benzene in Australian
homes is estimated at 4.8 ppb (Section 15.3.1) and the average additive effect of
ETS in homes with smokers at 1.2 ppb (Wallace, 1996). Therefore, the estimated
benzene levels in restaurants and bars with smoking occupancy are 8.0 and 21 ppb
respectively. These are higher than the measured values shown in Table 15.11, but
are considered reasonable worst case estimates.
15.3.3 Motor vehicles and other means of transportation
Several studies conducted in a number of locations have consistently found that
road users including drivers and passengers in all kinds of vehicle are exposed to
higher levels of benzene than background air quality data may suggest (Taylor &
Fergusson, 1997).
In parked vehicles, the excess benzene concentration is due to evaporative
emissions from the vehicle itself. Among others, these depend on the benzene
content and vapour pressure of the fuel, the fuel system, engine temperature,
ambient weather conditions, and the degree of enclosure of the passenger cabin. In
vehicles in traffic, however, part of the excess is due to the intake of exhaust fumes
from the tailpipes of preceding vehicles. As such, it depends not only on the above
factors, but also on traffic level, flow, and mix in terms of cars with or without
catalytic converters, trucks, buses and motorcycles. Generally, the excess would be
minimal in new cars with fuel injection travelling at high speed in light traffic on a
windy day with vents, windows and sunroof tightly closed and the air-conditioning
on. Conversely, it would be maximal in old, carburetted, poorly maintained cars
that travel slowly in congested traffic on a still day with vents and windows open
and fans on. High benzene levels may also build up in vehicles left in undercover
car parks or transiting tunnels and during refuelling at petrol stations (Duffy &
Nelson, 1997; Taylor & Fergusson, 1997).
Table 15.12 summarises the available Australian and New Zealand studies that
have measured the concentration of benzene inside moving vehicles during city
commutes.
Table 15.12: Summary of Australian and New Zealand studies of in-vehicle
benzene air concentrations during city commutes
Mean
benzene
No. of
commutes level (ppb) Reference
Location Conditions
Private cars
Auckland Catalyst-equipped car, summer 2 12 Stevenson & Narsey (1999)
Catalyst-equipped car, winter 2 20
Melbourne Post-1986 car 1 13 Torre et al. (1998)
Post-1986 cars 5 10 Torre et al. (2000)
Sydney Pre-1986 car 4 48 Duffy & Nelson (1997)
Post-1986 cars 8 22
Public transport
Melbourne Tram 1 7.7 Torre et al. (1998)
Train 5 1.6 Torre et al. (2000)
Sydney Diesel bus, air-conditioned 3 5.9 Duffy & Nelson (1997)
Diesel bus, not air-conditioned 4 8.8
Benzene 153
Average air levels were approximately 15 ppb and 48 ppb in cars with and without
catalytic converters respectively. Weighting the latter according to the estimated
number of post-1985 vehicles in the model urban environment described in Section
15.2.1 gives an estimated average benzene concentration in motorcars of about 28
ppb. This is higher than levels measured in the USA where the car fleet is newer
and petrol contains less benzene than in Australia, but within the range reported
from Europe and Korea (Jo & Park, 1999; Rodes et al, 1998; Taylor & Fergusson,
1997).
In trams and buses, benzene levels averaged 7.5 ppb. The lowest level was found in
trains, indicating that rail commuters are unlikely to be exposed to benzene levels
exceeding those in ambient air.
In Melbourne, personal monitoring of two individuals commuting by foot or
bicycle showed benzene exposure levels of 4.4 and 12.2 ppb respectively,
compared to a concentration of 6.0 ppb at a roadside point along their route (Torre
et al, 1998). Overseas data reviewed by Taylor & Fergusson (1997) suggest that
pedestrians and cyclists typically are exposed to two times ambient air levels. This
would equate to an average roadside concentration of 6.8 ppb in the model
Australian urban environment described in Section 15.2.2, where the predicted
atmospheric concentration of benzene is 3.4 ppb.
15.4 Concentrations in water and soil
15.4.1 Water
Predicted environmental concentration (local PEC)
Some release to wastewater may be expected to occur during benzene production.
Within the sewage treatment plant (STP), 86% of benzene will be removed in the
following manner, assuming benzene is inherently biodegradable and based on the
SIMPLETREAT tables provided in TGD (EC, 1996): 70% in air, 1% in sludge and
15% by degradation. This leaves 14% available in the water column on release to
receiving waters. This level of removal is supported by a report in IUCLID where
benzene levels in the influent and effluent from a municipal STP in The
Netherlands in 1989-1991 averaged 3.9 and <0.5 礸/L respectively. This suggests
removal of >87%.
By far the highest producer of benzene (excluding incidental production through
petrol combustion in motor vehicles) is the petroleum industry. Table 7.3 shows
that in Australia in the order of 440 kilotonnes per annum benzene is either
extracted, manufactured or imported. NPI data for the 1998-99 reporting year show
that only two refineries reported releases to water, namely 1100 kg from the Mobil
refinery in South Australia and 120 kg from the BP refinery in Queensland. The
calculated benzene production at the Mobil refinery in South Australia is 82 kt per
annum (Table 15.1). As such, the release of 1100 kg (which was derived through a
combination of measured data, engineering controls and emission estimation)
suggests a release of 0.0013%
Using the maximum reported release of 1100 kg per annum and assuming release
to a sewage treatment plant with a daily outflow of 250 ML and production on 300
days per annum, the PEClocal-surfacewater can be estimated as follows: Production =
82,000 t; days of operation per annum = 300; daily production = 273 t; daily release
Priority Existing Chemical Number 21
154
to STP = 273,000 kg x 0.000013 = 3.7 kg; removal from STP = 3.15 kg;
concentration in STP = 2 礸/L; PEClocal-surfacewater = 0.2 礸/L (dilution of 10:1).
A continental PEC will not be considered for this assessment, as there are
insufficient data to estimate the full extent of incidental benzene production and
release around the country. However, the continental PEC would be expected to be
lower than that derived for local conditions.
Comparison with measured data
Due to its high volatility and low residence time in water, benzene would not be
expected to be detected at significant levels in surface waters. The 1996 Australian
drinking water guidelines state that benzene has not been detected in Australian
drinking water (NHMRC, 1996).
International data provided in IPCS (1993) are summarised in Table 15.13.
Table 15.13: International data on benzene levels in water (IPCS, 1993)
Concentration
?br>
Source Country (礸/L) Comments
Rainwater UK 87.2 Appears high for unknown reason(s)
Germany 0.1-0.5
Surface water USA 0.004-0.9 Downriver chemical plant outfall
USA (13 locations) 1-13 Both upstream and downstream
near industrial outfall
USA (Potomac River) <2 Detection limit 2 礸/L
Switzerland (Lake Zurich) 0.03
UK (80 water bodies) 7.2 Average of 61of 154 samples above
the detection limit of 0.1 礸/L
Netherlands (Rhine River) <0.1 Sampling in 1979
Germany <0.1-1 Occasionally up to 200 礸/L
Sea water Gulf of Mexico 0.005-0.015 Unpolluted waters, sampling in 1977
USA (Brazos River estuary) 0.004-0.2 Flows into Gulf of Mexico
0.06 x 10-3 Open sea
Atlantic Ocean
0.1-4.6 x 10-3 Open sea
Baltic Sea
USA 1.6
Ground water 63 private wells, 3.2% of samples
contained benzene
Germany 0.02-0.005
USA 30-300 Contaminated well water
Netherlands 0.005-0.03 Unpolluted areas
Compared to these overseas river water measurements, the calculation for an
Australian PEC in surface water may be slightly less than expected. However, it is
considered realistic for the purposes of this assessment.
Benzene was detected in 37 of 987 bottom sediments in Japan at levels of 0.5-30
礸/kg. Lake Pontchartrain in USA showed sediment levels of 8-21 礸/kg in 1985.
Between 1980-82, benzene was detected in 9% of sediment samples taken from
335 observation sites in USA, the median level being <5 礸/kg (IPCS, 1993).
Benzene 155
15.4.2 Soil
NPI data show that the highest reported benzene release to soil is 45 kg per annum
from a bulk petroleum storage facility. The top five sites where benzene release to
land was reported total <80 kg per annum throughout the country. While it is not
possible to predict a concentration in soil that would have any meaning, the NPI
data indicate that benzene release to soil is likely to be marginal and not result in
significant soil contamination.
Some exposure may result though application of sewage sludge, although the full
extent of this is not known in Australia. However, it is understood that Sydney
Water sends >90% of their sludge (possibly up to 200,000 tonnes per annum) to
beneficial use. Some goes to agricultural use and is soil incorporated, while some
goes to compost and horticulture where surface application may occur.
Measurements of benzene in sewage sludge or its subsequent soil concentration
after application to land could not be identified. Additionally, as described above,
only in the order of 1% benzene released to a STP is expected to bind to sludge, so
sludge application to land is unlikely to provide a high exposure route.
Most measured data on benzene in soil were obtained to determine the extent of
direct contamination by spillage or leakage. In soils in the vicinity of five industrial
facilities using or producing benzene in USA, benzene levels ranged from <2 to
191 礸/kg, whereas the concentrations in unpolluted soils in The Netherlands were
less than those found in ground water, that is <0.005-0.03 礸/L (IPCS, 1993).
15.5 Summary
Table 15.14 summarises the predicted environmental benzene concentrations in air
and water, based on the assessment findings discussed above.
Table 15.14: Approximate predicted concentrations of benzene in air and
water
Benzene concentration
3
ppb
Environment Source type Description 礸/m
Outdoor air Point* Petrol refineries 17.6 5.5
Petrol terminals 13.4 4.2
Coal coking plants 91 28.4
Coal gas by-product plants 860 270
Coal tar distilleries 25 7.8
Alumina refineries 19 6.1
Chemical industry 6.5 2.0
Fossil fuel burning power plants 13 3.9
Landfills 0.44 0.14
Diffuse Urban atmosphere 11 3.4
Urban roadside air 22 6.8
Indoor air Diffuse Homes and other buildings 16 4.8
Restaurants, smoking 26 8.0
Bars, smoking 67 21
Cars with catalytic converters 48 15
Cars without catalytic converters 154 48
Buses and trams 24 7.5
Surface water Point Treated oil refinery wastewater 200 0.20
* Maximum predicted concentrations at 100 m from source.
Priority Existing Chemical Number 21
156
16. Public Exposure
16.1 Direct exposure
Active smoking
In Australia, 23.8% of the adult population are smokers; 27.4% are ex-smokers and
48.9% have never smoked (ABS, 2000b). In a survey conducted in Victoria in
1996-97, the self-reported number of factory-made cigarettes smoked per day
averaged 17.8 in regular smokers aged 16 years and over (Trotter et al, 1998).
The quantity of benzene emitted in mainstream cigarette smoke varies from 0.4-
104 礸/cigarette; it is proportional to the tar level and is not reduced by cigarette
filters (Smith et al, 1997). In 26 brands on the UK market, the yields ranged from
3-60 礸/cigarette, with over half the brands yielding 45-55 礸 (Darrall et al, 1998).
Based on a value of 50 礸/cigarette, the daily benzene intake of an average smoker
(17.8 cigarettes per day) is increased by 0.89 mg per day. For an adult person with
a respiration rate of 22 m3/day, this corresponds to the continuous inhalation of
ambient air containing 12.5 ppb of benzene.
Petrol
In Australia, the benzene content of petrol can range from 1-5% v/v. Members of
the public may be exposed directly to petrol used as fuel in private vehicles, lawn
mowers, outboard engines etc. Although skin contact can occur from accidental
drips or spills or the use of petrol for cleaning purposes, it is likely to be infrequent
and of short duration. Direct exposure to benzene vapours occurs in garages and
undercover parking stations, during petrol pumping at self-service petrol stations
and inside parked cars with hot-soaked engines. Reported air levels in these
locations vary widely depending on local circumstances, but are typically in the
order of 10-100 ppb (Duffy & Nelson, 1996; Leung & Harrison, 1998; Nordlinder
& Ljungkvist, 1992; Nordlinder & Ramn鋝, 1987; Thomas et al, 1993) and are
consistent with Australian data reported in Section 17.1.1.
Other consumer products
Paints, primers, paint strippers, lubricants, abrasives, model and hobby glues and
other consumer products may contain organic solvents which in turn may contain
very low concentrations of benzene as an impurity (Rastogi, 1993). The
contribution to public exposure to benzene from these sources has not been
quantified, but is expected to be very low.
16.2 Indirect exposure via the environment
Air
Although benzene is not persistent, it is ubiquitous in ambient air because of its
widespread sources of release.
In Australia, measured levels of benzene in air range up to 77 ppb for outdoor
urban environments (Table 15.10), 25 ppb in residential buildings (Brown, 2000)
and 343 ppb inside petrol-fuelled vehicles (Duffy & Nelson, 1997).
Benzene 157
The average atmospheric concentration of benzene in a model Australian urban
environment is estimated at 3.4 ppb, with indoor/in-vehicle air levels ranging from
4.9-48 ppb (Table 15.15). These levels would be higher in homes, workplaces and
vehicles with smoking occupancy. The contribution of ETS to indoor benzene
levels is poorly documented, but is likely to vary considerably depending on local
circumstances. In two large studies in Germany and USA, the average increase in
benzene levels was 1.2 ppb in homes with one or more smokers (Wallace, 1996).
Drinking water
Contamination of surface water and groundwater can result from removal of
benzene from the air in rain, leakage of underground storage tanks, and leaching of
oil well and landfill sites.
A number of US studies have reported benzene at levels in the order of 5 ng/L in
surface and well waters (Wallace, 1996). In Canada, benzene (detection limit 1
礸/L) was found in 50-60% of drinking water samples from 30 treatment facilities
in a national survey, although in provincial monitoring programs it has rarely been
detected at concentrations >1 礸/L (Government of Canada, 1993). In Germany,
drinking water has been found to contain 18-45 ng/L benzene (GDCh, 1988).
To date, benzene has not been detected in drinking water in Australia (NHMRC,
1996).
Soil
Benzene has been detected in soil as a result of direct contamination by spillage or
leakage, at concentrations 191 礸/kg (IPCS, 1993). The contribution from traffic
emissions is likely to be negligible, because of the rapid volatilisation of benzene to
air. Therefore, exposure of young children to benzene by ingestion of soil not
directly contaminated by petrol is likely to be negligible.
Food
As discussed in Section 8.2.5, benzene does not accumulate in the food chain.
However, the chemical may enter foods as a result of equilibration with
surrounding media or through migration from cooking utensils and food packaging
materials.
There are early reports of benzene being found in butter (0.5 ng/g), irradiated beef
(19 ng/g), rum (120 ng/mL), eggs (500-1900 ng/g), fish (3-88 ng/g) and clams and
oysters (220-260 ng/g) (IARC, 1982a; IPCS, 1993). More recent studies reviewed
by Wallace (1996) found insignificant amounts in most of 107 foods (including raw
eggs). Exceptions included preserved jams and sauces, shelled peanuts and fried
eggs, which contained 5-38 ng/g benzene. A 1993 survey in the UK found low
levels of benzene (1-18 ng/g) in carcass meat, offal, meat products, poultry, fish
and nuts but not in dairy products, bread, cereals, sugar, vegetables, fruit or
beverages (MAFF, 1995).
Benzene was, however, detected at low concentrations (27-56 ng/g) in the peel of
three (apple, kiwi fruit and orange) of 24 fruit and vegetable samples purchased
from local shops in Poland (G髍na-Binkul et al, 1996); it was suggested by the
authors that the likely source was absorption of benzene from the air by lipophilic
components of the peel. The chemical was also found in olive oil produced from
fruit stored in a shed housing harvesting machinery (Biedermann et al, 1996).
Parking a small grass mower in the shed caused air levels within the shed to
Priority Existing Chemical Number 21
158
increase from 0.1 to a maximum of 1.9 ppb in 3 h. The average benzene
concentrations in oil obtained from olives stored in such sheds at three different
locations were 3, 19 and 40 ng/g.
The mean airborne benzene levels in two petrol station kiosks in UK were 3.4 and
27 ppb (CONCAWE, 1998b). A survey of fatty foods sold from petrol stations or
roadside stalls in the UK found benzene present in less than half of 114 packages of
butter, margarine, lard and bacon (MAFF, 1996). Mean benzene levels were
generally in the order of 10-20 ng/g. The pattern of distribution throughout the food
samples indicated that the contamination was the result of either road transport or
diffusion from the air and that penetration of products protected by impermeable
packaging was negligible. Of 221 food products purchased at petrol service stations
in Germany, only one (ice cream) contained benzene in detectable amounts (8 ng/g)
(Eikmann et al, 1992). A recent, comprehensive review of studies conducted on
hydrocarbon contamination of foods sold at petrol stations and shops situated near
busy roads concluded that the levels of hydrocarbons (including benzene) in foods
from these outlets was comparable to those found in food sold from shops remote
from hydrocarbon sources (CONCAWE, 2000).
Benzene has been found in non-stick and thermoset polyester cookware, expanded
polystyrene food packaging articles, polyvinyl chloride water bottles exposed to
sunlight, containers made from contaminated recycled polyethylene terephthalate
bottles, and in microwave heat susceptors packaged with foods such as pizzas and
chips (Fayad et al, 1997; Gramshaw and Vandenburg, 1995; Jickells et al, 1990;
Komolprasert et al, 1997; McNeal & Hollifield, 1993). However, in no case was
migration considered likely to result in concentrations in foods exceeding 10 ng/g.
The daily dietary intake of benzene in the UK population is estimated at 0.5-2.4
礸/day (MAFF, 1995). There is no indication in the published or unpublished
literature that food is an important source of exposure to benzene, accounting for at
most 2.5% of total daily intake (CONCAWE, 2000).
16.3 Exposure assessment
Method and assumptions
It is widely agreed that inhalation is the predominant pathway for benzene exposure
in humans, with <1-3% of total intake apportioned to skin contact and ingestion of
food and water (Government of Canada, 1993; IPCS, 1993; Wallace, 1996; WHO,
2000). It has also been shown that the main microenvironments contributing to
inhalation exposure are the home, the workplace, road use and tobacco smoke,
while infrequent activities of short duration such as car refuelling have little impact
on total intake (Leung & Harrison, 1998; MacIntosh et al, 1995). In consequence,
this assessment of public exposure to benzene will disregard non-inhalation
exposure and focus on the key environments of the home, the workplace and the
road, and on active and passive smoking. In addition, although benzene has been
detected in human breast milk (Section 9.2.2), quantitative data are not available
and intake via this route is not included for the purposes of this report.
Exposures at home, at work and on the road are assumed to occur within the setting
of the model urban environment described in Section 15.2. The corresponding air
concentrations are those estimated in Section 15.3 and summarised in Table 15.15.
Daily and cumulative exposures are estimated for four different age groups
comprising 6 years of childhood, 14 years of education, a working life of 40 years
Benzene 159
and 18 years of retirement (ABS, 2000b) and for lifestyles identified as non-ETS
exposed, passive smoking and, in adults, active smoking. The estimated time spent
in relevant environments by each age group is given in Table 16.1, based on data
quoted in Langley et al. (1996). All age groups are assumed to spend 20 h/day in
residential and other buildings. Non-ETS exposed persons are assumed to avoid all
exposure to ETS and all schools and means of public transportation are assumed to
be smoke-free. ETS exposure is assumed to entail an increase in indoor/in-vehicle
air levels of benzene of 1.2 ppb, as described in Section 16.2. Finally, it is assumed
that active smokers consume 17.8 cigarettes a day, equivalent to the inhalation of
12.5 ppb benzene for 24 h/day from the age of 21 and are exposed to ETS
throughout.
Table 16.1: Public exposure scenarios
Age group (years)
Environment 0-6 7-20 21-60 61-78
Outdoors 4 h/day 4 h/day 4 h/day 4 h/day
Homes 19?h/day 13 h/day for 11 h/day for 19 h/day
190 days/year 225 days/year
19 h/day for 19 h/day for
175 days/year 140 days/year
Schools - 5?h/day for - -
190 days/year
Workplaces - - 8 h/day for 225 -
days/year
Car transport ?h/day ?h/day for 190 1 h/day -
days/year
Other road use* - 1 h/day - 1 h/day
* Walking along urban roads and bus, tram and bicycle riding.
Results
Table 16.2 summarises the estimated daily and cumulative exposures per age and
lifestyle group calculated in accordance with the above assumptions.
Table 16.2: Estimated 24 h benzene exposures (in ppb) and cumulative
exposures at the top of each age bracket (in ppb-years, rounded to the
nearest 5) of the general population in a model Australian urban environment
Non-ETS exposed Passive smokers Active smokers
Age group Ppb Ppb-years Ppb Ppb-years Ppb Ppb-years
0-6 years 5.1 30 6.0 35 - -
7-20 years 4.9 100 5.7 115 - -
21-60 years 5.5 320 6.5 375 19.0 760
61-78 years 4.7 405 5.6 485 18.1 1086
Based on the assessed cumulative exposures, the lifetime weighted 24-h exposure
is approximately 5.2 ppb in non-ETS exposed persons, 6.1 ppb in passive smokers
and 15.2 ppb in active smokers. The daily intake in a 10-year old child with a
bodyweight of 30 kg and a respiratory volume of 15 m3/day is 8.0 礸/kg/day in the
absence and 9.3 礸/kg/day in the presence of ETS exposure. In adult males aged
21-60 years with a bodyweight of 70 kg and a respiratory volume of 22 m3/day, the
Priority Existing Chemical Number 21
160
estimated intake is 5.6 礸/kg/day in non-ETS exposed persons, 6.6 礸/kg/day in
passive and 19 礸/kg/day in active smokers. In adult females aged 21-60 with a
bodyweight of 60 kg and a respiratory volume of 22 m3/day, the estimated intake is
6.6 礸/kg/day in non-ETS exposed persons, 7.7 礸/kg/day in passive and 22
礸/kg/day in active smokers.
In terms of apportionment, indoor air, road use and outdoor air account for 73, 16
and 11% respectively of the estimated lifetime exposure to benzene in non-ETS
exposed persons. In ETS exposed persons, passive smoking accounts for 15% of
lifetime exposure. In smokers, 6% of lifetime exposure is attributable to ETS and
60% to the inhalation of mainstream smoke.
Population groups likely to be exposed to extreme benzene levels
The estimates given in Table 16.2 refer to a cross-section of the population in the
model urban environment described in Section 15.2. Individual exposure levels
may, of course, be vastly different, depending primarily on where people live and
work, what car they drive, how much time they spend outdoors, on the road, or in
smoky environments, and, in active smokers, on the quantity and type of tobacco
they consume.
As a rule, exposures would be considerably below average in people who live in
semi-rural or rural areas, work outdoors and spend little time on the road.
Conversely, they would be well above average for a person who lives in a house
with an attached garage, spends several hours a day commuting in a pre-1986 car,
and works in an office or shop in a heavily trafficked street.
Comparison with overseas monitoring data and exposure estimates
Extensive monitoring studies conducted in 1980-87 by USEPA in about 800
subjects representing a cross-section of the populations of California, Maryland and
New Jersey found a global average personal exposure level of 4.7 ppb (Wallace,
1996). In subsequent, smaller US studies, the average level was 1.6 ppb in a rural
community in California and 7.4 ppb in a remote township in Alaska (Goldstein et
al, 1992; Sheldon et al, 1991; both as cited in Wallace, 1996). In a mixed urban and
rural subset of the Californian studies referred to above, the 24 h exposure level
averaged 3.7 ppb in non-ETS exposed persons and 4.6 ppb in passive smokers
(Miller et al, 1998). In Singapore, the measured personal exposure level in 20
persons with no known occupational exposure to benzene averaged 7 ppb (Foo,
1991). In Turin, Italy, the mean personal exposure level was 21.9 ppb in non-ETS
exposed subjects and 28.6 ppb in passive smokers (Gilli et al, 1996). In a small
study of students, homemakers and pensioners in Birmingham, UK, the measured
personal exposure levels averaged 4.7 ppb during the day and 3.4 ppb during the
night (Leung & Harrison, 1998). In nine council road and park workers in Nancy,
France, who were monitored continuously from Monday morning to Friday
evening, the mean personal exposure was 790 ppb-hours, corresponding to an
average of about 7.6 ppb (Gonzalez-Flesca et al, 1999). In 100 office workers from
Milan, Italy, the mean 24 h personal exposure amounted to 6.6 ppb (Carrer et al,
2000). In a large study in continental Europe, the annual average personal exposure
level was 4.4 ppb, based on more than 1500 samples collected from 50 non-
smokers in each of six cities (Cocheo et al, 2000). It was lowest in the northernmost
city of Copenhagen (2.0 ppb) and highest in the southernmost cities of Athens (5.8
ppb) and Murcia (7.2 ppb). A study conducted in 1990-91 of 113 persons
representing a cross-section of the adult Western German population found a mean
Benzene 161
personal exposure level of 4.2 ppb, with 95% of the sample population exposed to
9.9 ppb (Hoffmann et al, 2000).
In Canada, public exposure in the general environment has been assessed under the
Priority Substances Program (Government of Canada, 1993). The estimated intake
by 5-11-year old, non-ETS exposed children was 2.7 礸/kg/day, compared to 4.0
礸/kg/day in passive smokers. In 20-70-year old adults, the estimated intake was
2.4 礸/kg/day in non-ETS exposed persons, 3.3 礸/kg/day in passive and 29.3
礸/kg/day in active smokers. Benzene intake in adults in UK has been estimated at
1-12 礸/kg/day depending on lifestyle and geographical factors (IEH, 1999),
whereas CONCAWE (1999) arrived at an estimated airborne intake in non-smokers
which was equivalent to approximately 2-4 and 7-8 礸/kg/day in urban and inner
city environments respectively.
Ultimately, benzene intake in non-smokers derives primarily from vehicle and
petrol emissions. The estimated Australian intake is higher than the measured data
from California, Maryland and New Jersey in USA and the estimated intake in
Canada, where the car fleet is newer and petrol contains less benzene than in
Australia. However, it falls within the range measured in Alaska, Singapore and
several European countries, where the age of the car fleet and/or the composition of
petrol are more relevant to the Australian scenario.
As such, the estimated lifetime 24-h exposure level of 5.2-6.1 ppb in non-smokers
in the Australian model urban environment is considered sufficiently realistic to
serve as a point of reference for the assessment of public health risks from exposure
to benzene in the general environment.
16.4 Summary and conclusions
Inhaled tobacco smoke contains about 50 礸 benzene per cigarette, corresponding
to a daily intake of 0.89 mg benzene by the average smoker (17.8 cigarettes/day).
Non-smoking members of the general public are exposed to benzene through the
inhalation of indoor, in-vehicle and outdoor air contaminated with the chemical
through releases that predominantly derive from petrol evaporation, vehicle exhaust
and tobacco smoke. Skin contact with benzene-containing products such as petrol
and ingestion of contaminated water or food contribute minimally to human intake.
There is no evidence that industrial emissions are a significant source of public
exposure.
The 24 h average lifetime exposure in the Australian urban population is estimated
at 5.2 ppb in non-ETS exposed persons. It is approximately one-fifth higher in
passive smokers exposed to ETS at home, at work and in their cars (6.1 ppb) and
almost three times as high (15.2 ppb) in the average smoker. The average 24 h
exposure of the overall population of the model urban centre described in Section
15.2 can be estimated as follows:
Twenty-four per cent of the adult Australian population smokes (ABS, 2000b). At
the 1996 census, about 71% of the population of Canberra was aged 18 years and
over and the average household size was 2.7. Therefore, in the model city
population of 300,000, there would be 300,000 x 0.24 x 0.71 = approximately
51,000 active adult smokers. In a survey of 887 active smokers in Victoria in 1997,
28% reported that they always smoked outside (Trotter & Mullins, 1998).
Therefore, 51,000 x (1 - 0.28) = about 37,000 smokers would smoke indoors and
thus potentially expose other people to their sidestream smoke. Given the average
household size of 2.7, each indoor smoker is likely to expose about 1.7 other people
Priority Existing Chemical Number 21
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to his or her sidestream smoke, corresponding to 1.7 x 37,000 = approximately
63,000 ETS-exposed people. As such, the population of the model urban
environment is composed of 186,000 non-ETS exposed inhabitants, 63,000 ETS-
exposed inhabitants and 51,000 active smokers, which gives a fraction of 62, 21
and 17% respectively. Based on the average 24 h lifetime exposure levels
mentioned above, this results in an average exposure level for the population as a
whole of 0.62 x 5.2 + 0.21 x 6.1 + 0.17 x 15.2 = 7.1 ppb. Of this, 54% can be
attributed to ETS-free indoor air, 22% to active smoking, 11% to road use, 8% to
other outdoor activities and 5% to passive smoking.
The above exposure estimate is crude, but may nevertheless give guidance to the
relative importance of the various sources that contribute to public exposure to
benzene.
Benzene 163
17. Occupational Exposure
Workers in the petroleum, steel, chemical and associated industries may be exposed
to benzene during bulk manufacture, use, storage or distribution of the chemical or
products that contain the chemical, such as crude oil, petrol, BTX and coal tar (see
Section 7). Exposure may also occur in laboratories where benzene is used for
research or analysis. In addition, the contamination of workplace environments
with petrol vapours, engine exhaust or tobacco smoke may result in benzene
exposures that exceed the population average, for example, in vehicle mechanics,
professional drivers and hospitality workers.
Inhalation is the predominant route of occupational exposure to benzene, with the
possible exception of workers having prolonged skin contact with petrol, such as
mechanics during work on vehicle fuel systems (Laitinen et al, 1994). Incidental
dermal contact may occur as a consequence of spills or leaks and the occasional use
of petrol to clean tools or car parts, but would be infrequent and is unlikely to result
in significant absorption because of the rapid evaporation of benzene applied to the
skin (OECD, 2000). Pipetting and siphoning of benzene-containing liquids by
mouth may result in ingestion of the chemical, but nowadays would be very rare.
Occupational exposure to benzene often occurs outdoors, where daily breathing
zone levels may vary 10-fold depending on wind speed and other weather
conditions (Kromhout et al, 1993).
17.1 Petroleum industry
The petroleum industry comprises an upstream segment involved in getting oil and
gas out of the ground and a downstream segment involved in the refining,
distribution and marketing of petroleum products.
Information on the number of petroleum industry workers in jobs with the potential
for exposure to benzene was not available from applicants. However, it is known
that there were about 6400 upstream employees in 1999 (APPEA, 2000). Petroleum
refining is estimated to employ over 3000 people (DISR, 1999). As there are more
than 40 terminals (Glass et al, 1998) and 8000 petrol stations (AIP, 2000), the
number of workers engaged in petrol distribution and marketing is probably in the
order of 20,000-30,000.
17.1.1 Petroleum production and refining
The production of crude oil and its refining to petrol and other end products
comprise a series of continuous, fully enclosed processes which take place in
naturally ventilated, open-air facilities. As such, the principal sources of exposure
are fugitive emissions, waste streams, transfers resulting in vapour displacement,
and situations where there is a need to break open or enter the system, such as
sampling, cleaning and maintenance. All other things being equal, the potential for
exposure is proportional to the concentration of benzene in the process stream. This
is about 0.1% in crude oil, 0.5-2% in straight run gasoline, Avgas and cracked
gasoline, 1-5% in blended petrol, and 4-8% in reformate (Section 7.2.1).
Australian exposure data have been culled from the retrospective exposure
assessment for benzene conducted by Health Watch in the course of the nested
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case-control study reviewed in Section 11.6.2 (Glass et al, 1998, 2000). This
assessment primarily used local monitoring data from the participating petroleum
companies to arrive at exposure estimates for a range of job categories and tasks.
The available monitoring data were checked for correctness, completeness and
consistency and analysed across sites by standard statistical methods. Personal
samples taken over <180 min were excluded, except in the case of fitters whose
overall exposure was calculated as the mean of a reasonable cross-section of short-
term tasks that a fitter may perform. Non-detectable results were assigned a value
of half the detection limit. For some job categories, exposure levels were
normalised to a benzene concentration of 0.1% in crude oil and 3% in petrol.
Relevant summary statistics (arithmetic mean and range) that relate to current
processes and technologies are shown in Table 17.19.
Table 17.1: Measured personal benzene exposure levels in the Australian
petroleum industry (adapted from Glass et al, 1998)
Benzene exposure levels in ppm (TWA)
Sample
count
Job category or task Mean Minimum Maximum UTL95%,95%*
Crude oil production
Fitter 12 0.04 <0.01 0.09 1.6
Operator 43 0.05 <0.01 0.53 0.6
Refining
Catalytic cracking operator 295 0.16 0.02 5.52 0.5
Crude distillation operator 404 0.11 0.00 4.63 0.5
?br>
13 8.01 0.14 28.21 350
Crude storage tank cleaning
Fitters 369 0.62 0.01 39.00 4.8
?br>
12 9.08 0.09 58.21 620
Gas testing of storage tanks
Instrument fitter 42 0.48 0.01 10.60 1.7
Laboratory worker 65 0.15 0.01 1.13 1.3
Petrol blending 11 0.42 0.11 2.19 4.0
Plant-wide operator 25 0.08 0.01 0.31 0.7
Reformer operator 263 0.69 0.01 54.05 2.6
Separator cleaning 14 0.12 0.05 0.33 0.5
46 75.15 0.05 1043.89 2000
Slop tank cleaning*
Sour water treatment 28 0.06 0.05 0.22 0.2
Tank farm workers 104 0.12 0.01 2.30 0.9
Distribution
?br>
Drum filling 24 1.55 <0.01 6.15 38
Fitter 13 0.67 0.02 5.80 23
?br>
31 0.55 <0.01 7.85 8.7
Road tanker bottom loading
* Calculated for a lognormal distribution from the mean and standard deviation of the logtransformed
data included in the Health Watch report.
Respiratory protective equipment would have been worn.
?br>
Normalised to a concentration of 0.1% benzene in crude oil and 3% in petrol.
Table 17.1 above and some of the tables below also give the upper tolerance limit
of the distribution's 95th percentile (UTL95%,95%), which is a measure of the true
maximum exposure level in the population the samples were drawn from. It is 95%
9
Glass et al. (1998) tested their data for normality and, as expected, found that they generally showed
a lognormal distribution; however, the arithmetic mean is considered the best measure of average
long-term exposure.
Benzene 165
certain that 95% of all members of a given exposure group are not exposed to
levels that exceed the UTL95%,95%.
Additional Australian monitoring data are included in a report on crude oil
published by the European petroleum industry association, CONCAWE (1998a).
These data, which are reproduced in Table 17.2, were taken from a petroleum
company database covering the 1991-96 period. Some of them may have been
included in the Health Watch statistics presented in Table 17.1.
Table 17.2: Personal monitoring at an Australian crude oil production unit
(CONCAWE, 1998a)
Measured exposure levels (ppm)
Sample Duration
count
Job category or task (min) Mean Minimum Maximum
Full-shift exposure
Crude tanker loading 1 720 <0.01 - -
Maintenance worker 7 600 0.03 <0.01 0.09
Platform operator 6 720 0.02 <0.01 0.06
Shutdown technician 4 720 <0.01 - -
Stabilisation plant operator 25 720 0.03 <0.01 0.19
Storage tank cleaner 21 480 0.09 <0.01 0.34
Storage tank maintenance 3 480 0.01 <0.01 0.09
worker
Short-term exposure
Ballast tank cleaning, inside* 18 50-263 4.90 <0.03 34.10
Ballast tank cleaning, 7 67-310 2.82 0.01 5.89
outside*
Crude tank cleaning* 7 158-378 0.31 <0.01 0.93
Inlet separator cleaning 2 104 <0.02 - -
Manhole opening 2 21 0.62 0.12 1.12
Pipeline monitoring 8 50-200 0.34 <0.01 1.9
Plant equipment steaming 2 48-88 <0.01 - -
* Respiratory protective equipment was worn.
The available Australian exposure data are in agreement with a number of
Canadian, European or US surveys which generally report long-term exposure
levels <0.1 ppm in crude oil production personnel and <1 ppm in petroleum
refinery workers (CONCAWE, 1997, 1998a; Verma et al, 2000).
17.1.2 Petrol distribution and marketing
The delivery of petrol involves a series of transfers between stationary and mobile
tanks, interrupted by storage periods that vary from hours to months. The main
sources of release are tank breathing, vapour displacement during tank loading
operations, and evaporation of minor spills. There is also the potential for exposure
from vapour-filled pipework and tanks that are broken open or entered into during
cleaning or maintenance operations.
The Health Watch exposure assessment described above provides some data on the
exposure of workers at distribution terminals (Table 17.1). There are no Australian
monitoring data for road tanker drivers and shipping tanker crew.
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Overseas documentation on the exposure of workers involved in the distribution of
petroleum products is limited. In Europe, exposure levels in drum fillers averaged
8.4 ppm (TWA8) in a 1987 industry survey (CONCAWE, 1997). A US study from
the 1970s found exposure levels <0.5 ppm in 126/128 pipeline maintenance
workers, with levels 1.5 ppm in the remaining two (Domask, 1978, as cited in
Weaver et al, 1983). In drivers of bottom-loaded road tankers, average short-term
exposure levels during unloading ranged from 0.43-1.56 ppm benzene, with
average full-shift exposure levels from 0.04-0.37 ppm (CONCAWE, 1997; Kawai
et al, 1991; Weaver et al, 1983). Studies conducted in Europe in the 1980s and
early 1990s found average TWA8 levels ranging from 0.07-2.0 ppm in jetty
workers and ship or barge crew involved in closed or open petrol loading
operations (CONCAWE, 1997).
Data on Australian petrol station workers have been published by AIP (1996).
Limited measurements in 1982 showed benzene exposure levels <1 ppm (TWA8).
This was followed up in 1993 with a study of 10 high volume petrol stations in
Adelaide, Brisbane, Melbourne, Perth and Sydney, half of them self-service.
Personnel monitored included attendants working in the pump area as well as
managers, office and workshop staff. Area samplers were placed adjacent to the
pumps. Non-detectable results were assigned a value of 0.707 times the detection
limit. The results shown in Table 17.3 include the minimum variance unbiased
estimate of the arithmetic mean (estimated arithmetic mean) and UTL95%,95%
calculated from individual measurements by means of a commercially available
spreadsheet (Mulhausen & Damiano, 1998).10
Table 17.3: Personal and area monitoring at 10 Australian petrol stations
(benzene levels in ppm (TWA8))
Sample Estimated
count arithmetic mean Range UTL95%,95%
Full-service stations
25 0.21 0.03-0.61 0.86
?Attendants
18 0.09 0.02-0.62 0.59
?Other staff
40 0.15 0.02-0.60 0.69
?Area
Self-service stations
9 0.08 0.05-0.12 0.22
?Attendants
9 0.05 0.03-0.09 0.15
?Other staff
43 0.06 0.03-0.13 0.14
?Area
The exposure levels of attendants and the area levels were significantly higher at
full service than at self-service stations (p <0.05). The difference in area levels may
be due to attendants having a higher spill rate than motorists (AIP, 1996).
Overseas studies of exposure levels in petrol station attendants have been
summarised by CONCAWE (1997) and Lagorio et al. (1993, 1997). The exposure
levels shown in Table 17.3 are comparable to those in USA (0.03-0.31 ppm) and
Europe (0.04-0.80) and lower than in India (1.16-1.44 ppm).
The minimum variance unbiased estimate is the preferred point estimate of the arithmetic mean
10
of a lognormal distribution (Mulhausen & Damiano, 1998).
Benzene 167
17.1.3 Petroleum and petrol cleaning operations
Emergency crew and contractors may be exposed to evaporative emissions from
petroleum or petrol spills, or from residues in leaking fuel storage tanks. In workers
cleaning a beach after a major crude oil spill, full-shift personal exposure levels
were <0.1 ppm benzene in 343/350 samples, with levels ranging from 0.16-0.81
ppm in the remaining seven (NIOSH, 1991, as cited in CONCAWE, 1998a). In
contractors engaged to remove or repair leaking underground petrol tanks, benzene
exposure levels ranged up to 18.8 ppm during short-term tasks, but remained 1
ppm for the shift as a whole (Kramer, 1989; Shamsky & Samimi, 1987).
17.1.4 Conclusions
In conclusion, mean TWA8 exposure levels in the Australian petroleum industry are
expected to be <0.1 ppm in crude oil production workers and <0.7 ppm in refinery
and downstream distribution workers. A mean exposure of 1.55 ppm has been
recorded for petrol drumming, but this activity is rarely undertaken and is not
expected to result in long-term exposures 0.7 ppm. Higher individual full shift
exposure levels have been measured in reformer operators (up to 54 ppm) and in
distribution terminal workers (up to 7.9 ppm), but are not expected to be of regular
or frequent occurrence. Although high to very high breathing zone levels have been
measured during tank cleaning operations, actual exposures are likely to be much
lower because of the routine deployment of respiratory protective equipment in
confined spaces.
17.2 Steel and coal tar distillation industries
Workers in the steel industry may be exposed to benzene contained in coke oven
gas and its by-products, BTX and coal tar (Section 7.2.2).
Monitoring data were obtained from the steelworks at Port Kembla, New South
Wales, and Whyalla, South Australia, which recover BTX and coal tar from the
gas. Data were not available for coke works that burn the oven gas as is, or from
Koppers Coal Tar Products, who process coal tar to various end products.
17.2.1 Coke ovens
Coke oven workers are exposed to gas emissions through oven door leaks and
when the doors are opened to remove coke and recharge the ovens. Information
was not available on the number of workers employed at Australian coke ovens.
Personal monitoring data collected in 1995-97 were provided for a number of cab
drivers (30), oventop hands (6) and door adjusters (2) at Whyalla steelworks. The
results are shown in Table 17.4.
In the 1980s, the average exposure level was 0.3 ppm (TWA8) in British coke oven
workers, with individual exposures at 27 coke works ranging from <0.2-8 ppm
(Hurley et al, 1991). In a more recent study in Polish workers, the average level
was 0.14 ppm (TWA8), with a range from 0.02-0.42 ppm (Bienik, 1998). These
findings are in overall agreement with the levels at Whyalla.
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Table 17.4: Personal monitoring of coke oven and by-product workers at the
Whyalla and Port Kembla steelworks (benzene levels in ppm (TWA))
Site and job Sample Duration Estimated
UTL95%,95%*
category count (min) arithmetic mean* Range
Whyalla
Coke ovens 38 365-445 0.12 <0.01-1.04 0.74
By-product plant 27 350-420 0.72 <0.01-11.10 8.20
Port Kembla
BTX (gas) operator 30 405-485 0.12 <0.01-0.26 0.25
BTX (liquid) operator 30 295-485 0.35 0.02-8.10 3.86
Tar operator 26 395-485 0.16 <0.01-1.04 1.02
Maintenance worker 53 No data 0.48 <0.01-4.50 4.57
* Calculated according to Mulhausen & Damiano (1998), with non-detectable results assigned a value of
0.7 times the detection limit.
17.2.2 Coal gas by-product plants
A coal gas by-product plant is designed to recover BTX from coal gasses and
condense tar from gas wash oil and flushing liquor, as described in Section 7.2.2.
BTX systems, which are fully enclosed, process streams containing up to 80%
benzene. Tar systems are semi-enclosed, but handle streams with a much lower
content of benzene (0.00003% in flushing liquor and <0.2% in the end product).
Within the plant, the main sources of benzene exposure are fugitive emissions,
evaporation from decanters and sumps, and maintenance work on vessels and
pipework. At Whyalla, the final BTX product is re-injected into the gas system and
burnt as fuel. At Port Kembla, it is piped to storage tanks for subsequent transport
to Huntsman Chemical Company by road tanker (see below). The potential for
exposure during loading is low, as the tankers are bottom-loaded and equipped with
vapour return systems. The maximum number of exposed BTX and tar workers is
in the order of 30-50 persons per site.
The results of personal monitoring conducted at Whyalla in 1995-97 and Port
Kembla in 1997-99 are shown in Table 17.4 above.
At a US integrated steelworks, mean exposure levels in the by-product plant were
estimated at 10.5 ppm over the 1957-1977 period (Hancock & Moffitt, 1984).
However, the mean of 897 personal monitoring samples collected in 1978-83 by
the American Iron and Steel Institute was only 1.35 ppm (TWA8), with 25% of
measurements in the 1-5 ppm range (Runion & Scott, 1985). In the 1980s, the
average exposure level was 1.3 ppm (TWA8) in British BTX workers, with
individual exposures at 27 plants ranging from <0.2-12 ppm (Hurley et al, 1991). In
a recent study in a Polish plant, the average level (TWA8) was 0.63 ppm in BTX
(gas) operators and 1.04 ppm in BTX (liquid) operators, with a range from 0.05-
3.04 ppm (Bienik, 1998). The exposures measured in Australian workers fall within
the ranges reported from Poland and UK.
17.2.3 Coal tar distillation
Crude coal tar from the steelworks at Port Kembla and Whyalla is transported to
Koppers Coal Tar Products in Newcastle, where it is separated into various
fractions in a series of fully enclosed, outdoor systems (see Section 7.2.2). The
distillery employs 65 people, including fitters, laboratory chemists and operators.
The crude tar and distillation products contain 0.11-0.16% and 0-4% benzene
Benzene 169
respectively. The potential for exposure is limited to releases during unloading of
the crude tar, fugitive emissions, and situations where there is a need to access the
enclosed system, for example, to dip tanks and scrubber systems, collect and
analyse samples, or carry out cleaning and maintenance.
Workers at Koppers are not routinely monitored for exposure to benzene. Overseas
data on the exposure of coal tar distillation workers to benzene could not be
identified. However, the coal tar and petroleum industries handle process streams
with similar benzene content in similar, enclosed systems. By analogy, therefore,
exposure levels among coal tar distillation workers are probably of the same order
of magnitude as in petroleum refinery workers, that is, generally <0.7 ppm.
17.2.4 Conclusions
Based on the available data, mean benzene exposure levels are expected to be 0.7
ppm (TWA8) in the steel and coal tar distillation industries. Higher individual full
shift exposure levels have been measured in by-product plant operators (up to 11
ppm), but are not expected to be of regular or frequent occurrence. Mandatory
changes have since been introduced to personal protective equipment requirements.
17.3 Chemical industry
17.3.1 Ethane and naphtha (gas oil) cracking
The Qenos petrochemical plants in Altona and Botany Bay produce a by-product
known as pyrolysis gasoline which may contain from 6-36% benzene (Section
7.2.3). The pyrolysis gasoline stream is produced and contained in a fully enclosed,
outdoor system. At the Altona plant, it is transferred in closed pipework to a
neighbouring petroleum refinery, which stores the pyrolysis gasoline in floating-
roof tanks and eventually ships it overseas. At the Botany plant, it is stored in a
floating-roof tank until piped to Port Botany and shipped overseas for further
processing. In consequence, the potential for exposure is limited to fugitive
emissions at pumps and valves and to sampling and maintenance requiring access
to the closed system. Potentially exposed workers comprise a maximum of 85
operators, supervisors and maintenance personnel per site.
According to a summary of personal monitoring data provided by Qenos, long-term
full-shift exposure levels in a total of 14 job categories at the Altona and Botany
pyrolysis plants did not exceed 0.10 ppm benzene in 1998-99, based on 7-11
samples per similar exposure group. This is in agreement with Tsai et al. (1983)
who reported a mean exposure level of 0.11 ppm in 32 samples collected in the
ethylene unit of an integrated US refinery in 1978-1983. Furthermore, at the Altona
site, full-shift personal exposure levels were consistently <0.07 ppm in 32 fitters
and operators involved in a turn-around operation in 1998 and <0.05 ppm in 9
maintenance contractors who were sampled in 2000. Qenos also provided personal
monitoring data from a small number of contract surveyors and wharf operators
involved in a shore to ship transfer at Port Botany of pyrolysis gasoline containing
about 35% benzene. Full-shift exposure levels ranged from 0.1-0.4 ppm, which is
comparable to the levels measured in workers engaged in ship to shore transfer of
benzene feedstock (Table 17.5).
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17.3.2 Bulk distribution
The predominant end user of benzene feedstock is Huntsman Chemical Company
in Melbourne, with an approximate annual consumption of 20 kt BTX (see above)
and 80 kt 95-99% pure benzene imported through Terminals Pty Ltd on
Melbourne's waterfront (Section 7.2.3). About 0.05% of the imported quantity is
diverted to the Qenos butadiene rubber plant in Altona, Victoria. There are no other
users of bulk benzene in Australia.
BTX is transported from Port Kembla to Melbourne by road. The potential for
exposure is low, as the product is transferred via dedicated, closed lines and
transport takes place in bottom-loaded road tankers equipped with vapour return
systems. Loading and unloading last 30-40 min each and the volume transported is
equivalent to 2-3 trucks/day. The number of potentially exposed workers would be
<10.
Benzene is delivered to Terminals by ship about 30 times a year. There is the
potential for exposure from drips and spills when making and breaking the line
connections for ship to shore transfer. A pump onboard the ship moves the cargo
into one of six nitrogen-blanketed benzene storage tanks, which are vented to air
through a carbon bed system, minimising the potential for exposure to displaced
vapours. The time taken to connect, disconnect and pig the lines is <60 min. The
transfer itself lasts from 12-26 h depending on the size of the cargo. The transfer
requires a manning level of 4-5 operators. There is limited potential for exposure
during subsequent transfer to Huntsman, as the chemical is transported in
dedicated, bottom-loaded road tankers equipped with a vapour return system.
Dedicated pipelines are used for loading and unloading, which last 25-30 min each.
The results of personal monitoring conducted at Terminals in 1997-1999 and at the
Huntsman styrene plant in 1997 are shown in Table 17.5.
Table 17.5: Personal monitoring during road tanker loading/unloading of
benzene feedstock and ship to shore transfer (benzene levels in ppm (TWA))
Sample Duration Estimated
UTL95%,95%*
Process or task count (min) arithmetic mean* Range
Terminals
Road tanker loading 8 Full-shift 0.11 0.10-0.20 0.24
6 Short-term 0.51 0.10-1.00 14.28
Ship to shore transfer 12 Full-shift 0.25 0.10-5.60 3.36
12 Short-term 0.76 0.10-11.60 25.37
Huntsman
Road tanker loading/ 4 465-690 0.14 0.03-0.20 10.36
unloading
* Calculated according to Mulhausen & Damiano (1998).
The data indicate that short-term exposures during road tanker loading rarely
exceed 1 ppm, whereas ship to shore transfer of bulk benzene may result in short-
term exposures 12 ppm. Measured full-shift exposures are consistently <0.25 ppm
in the case of road tanker loading/unloading. Wharf operators may occasionally be
exposed to higher full-shift levels, but their average exposure over the year would
remain <0.5 ppm as Terminals only receive about 30 benzene shipments/year.
Wharf operators also wear a full face respirator mask with an organic canister while
disconnecting hoses and hence personal exposure levels will be lower.
Benzene 171
In 1978-83, the mean exposure level among 426 chemical industry workers loading
unspecified road tankers with benzene was 0.42 ppm (Runion & Scott, 1985).
There are no published data on the exposure of shipping tanker crew or wharf
operators during the unloading of bulk benzene.
17.3.3 Butadiene rubber manufacture
The Qenos elastomer plant in Altona uses pure benzene as a component of a
solvent employed in the manufacture of butadiene rubber in a fully enclosed batch
process, as described in Section 7.2.3. There are approximately 20 operators,
maintenance and laboratory workers in the rubber plant. These are potentially
exposed to benzene released through fugitive emissions or when the system is
opened for sampling or maintenance.
According to a summary of personal monitoring data provided by Qenos, long-term
breathing zone levels at the elastomer plant in 1998-99 ranged from 0.01-0.51 ppm
across a total of 11 job categories, based on 25-30 full-shift samples per similar
exposure group. The highest breathing zone levels were observed in workers
involved in the collection of samples of the rubber-solvent mixture and in the
cleaning of a strainer system that separates rubber particles from the recycled
solvent. However, these tasks require the use of respiratory protective equipment
and actual exposures are therefore likely to be <0.5 ppm in all cases.
Most published data on benzene exposure in the rubber industry refer to outdated
processes and workplace control measures. However, the Qenos findings are in
reasonable agreement with a recent assessment of chemical exposures at US
styrene-butadiene rubber plants which reported current benzene exposure levels in
the order of 0.5-0.7 ppm (Macaluso et al, 1996).
17.3.4 Styrene and phenol manufacture
At Huntsman, the styrene and phenol plants convert large quantities of BTX and
benzene to various intermediates in a series of interconnected, fully enclosed,
outdoor systems. The processes are described in Section 7.2.3. The principal
sources of exposure are fugitive emissions and maintenance operations such as the
periodic replacement or regeneration of catalysts. There is little potential for
exposure from transfers between systems, as these take place in closed pipework
and all benzene holding and storage tanks are connected to an organic vapour
recovery system. The potential exposure of quality assurance personnel is limited
through the use of closed sampling systems and fume cupboards. There are
approximately 100 workers in the styrene and phenol plants and about 30
laboratory and other service staff who may be exposed to benzene.
Full-shift personal monitoring data collected during routine operations in the
styrene and phenol plants in 1994-98 and in the main quality control laboratory in
2000 are shown in Table 17.6.
Priority Existing Chemical Number 21
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Table 17.6: Personal monitoring in the Huntsman styrene and phenol plants
and main quality control laboratory (benzene levels in ppm (TWA))
Site and job Sample Duration Estimated
UTL95%,95%*
category count (min) arithmetic mean* Range
Styrene plant
Outside operator 28 420-685 0.16 <0.01-0.82 1.21
Plant engineer 4 340-545 0.39 0.05-1.52 -
Technical process 4 540-660 0.05 0.01-0.10 -
leader
Phenol plant
Day co-ordinator 3 330-435 0.07 <0.01-0.10 -
Outside operator 13 320-700 0.10 0.05-0.21 0.27
Main laboratory
Technician 5 560-600 0.03 0.01-0.04 0.23
* Calculated according to Mulhausen & Damiano (1998), with non-detectable results assigned a value of
0.7 times the detection limit.
Short-term or instantaneous monitoring of workers engaged in maintenance tasks in
the styrene and phenol plants in 1990-99 showed breathing zone levels from 0.2-
4200 ppm benzene. The median result was 1.9 ppm in the styrene plant (83
readings) and <0.5 ppm in the phenol plant (199 readings). In a few instances,
short-term breathing zone levels ranging up to 6.25 ppm have been recorded in
workers collecting or disposing of quality control samples. In almost all cases,
respiratory protection was worn where benzene levels in the presence of other
hydrocarbons were unknown or exceeded 3 ppm and where benzene in the absence
of other hydrocarbons was present in unknown concentrations or exceeded 1 ppm.
Personal monitoring (11 samples) of maintenance workers during turnaround of the
phenol plant in 1994 indicated 6 to 12-hour TWA exposures of 0.02 to 0.38 ppm.
Static monitoring (3.5 ?18 hour sampling) of benzene in the phenol plant
conducted over three months in 1992-93 indicated that of 353 results, 161 were <
0.5 ppm, 104 were 0.5 ?1.0 ppm, 88 were > 1.0 ppm. The geometric mean was
0.73 ppm. Of the 88 results > 1.0 ppm, 25 were due to abnormal plant conditions
which the plant personnel were aware of at the time. The company stated it has
made some improvements in preventative maintenance and operating procedures
since 1993.
There is limited documentation on the exposure of styrene and phenol workers to
benzene. Based on 620 samples collected in 1990-94, average full-shift benzene
exposure levels at three German styrene/phenol plants varied from 0.10-0.60 ppm,
depending on job category (OECD, 2000). These findings are in reasonable
agreement with those reported by Huntsman.
17.3.5 Conclusions
Based on the above, mean benzene exposure levels are expected to be <0.5 ppm
(TWA8) in the chemical industry. Higher individual full shift exposure levels have
been measured in workers involved in ship to shore transfer of benzene feedstock
(up to 5.6 ppm) and in chemical plant engineers (up to 1.5 ppm), but are not
expected to be of regular or frequent occurrence. Although breathing zone levels up
to 4200 ppm benzene have been recorded during short-term maintenance tasks,
actual exposures would have been much lower because of the routine deployment
of respiratory protective equipment in such situations.
Benzene 173
17.4 Laboratory use for research or analysis
In telephone interviews conducted for this assessment with 55 laboratories
identified as having purchased reagent grade benzene within recent years, 38 stated
that they currently use benzene for research or analysis, 5 stated they no longer use
the chemical, while a further 7 claimed not to be using it and 5 laboratories could
not be contacted. The survey identified up to 620 potentially exposed laboratory
staff with a median value of 4 (range: 1-116) staff per laboratory. These numbers
do not include undergraduate students in university teaching laboratories but do
include post-graduate students. The typical amounts used at any one time were as
follows:
Volume (mL) Percentage of laboratories
29
5
6-100 42
101-1000 24
>1000 5
Although the potential for exposure is expected to vary considerably depending on
circumstances such as the quantity of benzene used, the opportunity for
evaporation, the size of the laboratory and the air shift rate, the survey revealed
that, in general, benzene is currently used in a manner likely to minimise the risk of
exposure. This is achieved by confining the use of benzene to fume cupboards
(95% of laboratories), providing other exhaust ventilation (29% of laboratories),
the limited amount and duration of use, and appropriate procedures for the disposal
of contaminated materials. However, some laboratories reported procedures that
may increase the risk of exposure. These include the practice of decanting benzene
from large bottles into measuring cylinders or beakers where splashing or spills are
likely to occur; the disposal of contaminated pipette tips into open general purpose
waste bins; and the storage of small quantities of benzene on work benches or
shelves in containers that are permeable to benzene.
As relevant monitoring data were not identified, the Estimation and Assessment of
Substance Exposure (EASE, 1997) model (version 2.0) was used to predict
exposure levels. Based on the survey information, pure benzene was assumed to be
handled directly in a non-dispersive manner, at room temperature and in the
presence of local exhaust ventilation. According to this inherently conservative
model, exposure levels of 10-20 ppm may be expected. As benzene typically is
used for <1h/week, the corresponding long-term average would be 0.25-0.50 ppm.
This is higher than the mean exposure levels measured in industrial laboratory
workers, which range from 0.03 ppm in the chemical industry (Table 17.6) to 0.15
ppm in petroleum refineries (Table 17.1).
17.5 Contaminated workplace environments
17.5.1 Petrol vapours and vehicle exhaust
Occupational exposure to petrol vapours and vehicle exhaust fumes may occur in
vehicle mechanics, professional users of petrol-fuelled implements such as
gardeners and loggers, and people who work on or in the immediate vicinity of
busy roads, such as professional drivers, road labourers, staff at fast food drive-in
outlets, toll collectors and traffic wardens. Detailed information on the number of
workers in such jobs was not collected. However, there were in the order of
Priority Existing Chemical Number 21
174
150,000 vehicle tradespersons, 60,000 amenity horticultural tradespersons, 10,000
forestry and logging and 200,000 road transport workers in the Australian labour
force in 1996 (ABS, 1996).
Australian monitoring data were not available for any of the above occupations.
However, the Australian and New Zealand studies reviewed in Section 15.3.3
indicate that professional city drivers would be exposed to full-shift breathing zone
levels of approximately 7.5 ppb in non-petrol fuelled vehicles such as buses, taxis
and trucks, 15 ppb in post-1986 and 48 ppb in pre-1986 petrol-fuelled cars and
vans. Furthermore, the exposure of roadside workers is likely to be similar to that
of pedestrians and cyclists, that is, approximately 7 ppb (TWA8) in the model
Australian urban environment described in Section 15.2.
Overseas monitoring data are available for bus drivers, loggers, traffic wardens and
vehicle mechanics, as shown in Table 17.7.
Table 17.7: Personal monitoring of bus drivers, loggers, traffic wardens and
vehicle mechanics (full-shift benzene levels in ppm (TWA))
Occupation No. of workers Arithmetic mean Range Reference
Bus drivers 59 0.03 0.01-0.05 Rossi et al. (1999)
Loggers* 22 0.15 0.02-0.74 Nilsson et al. (1987)
Traffic wardens 20 0.02 <0.01-0.03 Fustinoni et al. (1995)
Vehicle 54 0.17 0.01-1.70 Foo (1991)
mechanics 65 0.15 <0.01-2.89 Javelaud et al. (1998)
70 0.14 0.01-1.77 Muzyka et al. (1998)
* Loggers using two-stroke chainsaws in sparse to thick pine forest stands at an ambient temperature of
?6 to 8癈 and wind speeds of 0-4 m/s.
Workers in a garage servicing buses running on a particular diesel blend containing 2.1% benzene.
With regard to bus drivers and traffic wardens, the exposure levels shown in Table
17.7 are 3-4 times higher than those estimated above. However, they were recorded
in Bologna and Milan in Italy, where traffic congestion in narrow streets is likely to
result in in-vehicle and roadside benzene air concentrations that are substantially
higher than in urban environments in Australia.
With regard to vehicle mechanics, the findings summarised in Table 17.7 are
consistent with an average exposure level <0.2 ppm (TWA8). This is in accordance
with the personal exposure levels measured in car repair shops in Germany in
1996-97 (OECD, 2000). Tasks that require the fuel system to be broken open may
result in short-term breathing zone levels 15 ppm benzene and may also entail a
component of dermal exposure (Laitinen et al, 1994; Nordlinder & Ramn鋝, 1987).
Although the concentration of benzene in jet fuel is very low, static air monitoring
has shown benzene levels 1.3 ppm in a freshly drained commercial aircraft tank
and 15 ppm in military aircraft tanks equipped with explosion suppression foams
(Carlton & Smith, 2000; Yeung et al, 1997). However, entry into such tanks would
be subject to confined space regulations and entrants would wear suitable
respiratory protective equipment.
17.5.2 Environmental tobacco smoke
Occupational exposure to benzene contained in ETS may occur in waiters and other
staff in restaurants and bars. Detailed information on the number of workers in such
Benzene 175
jobs was not collected, however, there are about 150,000 employees in the
Australian clubs and pubs, taverns and bars industries (ABS, 2000b).
Monitoring data for these occupations could not be identified. However, based on
the indoor air levels in restaurants and bars with smoking occupancy assessed in
Section 15.3.2, personal exposure levels are estimated at 8-21 ppb benzene
(TWA8).
17.5.3 Conclusions
Based on overseas studies, benzene exposure in professional users of petrol-fuelled
implements and vehicle mechanics is estimated at <0.2 ppm (TWA8). Occupational
exposure to benzene in air contaminated with vehicle exhaust or ETS is estimated
at 7.5-48 ppb (TWA8) in professional city drivers, 7 ppb (TWA8) in roadside
workers and 8-21 ppb (TWA8) in hospitality staff.
17.6 Aluminium industry
There are no published studies of benzene exposure in the aluminium industry and
epidemiological studies do not indicate an excess incidence of benzene-related
diseases. However, data reported to NPI show that one aluminium refinery is
emitting benzene to the atmosphere in a quantity corresponding to 0.001% of
alumina production (Section 15.1.3). Moreover, it has been hypothesised that
benzene could form from coal tar pitch used at smelter facilities in the preparation
of carbon anodes and smelting pot bases. In consequence, the industry was asked to
provide any data in its possession that could clarify the potential for occupational
exposure to benzene at aluminium refineries and smelters.
There is no routine personal or area monitoring for benzene in the aluminium
industry. Some refineries reported that benzene had been determined at normal
background levels in the course of broader studies of the release of volatile organic
chemicals. Three smelter operations reported ad hoc monitoring projects in the
anode manufacturing and baking departments and/or during the relining of smelting
pot bases. In one case, benzene was not detected. The results obtained in the other
two cases are shown in Table 17.8.
Table 17.8: Personal monitoring during anode manufacturing and pot
construction at two Australian aluminium smelter facilities (benzene levels in
ppm (TWA))
Estimated
Sample Duration arithmetic
UTL95%,95%*
Process or task count (min) mean* Range
Smelter A
-3 -3 -3 -3
Anode baking 11 300-585 0.94 x 10 0.16 x 10 - 9.39 x 10 14.53 x 10
-3 -3 -3 -3
0.01 x 10 - 2.70 x 10 18.26 x 10
Anode 12 360-645 0.75 x 10
manufacturing
Smelter B
-3
Potlining cathode 21 240-360 0.06 0.31 x 10 - 0.43 1.06
rodding
-3 -3 -3
<0.01 x 10 - 8.99 x 10 0.32
Potlining slotting/ 10 330-415 4.03 x 10
sidewalling
* Calculated according to Mulhausen & Damiano (1998).
Priority Existing Chemical Number 21
176
Although liquor burning at aluminium refineries may result in the release of
benzene, there is no evidence that this results in any measurable occupational
exposure to the chemical.
Monitoring data collected at two aluminium smelters show that the preparation of
anodes and smelting pots produce levels consistently <0.01 ppm benzene. At one
smelter, cathode rodding was associated with exposures that averaged 0.06 ppm but
ranged up to 0.43 ppm. However, a subsequent biological monitoring study found
no increase in benzene breath levels in workers exposed to potlining fumes (Brown,
1996). Overall, these findings indicate that coal tar pitch is unlikely to be a
significant source of occupational exposure to benzene.
17.7 Summary
The estimated average benzene exposure levels across various Australian industries
and industry sectors discussed above can be summed up as follows:
Long-term occupational exposures are estimated to range from 7-48 ppb
?br>
benzene in people who work in roadside, indoor or in-vehicle environments
contaminated with vehicle exhaust fumes or tobacco smoke;
Workers in the upstream petroleum industry are generally exposed to benzene
?br>
levels <0.1 ppm (TWA8);
Vehicle mechanics and professional users of petrol-fuelled implements are
?br>
estimated to be exposed to benzene levels <0.2 ppm (TWA8);
Workers in the chemical industry are generally exposed to benzene levels <0.5
?br>
ppm (TWA8) with some maintenance workers in phenol manufacture
potentially exposed to levels of < 0.7 ppm (TWA8), as indicated by static
monitoring;
Laboratory workers using benzene for research or analysis are estimated to be
?br>
exposed to benzene levels from 0.25-0.50 ppm (TWA8);
Workers in the downstream petroleum industry are generally exposed to
?br>
benzene levels <0.7 ppm (TWA8);
Workers in the coal tar distillation industry are estimated to be exposed to
?br>
benzene levels <0.7 ppm (TWA8);
In the steel industry, coke oven and coal gas by-product workers are generally
?br>
exposed to benzene levels 0.7 ppm (TWA8);
Occasional short-term exposures to benzene levels ranging from 10-20 ppm
?br>
may occur in wharf operators involved in ship to shore transfer of benzene
feedstock, in laboratory workers using pure benzene for research or analysis,
and in vehicle mechanics with tasks that require fuel systems to be broken
open; and
Higher breathing zone levels may occur during maintenance tasks, particularly
?br>
in confined spaces, but are generally short-term and limited to work situations
that require the use of respiratory protective equipment.
Benzene 177
18. Risk Characterisation
This section integrates the information on the biological effects of benzene
presented in Sections 8-13 with the environmental, public and occupational
exposure estimates developed in Sections 15-17, in an overall estimation of the
incidence and severity of the adverse effects the chemical may cause on the
environment and people of Australia. This process provides the basis for
identifying areas of concern and evaluating risk management strategies, including
the setting of ambient air quality and occupational exposure standards.
There is very little documentation on adverse human health effects in people
exposed to benzene at non-occupational levels. Therefore, the risks to human health
are first assessed with regard to occupational exposures and then extrapolated to the
general public.
18.1 Environmental risks
Benzene is a volatile and water-soluble chemical. Its major release in Australia is
expected to be to the atmosphere, predominantly through fumes released during
petrol combustion in motor vehicles. Direct release to the aquatic compartment is
expected to be minor by comparison and removal through degradation and
volatilisation from sewage treatment plants is likely to greatly reduce the amounts
of benzene reaching receiving waters. Monitoring data from around the world
confirm the widespread transport of this chemical with substantial detections
obtained in air and surface waters overseas. No surface water monitoring data is
available in Australia , while international results show that where benzene was
detected in surface waters, it was generally less than 10 礸/L.
18.1.1 Atmospheric risk
Limited experimental data on environmental organisms exposed through the gas
phase are available. Exposure to benzene in the vapour phase exhibited toxic action
on the grain weevil, but the concentration of benzene was not reported. At
concentrations >50 mg/m3 (>15.5 ppm), lethal effects may be expected in plants. It
appears plants recover from sublethal effects, and plants are not expected to be
exposed to concentrations at the level reported above, so a minimal risk to
terrestrial plants is predicted when exposed through the gas phase.
Abiotic effects can also be assessed. While direct photolysis is not considered to be
a significant removal process, the atmospheric half-life is relatively short (expected
to be <20 days) due to reaction with photochemically produced hydroxyl radicals.
The chemical contains no halogenated substituents and due to its short residence
time is not expected to have a potential effect on stratospheric ozone.
Webster et al. (1998) state that transport times to the Arctic can be measured in
weeks. With a half-life of up to 3 weeks for benzene, it can be expected that the
chemical could undergo significant transport in the atmosphere and may migrate to
the poles. No measurements appear to be available from these regions.
For chemicals to be considered persistent organic pollutants (POPs), they need to
meet certain criteria with respect to persistence, bioaccumulation and the potential
for long-range transport. Benzene meets the criteria for persistence in air (half-life
Priority Existing Chemical Number 21
178
>2 days) and, therefore, possibly the criterion for long-range transport. Half-lives in
soil and sediments need to be >6 months. There are no measurements in this area so
no conclusions can be drawn, although benzene is not likely to remain associated
with soil for extended periods as it is likely to be mobile (relatively low log Koc),
and is also expected to be removed significantly through volatilisation. Benzene
fails the criteria of persistence in water for >2 months. While a small number of
bioaccumulation results indicate a BCF >5000, the vast majority of results are
much less than this and benzene also fails the bioaccumulation criterion of
BCF>5000. Therefore, benzene cannot be considered a POP.
18.1.2 Aquatic risk
PEC/PNEC ratios for the aquatic compartment can be calculated using the worst
case local scenario, in this instance, the PEClocal of 0.2 礸/L (see Section 15.4.1),
and the derived PNEC of 17 礸/L (Section 8.3.2).
The ratio of PEC/PNEC has been calculated for local and continental compartments
as follows: PEC/PNEClocal = 0.01.
In order to predict a low potential for an environmental hazard, the PEC/PNEC
ratio must be <1. The PNEC has been conservatively determined by taking the
lowest chronic effect from a large data source and applying a further safety factor
of 10.
In determining the PEC/PNEC ratio, the PEC may be slightly underestimated as
more than one major benzene emitting plant may be found in a local situation.
However, surface waters in heavily industrialised areas of USA and UK show
detections of benzene <10 礸/L, which would still result in a PEC/PNEC <1.
International measurements of benzene in sediments show a maximum
concentration of 20.4 礸/kg (dry weight) in surface sediment. However, no benthic
tests are available from which to conduct a meaningful risk assessment for
sediments. It is reasonable to assume that benzene associated with the sediments is
in fact adsorbed and so not bioavailable. If this were not the case, the chemical
would be expected to volatilise. Based on this, the hazard to benthic organisms is
anticipated to be low. However, anaerobic degradation studies indicate that
benzene may be relatively resistant to biodegradation under the conditions expected
in sediments.
This evidence supports a conclusion of a low expected risk to the aquatic
environment. This assessment has not taken into account the environmental effects
of large accidental releases of benzene.
18.1.3 Terrestrial risk
While a PEC was not determined (Section 15.4.2), measured data from
contaminated sites overseas could be used as an approximation. Benzene in soil is
usually the result of direct contamination through spillage or leakage, with the
highest level found being 191 礸/kg in the US. Soil concentrations in the
Netherlands are reported as less than those found in ground water (<0.005-0.03
礸/L).
The only soil dwelling terrestrial organism for which tests were available was the
earthworm, and the only test performed in this regard was a contact test from
benzene application to filter paper where an LC50 of 98 礸/cm2 was determined. As
such, a PNEC was not able to be determined.
Benzene 179
However, for an industry to pollute soil surface at the reported LC50 concentration,
it would be required to release around 100 kg of the chemical over a 1 ha area at
the lethal concentration (10 kg to cover a 100 m2 area) at any one time. The highest
reported annual release to land in the NPI database is 45 kg from a petroleum bulk
storage facility. While it is not known what area this applies to, it is highly unlikely
that enough chemical would be released at any one time to cause an adverse impact
on terrestrial organisms.
Therefore, a low risk to the terrestrial environment is expected.
18.2 Occupational health risks
Occupational exposure to benzene is predominantly by inhalation and may occur in
workers in the petroleum, steel, chemical and associated industries, in laboratories
where benzene is used for research or analysis, and in workplace environments
contaminated with petrol vapours, engine exhaust or tobacco smoke (Section 17).
Dermal absorption may be of significance for workers who have prolonged skin
contact with petrol, such as mechanics during work on vehicle fuel systems.
18.2.1 Acute effects
For acute occupational effects, the risk characterisation process considers likely
exposure patterns to assess whether single exposures are high enough to indicate a
health concern.
Acute inhalation of benzene vapours has dose-dependent CNS depressant or
anaesthetic effects, with clinical signs such as dizziness, headache and vertigo at
levels of 250-3000 ppm, leading to drowsiness, tremor, delirium and loss of
consciousness at 700-3000 ppm. Benzene vapours have been observed to cause
skin, eye and respiratory tract irritation in workers exposed to concentrations >33
ppm. Exposure to 25 ppm benzene for 8 h is not associated with any adverse signs
or symptoms.
As discussed in Section 17, occasional short-term exposures to benzene levels
ranging from 10-20 ppm cannot be excluded in wharf operators involved in ship to
shore transfer of benzene feedstock, laboratory workers who use pure benzene for
research or analysis, or vehicle mechanics with tasks that require fuel systems to be
broken open. There is also the potential for short-term air levels ranging up to
several thousand ppm benzene during maintenance work in confined spaces such as
tanks used for storage of benzene or benzene-containing products in the petroleum,
coal gas, coal tar and chemical industries. However, these industries have
procedures that prescribe the use of suitable controls (including eye, respiratory and
skin protection) in all such situations. As such, Australian workers are unlikely to
be effectively exposed to benzene vapours at concentrations exceeding 25 ppm.
Therefore, occupational exposure to benzene is not expected to pose any
appreciable risk of acute health effects, given the control measures already in place.
18.2.2 Effects from repeated exposure
The most significant adverse effects from chronic exposure to benzene are
haematotoxicity, genotoxicity and carcinogenicity. Human health hazards for
Priority Existing Chemical Number 21
180
which a causative association with benzene exposure is established are bone
marrow depression and leukaemia, in particular AML. There is also some evidence
of an association between benzene exposure and the risk for lymphoma,
particularly NHL and MM, but a dose-time-response relationship cannot be
determined from the available data. In experimental animals, benzene has also been
found to have reproductive effects and cause mammary gland and skin tumours at
high exposure levels. However, the available epidemiological data indicate that
these effects are only weakly associated with benzene exposure in humans and
there is no evidence of a dose-response relationship. For these reasons, the critical
health effects from repeated exposure to benzene are considered to be bone marrow
depression and leukaemia. Whereas bone marrow depression is likely to have a
threshold mechanism of action, leukaemia is considered a non-threshold effect.
Bone marrow depression
No data are available to determine an inhalation NOAEL based on bone marrow
depression, although human studies with various limitations indicate that it is likely
to be >0.5 ppm (TWA8) in healthy workers. As discussed in Sections 11.4.4 and
13.2.3, based on current human data, 7.6 ppm (TWA8) is considered the best
estimate for a LOAEL which may be close to the point of departure for the onset of
haematological effects. This LOAEL is derived from a study in 44 workers with
long-term exposure to benzene where the only haematological abnormality in the
lowest exposure group (n = 11; median exposure (TWA8) = 7.6 ppm; range 1-20
ppm) was a modest decrease (16%) in ALC.
Long-term occupational exposure levels in Australia are assessed to be 0.7 ppm
(TWA8) (Section 17). An appropriate NOAEL is not available. However, since the
observed haematological effects at the human LOAEL were minimal and unlikely
to give rise to clinical signs in otherwise healthy people, the LOAEL is expected to
be close to the NOAEL, justifying a risk characterisation based on the margin of
exposure between the LOAEL and the estimated human exposure. This margin of
exposure is >10 in all workers, which is likely to imply a low to negligible risk for
bone marrow depression.
Leukaemia
Data from the most recent follow-up of the Pliofilm cohort indicate that the risk for
leukaemia is significantly elevated at cumulative exposures >50 ppm-years,
corresponding to a long-term occupational exposure level >1.25 ppm benzene over
a working life of 40 years. This is higher than any of the assessed long-term
exposure levels in Australian workers, which range from 7 ppb to 0.7 ppm.
However, although exposures from 7 ppb to 0.7 ppm indicate a margin of exposure
from 1.8-180, this is difficult to interpret as the human dose-response analysis
derives from a single cohort with insufficient statistical power to rule out the
possibility of some increase in leukaemia risk in individuals exposed to benzene
levels <1.25 ppm over an entire working life.
In the absence of evidence to the contrary, genotoxic carcinogens such as benzene
are assumed to have a non-threshold mechanism of action. As a `safe'or `no effect'
level therefore cannot be identified, quantitative risk estimation is often used to
express the cancer risk (probability) in numerical terms. The quantitative estimate
is derived from the slope of a modelled dose-response curve fitting the available
data points for the carcinogenicity end point and then extrapolated downwards to
(x,y) = (0,0) to predict the risk at lower exposure levels.
Benzene 181
The available quantitative risk estimates based on the most recent follow-up of the
Pliofilm cohort are summarised in Table 18.1.
Table 18.1: Estimates of human leukaemia risk from occupational exposure
to a cumulative benzene dose of 45 ppm-years, based on dose-response data
from the most recent follow-up of the Pliofilm cohort
Additional lifetime
leukaemia deaths
per 1000 workers* Reference
Mathematical model Exposure estimate
Linear Crump & Allen (1984, 5 Crump (1994)
unpublished)
Paustenbach et al. 3
(1992)
Nonlinear (AUC- Crump & Allen (1984, 5 Crump (1994)
dependent) unpublished)
Paustenbach et al. 3
(1992)
Nonlinear (intensity- Crump & Allen (1984, 5 Crump (1994)
dependent) unpublished)
Paustenbach et al. 0.04
(1992)
Proportional hazards Crump & Allen (1984, 0.3 Paxton et al.
regression unpublished) (1994b)
Paustenbach et al. 0.5
(1992)
Rinsky et al. (1981, 1
1987)
* Rounded to one significant figure
AUC = area under the curve = cumulative exposure
The estimated number of additional lifetime deaths from leukaemia assumes a
cumulative occupational exposure of 45 ppm-years for which estimates are
available from both Crump (1994) and Paxton et al. (1994b). Because 45 ppm-
years is mid-range in the cumulative exposure distributions in the Pliofilm cohort
for all three sets of exposure estimates, the estimations did not require extrapolation
below the range of observation. Furthermore, 45 ppm-years correspond to an
average exposure of 1.125 ppm, which is reasonably close to the assessed
maximum average long-term exposure level in Australian workers of 0.7 ppm.
The mathematical dose-response models listed in the table are statistical in nature
and make no assumptions about the mechanisms of carcinogenesis, other than the
absence of a threshold level. Although 3 out of 9 risk estimates are 1-2 orders of
magnitude lower than the others, the majority lie in the range from 1-5 additional
deaths, irrespective of the choice of model and exposure estimate. It is therefore
prudent to base the quantitative characterisation of the risk for leukaemia on an
incidence of 5 additional lifetime leukaemia deaths per 1000 workers exposed to a
cumulative benzene dose of 45 ppm-years.
To predict the risk at other occupational exposure levels, it can be assumed to be
directly proportional to the cumulative exposure, with exposure spread evenly
across the entire working life (40 years). The results of this estimation are shown
below for the current national exposure standard and a range of assessed
occupational exposures:
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At the current national exposure standard of 5 ppm (Section 19.2.1), the
?br>
estimated additional lifetime risk for leukaemia is 22/1000 workers.
The assessed maximum long-term benzene exposure level is 0.7 ppm in the
?br>
downstream petroleum, steel and coal tar distillation industries. At an exposure
level averaging 0.7 ppm over 40 years, the estimated additional lifetime risk for
leukaemia is 3/1000 workers.
The assessed maximum benzene exposure level is 0.5 ppm in the chemical
?br>
industry and in laboratories using benzene for research and analysis. At an
exposure level averaging 0.5 ppm over 40 years, the estimated additional
lifetime risk for leukaemia is 2/1000 workers.
The assessed maximum benzene exposure level is 0.2 ppm in vehicle
?br>
mechanics and professional users of petrol-fuelled implements. At an exposure
level averaging 0.2 ppm over 40 years, the estimated additional lifetime risk for
leukaemia is 1/1000 workers.
The assessed maximum benzene exposure level is 0.1 ppm in the upstream
?br>
petroleum industry. At an exposure level averaging 0.1 ppm over 40 years, the
estimated additional lifetime risk for leukaemia is 0.4/1000 workers.
The assessed maximum benzene exposure level is 48 ppb in people who work
?br>
in roadside, indoor or in-vehicle environments contaminated with vehicle
exhaust fumes or tobacco smoke. At an exposure level averaging 48 ppb over
40 years, the estimated additional lifetime risk for leukaemia is 0.2/1000
workers.
In comparison, the lifetime risk (0-78 years, males and females combined) for
leukaemia from any cause is 1 in 118, or 8.5/1000 population, based on 1996
incidence figures for Australia (AIHW, 1999).
18.2.3 Uncertainties involved
The risk characterisation for acute effects and bone marrow depression involves
uncertainties due to limitations in the amount and/or quality of relevant animal and
human data. In the case of bone marrow depression, further uncertainties arise from
the lack of an appropriate NOAEL and the use of data from a single ethnic group.
Additional uncertainties are inherent in the assessment of benzene exposure levels
among Australian workers.
Large uncertainties are involved in the characterisation of the risk for benzene-
induced leukaemia. These arise in part from deficiencies in the critical study itself
(the Pliofilm cohort), such as its limited size and the assumptions and
approximations made to assess exposure levels in the absence of personal
monitoring data. They also arise from the lack of sufficient data to validate the
mathematical models used to estimate the risk at different levels of cumulative
exposure. Furthermore, in extrapolating the estimated risk at 45 ppm-years to a 40-
year occupational exposure at average exposure levels from 48 ppb to 0.7 ppm, risk
has been assumed to be directly proportional to cumulative exposure (average
exposure level multiplied with the duration of exposure), although it is unknown
whether a low continuous exposure over a long period of time is equivalent in
terms of cancer risk to a shorter exposure to higher benzene levels. There are also
uncertainties associated with the assessment of benzene exposure levels among
Australian workers.
Benzene 183
18.2.4 Areas of concern
The above risk characterisation does not give cause for concern about acute health
effects from occupational exposure to benzene, given the control measures which
are already in place in Australia.
With regard to chronic exposure to benzene, the risk characterisation suggests that
there is little cause for concern about bone marrow depression in Australian
workers. However, given the uncertainties involved in the risk characterisation and
the likely intra-individual variation in susceptibility to benzene-induced
haematotoxicity, it cannot be excluded that cases may occur at the exposure levels
encountered in the downstream petroleum, coal gas by-product, coal tar distillation
and chemical industries. However, such cases are expected to be mild and,
therefore, reversible upon cessation of exposure.
With regard to leukaemia, there are reasons for concern in all workers with
repeated occupational exposure to benzene, as no threshold has been established for
the genotoxic and carcinogenic effects of the chemical. Based on the available
quantitative risk estimates, the magnitude of the concern can be ranked
approximately as follows: downstream petroleum industry, coke oven, coal gas by-
product and coal tar distillation workers > workers in the chemical industry and in
laboratories using benzene for research or analysis > vehicle mechanics and
professional users of petrol-fuelled implements > workers in the upstream
petroleum industry > workers in roadside, indoor or in-vehicle environments
contaminated with vehicle exhaust fumes or tobacco smoke.
18.3 Public health risks
The public are exposed to benzene through the inhalation of indoor, in-vehicle and
outdoor air contaminated with the chemical through releases that predominantly
derive from vehicle exhaust, petrol evaporation and tobacco smoke. The 24-h
average lifetime exposure in the Australian urban population is estimated at 5.2
ppb. It is one-fifth higher in passive smokers exposed to ETS at home, at work and
in their cars (6.1 ppb) and almost three times as high (15.2 ppb) in the average
smoker (Section 16). Other significant sources of benzene exposure are extended
travel in automobiles and from attached garages with access directly from the
garage into the house.
The critical effects for public health risk characterisation are the same as those for
repeated occupational exposure, that is, bone marrow depression and leukaemia.
18.3.1 Bone marrow depression
As described in Section 18.2.2, a LOAEL of 7.6 ppm (TWA8) for haematological
effects was identified in workers. An occupational exposure level of 7.6 ppm can
be considered equivalent to a 24 h, 7-day-a-week level of 7.6 x 8/24 x 5/7 = 1.8
ppm, or 1800 ppb. This is 320 - 375 times higher than the estimated average
exposure in any non-ETS-exposed age group in the population in the Australian
urban model used in this assessment (Table 16.2). However, the general population
is expected to include subpopulations that are more susceptible to benzene-induced
bone marrow depression, for example, those with specific genetic polymorphisms
(Section 12.4.2) that are expressed with a greater frequency within certain ethnic
groups, or lifestyle factors, such as alcohol consumption, that may act as additional
risk factors. Even so, in considering the margins of exposure and the type of effects
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seen at the LOAEL, the risk for bone marrow depression from environmental
exposure to benzene at the assessed levels is likely to be low.
18.3.2 Leukaemia
As mentioned in Section 18.2.2, data from the most recent follow-up of the
Pliofilm cohort indicate that the risk for leukaemia is significantly elevated at
cumulative exposures >50 ppm-years, corresponding to a long-term occupational
exposure level >1.25 ppm benzene over a working life of 40 years. In terms of
cumulative dose, occupational exposure to 1.25 ppm over an entire working life is
equivalent to lifelong continuous exposure to a benzene level of approximately 130
ppb10. This is 25 times higher than the estimated average lifetime exposure of an
individual living in an urban area of an Australian city (5.2 ppb; Section 16).
However, this margin of exposure is difficult to interpret as the human dose-
response analysis derives from a single occupational cohort study with insufficient
statistical power to rule out the possibility of some increase in leukaemia risk at
cumulative exposure levels which correspond to continuous exposure levels <130
ppb over a lifetime.
The additional risk for leukaemia attributable to environmental exposure to
benzene can be predicted by low-dose extrapolation of the quantitative estimates
used above to characterise the excess lifetime leukaemia risk associated with
occupational exposure to the chemical (Table 18.2). Crump (1994) and USEPA
(1998a) both predict the number of additional leukaemia deaths at two lifetime
exposure levels, namely 1 ppm and 1 ppb, however, only the latter is relevant for
exposure to benzene in the general environment.
Table 18.2: Predicted human leukaemia risk from continuous lifetime
exposure to 1 ppb benzene, based on the occupational risk estimates shown
in Table 18.1 (from Crump (1994) and USEPA (1998a))
Additional lifetime
leukaemia deaths per
100,000 population* Data source
Mathematical model Exposure estimate
2 Crump (1994)
Linear Crump & Allen (1984,
unpublished)
Paustenbach et al. (1992) 2
2 Crump (1994)
Nonlinear (AUC- Crump & Allen (1984,
dependent) unpublished)
Paustenbach et al. (1992) 1
2 Crump (1994)
Nonlinear (intensity- Crump & Allen (1984,
dependent) unpublished)
Paustenbach et al. (1992) 0.00002
0.2
Proportional hazards Crump & Allen (1984, Paxton et al.
regression unpublished) (1994b)
Paustenbach et al. (1992) 0.4
Rinsky et al. (1981, 1987) 0.9
AUC = area under the curve = cumulative exposure
* Rounded to one significant figure
10
A working life is assumed to comprise 8 h/day x 225 days/year x 40 years = 72,000 hours. A
lifetime is assumed to comprise 24 h/day x 365 days/year x 78 years = 683,280 hours. Therefore, in
terms of cumulative dose, an average occupational exposure of 1.25 ppm over 40 years is equivalent
to a 24-h average lifetime exposure of 1.25 x (72,000/683,280) = 0.132 ppm, or approximately 130
ppb.
Benzene 185
With the exception of one outlier which is 4-5 orders of magnitude lower than the
remaining predictions, the risks shown in the table do not differ by more than one
order of magnitude, irrespective of the choice of model and exposure estimate. It is
therefore reasonable to base the risk characterisation on the most conservative
prediction, that is, a lifetime leukaemia risk equivalent to 2 additional deaths per
100,000 population at 1 ppb.
By extrapolation, the lifetime leukaemia risk equivalent for increasing exposure
levels can be calculated as follows:
1 ppb 2 additional deaths/ 100,000 population
2 ppb 4 additional deaths/ 100,000 population
5 ppb 10 additional deaths/ 100,000 population
10 ppb 20 additional deaths/ 100,000 population
20 ppb 40 additional deaths/ 100,000 population
The estimated average lifetime exposure of an individual living in an urban area of
an Australian city is 5.2 ppb. The predicted excess lifetime risk of leukaemia is
therefore 1/10,000, or 1.2% of the lifetime risk of contracting leukaemia of any
cause (1 in 118, or 85/10,000 population, based on 1996 incidence figures for
Australia (AIHW, 1999)).
18.3.3 Uncertainties involved
Substantial uncertainties are involved in the above public health risk
characterisations. These derive in part from the database limitations and lack of a
validated risk estimation model. Moreover, the prediction of leukaemia risk at low
environmental exposure levels by extrapolation from high occupational exposures
may overestimate the risk, since the efficiency of DNA repair systems at low
exposure levels may be increased. In addition, uncertainties are inherent in the
assumptions and approximations made in order to estimate the likely exposure to
benzene in the Australian urban population. The model assumes, for example, a
relatively high population density, with associated high levels of benzene due to car
use. At the same time, there is an assumption that each of the households in the
model population will have a lawn which they mow on a weekly basis. The indoor
levels, which contribute significantly to overall benzene exposure, are derived from
the outdoor levels by the application of a standard ratio. The ratio was estimated
by using ratios found in a range of overseas cities, and making conservative
assumptions to extrapolate these findings to the Australian situation. This may
result in an overestimation of indoor levels both from conservatively high outdoor
levels, and also from a ratio which may overestimate the indoor levels.
18.3.4 Conclusions
Notwithstanding the considerable uncertainties involved in the public health risk
characterisation, the findings set out above can be considered indicative of the risks
to the public based on estimates of benzene levels in urban air. However, the
general population will include subpopulations with a greater exposure to benzene
and hence at greater risk. These subpopulations include smokers, those frequently
using petrol powered devices (e.g. private motor vehicles, lawn mowers, outboard
engines) and individuals who live or work in areas with a high traffic density or
near to industrial sources of benzene emission. As such, adverse health effects
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from benzene-induced bone marrow toxicity are not expected to constitute a
significant public health risk.
With regard to leukaemia, no safe level of exposure has been established. USEPA
(1989) and the Dutch Ministry of Housing, Physical Planning and the Environment
(OECD, 1995) have provided guidance which effectively states that an additional
lifetime cancer risk of 1/1,000,000 can be considered negligible, while an
additional lifetime cancer risk of 1/10,000 is the maximum permissible risk to an
individual for any single substance under consideration. At the assessed public
exposure level in a model Australian urban environment, that is, at 5.2 ppb, the
excess lifetime risk of benzene-induced leukaemia is estimated to be 1/10,000, or
1.2% of the lifetime risk of contracting leukaemia of any cause. This is a
conservative estimate, based on the conservative nature of the quantitative risk
prediction at low environmental exposure levels, and also based on the
conservative exposure assessment. The risk could be estimated more accurately
following collection of monitoring data which better represents the Australian
benzene levels, including both indoor and outdoor levels.
18.4 Risk assessments by other national or international bodies
Government of Canada
Benzene has been assessed for environmental and public health effects
(Government of Canada, 1993). It is considered to be of low risk to the
environment, but is characterised as a non-threshold human carcinogen and as such
meets the Canadian criteria for being considered a chemical that constitutes or may
constitute a danger to human life or health. For AML, the TD0.05 (the lower
confidence limit of the benchmark dose that corresponds to a 5% increase in
mortality) is calculated at 4.6 ppm, based on an early report on the Pliofilm cohort
(Rinsky et al, 1987), the exposure estimates by Crump & Allen (1984,
unpublished) and a linear-quadratic mathematical model. With an estimated
average ambient air concentration of 1.4 ppb, the exposure level is about 3000
times lower than the TD0.05. Under the Canadian criteria, the priority for further
analysis of options to reduce exposure was therefore considered to be high.
UK Department of the Environment, Transport and the Regions
The Department's Expert Panel on Air Quality Standards took the view that
although benzene is genotoxic and as such may be presumed to be a non-threshold
carcinogen, the risks become smaller as the cumulative exposure of an individual is
reduced and that, for all practical purposes, there is a concentration at which the
risks are exceedingly small and unlikely to be detectable by any practicable method
(DoE, 1994). Based on the available epidemiological studies, the Panel determined
that the risk of leukaemia in workers was not detectable when average exposures
over a working lifetime were around 0.5 ppm. Allowing for a 100-fold uncertainty
factor to account for the difference between working lifetime and chronological life
and for interindividual differences in sensitivity, the Panel concluded that an
ambient air level of 5 ppb (as a running annual average) presented an exceedingly
small risk to the health of the general public.
The Department subsequently commissioned the UK Medical Research Council's
Institute for Environment and Health to prepare a more detailed evaluation of the
possible adverse health effects resulting from exposure of the UK general
population to benzene. This assessment found that the major health risk associated
Benzene 187
with low-level benzene exposure is leukaemia, particularly ANLL, and that there is
no evidence to suggest that continuous exposure to environmental levels of benzene
manifests as any other adverse health effect. Based on the work by Schnatter et al.
(1996b) discussed in Section 11.6.1, the lowest level of exposure at which an
increased incidence of ANLL was reliably detected among occupationally exposed
workers was estimated to be in the range of 10-25 ppm. The general population
exposure levels were estimated to range from 1.19-12.80 ppb, or three orders of
magnitude less than the occupational lowest observed effect level. As such, the
assessment concluded that any risk of leukaemia to the general population is likely
to be exceedingly small and probably not detectable using current methodology
(IEH, 1999).
US Environmental Protection Agency
The critical public health effects considered by USEPA are haematotoxicity,
immunotoxicity and leukaemia.
The risk for haemato- and immunotoxicity was assessed on the basis of an
occupational study that identified a concentration of 7.6 ppm as a LOAEL for a
reduction in ALC (Rothman et al, 1996a, 1996b; see Section 11.4.4). This value
was multiplied by 10/20 x 5/7 to correct for differences between occupational and
non-occupational respiratory volumes and a 5-day work week and divided by an
uncertainty factor of 1000 to account for human variability, lack of an appropriate
NOAEL, subacute exposure (<10% of a lifetime) and database deficiencies. The
final result was a human chronic air concentration, considered to be safe, equal to 3
ppb (USEPA, 1998c).
The estimated additional lifetime risk for leukaemia due to continuous exposure to
benzene is 26/1000 at 1 ppm (USEPA, 1985). This estimate was originally
developed by Crump & Allen (1984, unpublished) as the geometric mean of a set
of risk estimates determined separately for each of three occupational cohorts (the
CMA, Dow Chemical and Pliofilm cohorts described in Section 11.6.1) and
adjusted for the difference between working lifetime and chronological life. Since
the mathematical model is linear, the predicted risk at 1 ppb is equal to the unit risk
divided by 1000, that is, 26/1,000,000 population. The public health risk for
leukaemia was reassessed in 1998 (USEPA, 1998a). USEPA concluded that the
evidence made available since 1985 was insufficient to reject a linear dose-
response curve for benzene and that more recent unit risk estimates based on a
linear model ranged from 7-25/1000 and thus were close to the 1985 USEPA
estimate.
However, in accordance with the proposed 1996 draft USEPA guidelines for
carcinogen risk assessment, the USEPA (1998a) update includes an alternative risk
characterisation based on a margin of exposure approach, in which exposure levels
in the general population are compared to the lowest cumulative dose for which
there is evidence of a carcinogenic effect (`the point of departure'). The point of
departure is taken to be 40 ppm-years of occupational exposure, equivalent to a
lifetime (76 years) environmental exposure of 120 ppb. Using the value of 4.7 ppb
reported by Wallace (1996) as an example of a reasonable estimate of long-term
average exposures in the general population, the margin of exposure for the general
public equals 120/4.7, or about 26, which must then be interpreted in light of the
uncertainty about the slope of the dose-response curve below the point of departure,
the nature and magnitude of higher short-term exposures, the extent of individual
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differences in sensitivity, and the modes of action of benzene and its metabolites
(USEPA, 1998a).
World Health Organization (WHO) programs
Benzene risk assessments have been carried out by the International Agency for
Research on Cancer (IARC), under the International Programme on Chemical
Safety (IPCS), and in the course of the development of WHO drinking water and
air quality guidelines.
In general, IARC does not provide risk estimates; however, an exception has been
made for two chemicals classified as carcinogenic to man: benzidine and benzene
(IARC, 1982b). Based on preliminary data from the Pliofilm cohort (Rinsky et al,
1981) and supported by other published evidence, IARC concluded that a working
lifetime exposure to 100 ppm of benzene would be likely to result in 140-170 cases
of leukaemia per 1000 exposed workers.
The IPCS (1993) assessment concluded that occupational exposure to benzene may
lead to bone marrow depression and myelogenous leukaemia. With regard to the
former, IPCS estimated very approximately that exposure to high benzene levels
(50-100 ppm) for one year would most likely produce bone marrow toxicity in a
large percentage of workers and aplastic anaemia in some cases, whereas little
effect would be expected at lower doses. In contrast, exposure to low doses (1-10
ppm) for 10 years was roughly estimated to have the potential to result in a 1-5%
incidence of bone marrow depression. With regard to carcinogenicity, IPCS
concluded that a TWA of 1 ppm over a 40-year working period has not been
statistically associated with any increase in deaths from leukaemia, although it
emphasised that the epidemiological evidence was not capable of distinguishing
between a small increase in mortality and a no-risk situation. IPCS also cautioned
that since benzene is a human carcinogen, exposures should be limited to the
lowest technically feasible level.
The drinking water quality guideline for benzene (10 礸/L) is stated to be derived
from a rounded estimate of the inhalation exposure level associated with a low
level excess risk of leukaemia (1/100,000), as calculated by the application of a
linear extrapolation model to unspecified occupational data (WHO, 1984).
According to the most recent air quality guideline document, the predicted excess
lifetime risk for leukaemia is 6/1,000,000 at a 24-h environmental exposure level of
1 礸/m3 (19/1,000,000 at 1 ppb), based on the geometric mean of four occupational
risk estimates selected from Crump (1994). This corresponds to an excess lifetime
risk of 1/10,000 at a 24-h benzene exposure level of 5.3 ppb, 1/100,000 at 0.53 ppb
and 1/1,000,000 at 0.053 ppb (WHO, 2000).
Organisation for Economic Cooperation and Development
An OECD Screening Information Assessment Report for benzene has been drafted,
but is not available in final form at this time (OECD, 2000).
Benzene 189
19. Risk Management
This section discusses currently employed measures to reduce the likelihood of
adverse human health effects from exposure to benzene. The information reviewed
was obtained from applicants, site visits and the open literature.
19.1 Environmental and public health controls
Several countries around the world have introduced regulations that aim to limit the
exposure of the general public to benzene. Examples include standards for the
maximum annual average concentration of benzene in ambient air in Japan (1 ppb),
The Netherlands (3.1 ppb) and UK (5 ppb); maximum acceptable concentrations of
benzene in drinking water ranging from 1 礸/L in the European Union to 10 礸/L
in Japan and New Zealand; and limits on the concentration of benzene in petrol in
Canada, Japan and New Zealand (all at a maximum of 1% v/v).
In Australia, the industrial use and discharge to the environment of benzene are
controlled by State and Territory regulations pertaining to dangerous goods and
protection of the environment that are enforced by means of a system of conditional
permits, licenses and warrants.
Among other conditions, such permits may set limits relating to the emissions of
benzene to the environment. As described in Section 7.2, systems employed to
reduce industrial emissions of benzene to air include vapour return and recovery
systems, carbon bed filters, fume-scrubbing systems and the burning of off-gases.
Systems employed to reduce emissions to water include the treatment of effluents
by steam stripping, in water/oil separators and/or in biological treatment plants.
Benzene is also one of 36 chemicals included in the National Pollutant Inventory,
which was established in 1998 as a joint Commonwealth, State and Territory
initiative, and must be reported if the quantity used or handled per site exceeds 10 t
per annum (EA, 1999b).
Australian water quality guidelines for fresh and marine waters were established in
1992 and suggested a maximum benzene concentration of 300 礸/L. These
guidelines are currently under revision, with the previous benzene limit likely to be
replaced by freshwater and marine trigger levels equal to 230 礸/L and 170 礸/L
respectively (ANZECC, 2000). These trigger levels are similar to the lowest NOEC
of 170 礸/L for chronic exposure in aquatic organisms (Section 8.3.1). The current
Australian drinking water guidelines propose a limit of 1 礸/L, based on a
consideration of health effects in relation to the limit of determination, to provide
guidance in the unlikely event of contamination and because benzene has been
detected in drinking water overseas (NHMRC, 1996).
The Australian Standard for the Uniform Scheduling of Drugs and Poisons
(SUSDP) lists benzene in Schedule 7, except for preparations containing 15 mL/L
(1.5% v/v) or petrol containing 50 mL/L (5% v/v) of benzene (Australian Health
Ministers' Advisory Council, 1999). Schedule 7 poisons must not be possessed,
sold or supplied for domestic purposes. Furthermore, benzene is listed with a
recommended condition in Part 2 of Appendix J that it is `not to be available except
to authorised or licensed persons'. The labelling requirements for benzene include
the warning statement `Vapour is harmful to health on prolonged exposure' and the
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safety directions `Avoid contact with eyes', `Avoid contact with skin' and `Use
only in well ventilated area'. The recommended first aid instructions are: `If
poisoning occurs, contact a doctor or Poisons Information Centre'; `If swallowed,
do NOT induce vomiting; give a glass of water'; `If skin contact occurs, remove
contaminated clothing and wash skin thoroughly'; and `Remove from contaminated
area; apply artificial respiration if not breathing'. This schedule has been adopted
by all jurisdictions and any use of preparations or petrol containing more than 1.5%
or 5% benzene respectively requires the permission of the relevant state or territory
health authority.
A voluntary Australian Standard limits the benzene content of petrol for motor
vehicles to a maximum of 5% v/v (Standards Australia, 1990). In Western
Australia, the Environmental Protection (Diesel and Petrol) Regulations 1999
stipulate a maximum level of benzene in petrol of 2.0% v/v, with a further
reduction to 1.0% v/v from 1 January 2001. In Queensland, the Environmental
Protection Amendment Regulation (No. 3) 2000, which came into effect on 14 July
2000, prohibits the distribution of petrol with a benzene content exceeding 3.5%
v/v (as an average over 6 months or over 6 consecutive batches). At the national
level, the Fuel Quality Standards Act 2000 enables the Commonwealth to make
mandatory quality standards for fuel supplied in Australia. Among others, these
will include a maximum content of benzene in petrol of 1% v/v from January 1
2006 (EA, 2000b).
The Victorian EPA has proposed setting an intervention level of 0.075 mg/m3 (1 h
average; 23.3 ppb) for benzene under their State Environment Protection Policy
(The Air Quality Management (EPA, 2000). Intervention levels will be used to
determine whether air quality within a local area or neighbourhood is acceptable.
These are risk-based numbers designed for the protection of human health. The
proposed intervention level for benzene is based upon the Effects Screening Level
(ESL) set by the Texas Natural Resources Conservation Commission (TNRCC),
which was set to protect against the carcinogenic effects of benzene.
In 1999 the Commonwealth Government established the Living Cities - Air Toxics
Program (http://www.environment.gov.au/epg/airtoxics/). Under this program the
Commonwealth is committed to supporting the development of national
management strategies to address air toxics, including benzene. In February 2001,
the National Environment Protection Council (NEPC) established a working group
to scope an air toxics National Environment Protection Measure (NEPM). NEPMs
are broad framework-setting statutory instruments outlining agreed national
objectives for protecting or managing particular aspects of the environment. NEPC
will consider commencing the development of an Air Toxics NEPM in June 2001.
Subject to appropriate approvals from NEPC, the Air Toxics NEPM could be
finalised by December 2002. The NEPM development process provides for
extensive public consultation.
19.2 Occupational health and safety controls
19.2.1 Regulatory controls
Exposure standard
Table 19.1 summarises the current occupational exposure standards in Australia
and several overseas countries, including 8-h TWA and short-term exposure limits
Benzene 191
and the presence or absence of a skin notation to indicate that absorption through
the skin may be a significant source of exposure.
In Australia, the current national exposure standard for benzene is 5 ppm (16
mg/m3) expressed as an 8-h TWA airborne concentration, Carcinogen Category 1
(NOHSC, 1995a). This standard was established in 1990 and has been adopted by
all States and Territories. Category 1 includes substances that are known to cause
cancer in humans. There is no short-term exposure limit and no skin notation.
The current exposure standard is close to the level at which there is statistically
significant evidence of haematotoxicity in humans (7.6 ppm (TWA8)) and it is
higher than the level at which there is statistically significant evidence of an
increased risk for leukaemia (1.25 ppm (TWA8)). Furthermore, benzene is a
genotoxic carcinogen for which no safe level of exposure has been established.
The recommendations made by the NOHSC Exposure Standards Working Group
were based on a review of the then available information about exposure levels
associated with haematological, carcinogenic and genotoxic effects in animals and
humans (NOHSC, 1996a). The Working Group did not agree with the exposure
limit of 10 ppm recommended at the time by the American Conference of
Governmental Industrial Hygienists (ACGIH), as cases of leukaemia could be
identified with exposure of less than 10 ppm in some human studies. Nor did it
support the US Occupational Safety and Health Administration (OSHA) limit of 1
ppm, which it considered to be based on inadequate epidemiological studies.
ACGIH first recommended an 8-h TWA threshold limit value for benzene of 35
ppm in 1948. The recommended limit was lowered to 25 ppm in 1952, 10 ppm in
1974 and 0.5 ppm in 1997. The basis for the currently recommended limit was the
re-analysis of the Pliofilm cohort by Schnatter et al. (1996b) (Table 11.6 in Section
11.6.1) which was interpreted to suggest that at a TWA of 0.5 ppm, the odds of
death from leukaemia due to occupational exposure to benzene would be
indistinguishable from the odds of death from leukaemia for a worker who is not
exposed to benzene (ACGIH, 2000).
A US federal standard of 10 ppm was established in 1970. Based on the reports by
Infante et al. (1977) and Ott et al. (1978) of an excess mortality from leukaemia in
rubber and chemical workers exposed to benzene, OSHA lowered the statutory
limit to 1 ppm in 1978. This action was challenged by the US petroleum industry,
and the US Supreme Court barred OSHA from upholding the lower limit on the
grounds that it had not demonstrated that the new limit would achieve a substantial
health risk reduction (Nicholson & Landrigan, 1989). OSHA subsequently
developed a quantitative risk estimate for benzene-induced leukaemia and
reimposed the 1 ppm limit in 1987.
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Table 19.1: National occupational exposure standards for benzene (from
ACGIH (2000) and EC (2000))
Exposure limit (ppm)
Country* 8-h TWA STEL Skin notation
Australia 5 - -
European Union
?br>
10 - -
?Belgium
?br>
5 - +
?Denmark
?br>
5 10 +
?Finland
?br>
5 - -
?France
?br>
1** 4 +
?Germany
?br>
5 - -
?Ireland
1 - +
?The Netherlands
0.5 3 +
?Sweden
?br>
5 - -
?United Kingdom
European Union as of 26/06/03 1 Optional Optional
USA
0.5 2.5 +
?ACGIH
0.1 1 -
?NIOSH
1 5 -
?OSHA
* ACGIH = American Conference of Governmental Industrial Hygienists (recommended limits); NIOSH =
National Institute of Occupational Safety and Health (recommended limits); OSHA = Occupational
Safety and Health Administration (statutory limits)
STEL = short-term (15-min) exposure limit
A skin notation indicates that absorption through the skin may be a significant source of exposure.
?br>
According to EC (2000), Council Directive 97/42/EC (27 June 1997, amending Directive 90/394/EEC)
requires these European Union member states to implement a regulation in their national legislation
which reduces the exposure limit to 1 ppm as of 26 June 2003
** In Germany, the exposure limit is 2.5 ppm for coking plants, tank farms and work on benzene- or
petrol-conducting plant in the chemical and petroleum industries (OECD, 2000)
Atmospheric monitoring
The use of Category 1 carcinogens, such as benzene, should be controlled to the
highest practicable standard. According to the NOHSC Exposure Standards for
Atmospheric Contaminants in the Occupational Environment (NOHSC, 1995a),
routine monitoring of the workplace is essential for indication of control
performance.
Health surveillance
Following an amendment in 1995, Schedule 3 of the NOHSC National Model
Regulations for the Control of Workplace Hazardous Substances (NOHSC, 1994b)
lists benzene as a hazardous substance for which health surveillance is required
where there is a significant health risk to workers from exposure to the substance.
For benzene, the health surveillance must include demography, occupational and
medical history and health advice, a baseline blood sample for haematological
profile, and records of personal exposure (NOHSC, 1995b). A specific health
surveillance guideline for benzene is available (NOHSC, 1996b).
Scheduled carcinogenic substances
The NOHSC Model Regulations for the Control of Scheduled Substances
(NOHSC, 1995c) lists benzene as a Schedule 2 notifiable carcinogenic substance
Benzene 193
when used as a feedstock containing more than 50% v/v of the chemical.
Requirements of the regulation include:
notification to the relevant public authority of any proposed use of benzene and
?br>
the quantity to be used per annum;
a work assessment including an assessment of potential exposure, to be carried
?br>
out prior to its use;
the keeping of records of employees likely to be exposed;
?br>
the reporting of exposure incidents to the relevant public authority; and
?br>
advising employees of any accidental exposure.
?br>
Employers who use any scheduled carcinogenic substance in a laboratory for
research or analysis must make a separate notification to the relevant authority.
Control of major hazard facilities
Because of its Australian Dangerous Goods Class and Packaging Group status,
benzene must be taken into account when determining whether a site is a major
hazard facility under the NOHSC National Standard for the Control of Major
Hazard Facilities (NOHSC, 1996c). For flammable liquids in Packaging Group II,
such as benzene, the threshold quantity is 50,000 t. The purpose of this standard is
to prevent, and minimise the effects of, major accidents and near misses by
requiring the person in control of the facility to:
identify and assess all hazards and implement control measures to reduce the
?br>
likelihood and effects of a major accident;
provide information to the relevant public authority and the community,
?br>
including other closely located facilities, regarding the nature of hazards of a
major hazard facility and emergency procedures in the event of a major
accident;
report and investigate major accidents and near misses, and take appropriate
?br>
corrective action; and
record and discuss the lessons learnt and the analysis of major accidents and
?br>
near misses with employees and employee representatives.
State and Territory regulations
The States and Territories have included the NOHSC model regulations and
standards referred to above in relevant workplace health and safety or dangerous
goods legislation. Benzene is a flammable liquid and should be stored and handled
in accordance with relevant state and territory dangerous goods legislation. In
addition, some jurisdictions have regulations prescribing an upper limit on the
concentration of benzene in paint, including New South Wales and the Northern
Territory where the limit is 1% in all paints, and Western Australia where it is 1.5%
in spray painting materials. However, benzene is no longer used in paints and
painting materials.
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19.2.2 Current control measures
Workplace control measures
Workplace control measures include isolation by distance or full containment in
enclosed systems, engineering controls, safe work practices and personal protective
equipment (PPE).
Petroleum industry
The petroleum industry has developed a guideline for the protection of employees
from exposure to benzene (AIP, 1994). The guideline emphasises the importance of
full containment and engineering controls such as closed sampling systems in
reducing exposure to benzene, particularly in locations where streams containing
>5% benzene are handled. It also recommends that areas where airborne benzene
levels may exceed 1 ppm have restricted access and be clearly marked.
The recommended PPE includes suitable gloves and boots; a full apron and sleeves
where contact with any liquids containing benzene is foreseeable; eye protection
when handling products or streams containing >5% benzene; and suitable
respiratory protection in all situations where benzene levels are expected or known
to approach or exceed 1 ppm.
In the distribution sector, engineering controls include floating-roof tanks with
electronic gauging systems, vapour return and recovery systems, and the use of
bottom-loaded rail and road tankers fitted with dry break couplings, capacitance
probes and earthing points. Workers are required to wear gloves during loading and
unloading.
Steel and associated industries
At the Port Kembla steelworks, the coal gas by-product plant and BTX road tanker
loading bay are fenced off and access restricted to inducted personnel and
contractors. An emission control system under completion involves equipping all
tank vents in the by-product plant with a sealpot arrangement to minimise releases
to air from tank breathing.
At the Whyalla steelworks, personnel must wear gloves, protective clothing,
waterproof boots and vapour cartridge masks to access the coke ovens and by-
product plant for inspection and maintenance.
At Koppers coal tar distillery, control measures include full enclosure, fume
scrubbing and written operating procedures specifying safe work practices and PPE
for each task where there is the potential for exposure to hazardous chemicals.
Chemical industry
In the chemical industry, the main control measures are full containment in
enclosed systems and engineering controls such as closed sampling systems. In
addition, skin and eye protection is used where contact with liquids containing
benzene may occur and suitable respiratory protection is worn in situations where
airborne levels of benzene are likely to exceed a limit which varies from 1-3 ppm
depending on company policy and the limit of detection of `instantaneous'
measuring equipment. Engineering controls applied to minimise emissions during
transport and storage of BTX and feedstock benzene include the use of bottom-
loaded road tankers fitted with dry break couplings, capacitance probes and
Benzene 195
earthing points; closed dipping or electronic gauging of tanks; and vapour return
and recovery systems to prevent releases to the atmosphere from vapour
displacement and tank breathing.
Industrial and research laboratories
The main control measure in laboratories is the confinement of all handling
procedures to a fume cupboard.
Contaminated workplace environments
Ventilation is the predominant control measure in workplaces such as garages and
bars contaminated with petrol vapours, engine exhaust fumes or tobacco smoke
from indoor sources. Air purification systems may be used in environments
contaminated with vehicle exhaust from outdoor sources, such as vehicle cabins,
tollbooths and drive-in outlets.
Emergency procedures
All applicants in the petroleum, chemical and steel and associated industries that
manufacture, use or handle benzene have comprehensive written emergency
response plans setting out how workers and emergency services should deal with
on-site leaks, spills, releases, fires and explosions. These sites routinely handle or
use a number of hazardous chemicals in large quantities and have on-site
emergency squads which can be activated via alarm buttons posted throughout the
site. Workers are trained to respond to emergencies by sounding the alarm,
informing a manager and then promptly evacuating the incident area.
Separate exposure and first-aid procedures for emergencies involving benzene are
in use in the petroleum industry (AIP, 1994). The exposure procedures include the
following instructions:
remove affected person immediately from contaminated area;
?br>
urgently seek medical advice;
?br>
give artificial respiration with oxygen if required;
?br>
in the event of benzene being swallowed advise the hospital that a lavage of the
?br>
stomach will be required.
Advice for doctors comprises the following:
aspiration can take place. Aspiration after ingestion may cause chemical
?br>
pneumonitis;
acute exposure to high concentrations of benzene by inhalation may kill by
?br>
depression of the CNS leading to unconsciousness and death or by fatal
acardiac arrhythmia;
keep victim under close observation and treat symptomatically as indicated by
?br>
the patient's condition.
Hazard communication
Labels
Under the NOHSC National Model Regulations for the Control of Workplace
Hazardous Substances (NOHSC, 1994c) and the corresponding State and Territory
legislation, suppliers or employers shall ensure that all containers of hazardous
Priority Existing Chemical Number 21
196
substances used at work are appropriately labelled in accordance with the NOHSC
Code of Practice for the Labelling of Workplace Substances (NOHSC, 1994a).
In accordance with the current version of the NOHSC List of Designated
Hazardous Substances (NOHSC, 1999b), labels for containers of benzene should
contain the following risk and safety phrases:
R11 Highly flammable S45 In case of accident or if
you feel unwell, seek
R45(1) May cause cancer medical advice
(Category 1) immediately (show the
label whenever possible)
R48/23/24/25 Toxic: Danger of serious
damage to health by S53 Avoid exposure ?obtain
prolonged exposure through special instructions
inhalation, in contact with before use
skin and if swallowed
However, Section 14.3 lists additional risk phrases that will apply as a result of this
assessment.
Labelling with risk phrase R45(1) is required for all mixtures containing 0.1%
benzene. Risk phrase R48/23/24/25 applies to liquid mixtures containing 10% and
gaseous mixtures containing 5% benzene. Liquid mixtures containing 1% but
<10% and gaseous mixtures containing 0.5% but <5% benzene must be labelled
with risk phrase R48/20/21/22 (`Harmful: Danger of serious damage to health by
prolonged exposure through inhalation, in contact with skin and if swallowed').
Liquid mixtures containing <1% and gaseous mixtures containing <0.5% benzene
are not required to be labelled with risk phrase R48.
Labels for containers of reagent grade benzene for laboratory use were not
available for assessment. One applicant provided a label from a cardboard box used
to transport individual containers of the chemical. This label was found to meet all
relevant requirements in the ADG Code (Section 19.3).
Bulk storage vessels and tanks must be labelled according to the appropriate State
or Territory dangerous goods regulation, generally with an affixed hazard sign or
placard similar to the one required for road tankers under the ADG Code. As a
minimum, dedicated benzene lines and pipes must be labelled with the name of the
chemical.
Material Safety Data Sheets
Material safety data sheets (MSDS) are the primary source of information for
workers involved in the handling of chemicals. Under the NOHSC National Model
Regulations for the Control of Workplace Hazardous Substances (NOHSC, 1994c)
and the corresponding State and Territory legislation, suppliers of a hazardous
chemical for use at work are obliged to provide a current MSDS to their customers.
Employers must ensure that an MSDS is readily accessible to employees with
potential for exposure to the chemical.
A total of five MSDS for BTX, feedstock and analytical grade benzene were
available for assessment against the NOHSC National Code of Practice for the
Preparation of Material Safety Data Sheets (NOHSC, 1994b). No major
deficiencies were identified.
A sample MSDS prepared in accordance with the findings of this assessment and
the NOHSC National Code of Practice for the Preparation of Material Safety Data
Benzene 197
Sheets (NOHSC, 1994b) is provided at Appendix 1. Although it refers to analytical
grade benzene for laboratory use, some of the information may also be appropriate
for other benzene-containing substances. The sample is for guidance purposes only,
as manufacturers and importers are responsible for preparing their own MSDS and
ensuring that the information is accurate and up-to-date.
Education and training
All applicants in the petroleum, chemical and steel and associated industries that
manufacture, use or handle benzene have specific induction and refresher training
for employees and contractors in benzene hazards and safety procedures. Workers
potentially exposed to benzene are also trained in the proper use and maintenance
of respiratory protective equipment.
19.3 National transport regulation (ADG Code)
Under the ADG Code, benzene (UN Number 1114) is classified in Class 3,
flammable liquids, and assigned Packaging Group II (FORS, 1998).
According to the Code, road and rail tankers carrying benzene in bulk must be
placarded with class 3 (`flammable liquid') and an emergency information panel
containing additional information such as the proper shipping name of the chemical
(`benzene'), its UN Number, Hazchem Code and the name and telephone number
of the consignor of the goods. The Hazchem Code for benzene, 3WE, reflects the
initial emergency response recommended in case of fire, leakage or spillage. The
number `3' indicates that foam should be used for firefighting. The letter `W'
means that there is a risk of violent reaction or explosion; that emergency personnel
should wear full protective clothing (breathing apparatus, protective gloves,
appropriate boots and a chemical splash suit); and that any spillage should be
contained so as to prevent the chemical from entering drains or water courses. The
letter `E' denotes that evacuation of people from the neighbourhood of an incident
should be considered.
The ADG Code also contains provisions for the marking of packages containing
benzene with its UN Number, shipping name, class label and the name and address
in Australia of the consignor of the goods.
Priority Existing Chemical Number 21
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20. Discussion and Conclusions
Benzene is ubiquitous in the environment, with numerous sources of entry
including bush fires, crop residue and forest management burning, petrol
combustion and evaporation, wood fires, tobacco smoking and emissions and waste
streams from various industries. In a modelled Australian urban environment, 85%
of benzene in outdoor air is due to petrol engine exhaust fumes, with industry and
petrol service station emissions accounting for 13% and solid fuel combustion for
2% of the total.
Based on 1998-99 data, industrial use of benzene in Australia is estimated at 535 kt
per year. All of the benzene introduced by the petroleum industry (82% of total
consumption) was retained as a component in petrol. Benzene feedstock for the
synthesis of other organic chemicals accounted for 18% of total consumption and
less than 1% was either burned as fuel or utilised as solvent or reagent. In
consequence, future developments in petrol demand and composition will have a
major impact on the introduction of benzene. Thus, the annual use of benzene as a
component in petrol is predicted to increase from 434 kt in 1998 to 461 kt in 2007
if the average concentration of benzene in petrol is maintained at 2.6-3.3% v/v,
whereas a nationwide standard limiting benzene content to a maximum of 1%
would reduce the quantity to 176 kt in 2007.
20.1 Environmental exposure and risks
Benzene may be considered biodegradable and in environmental terms is soluble in
water. Its removal from aqueous systems occurs significantly as a result of
volatilisation and, at equilibrium, over 99% of the chemical would be expected to
partition to the atmosphere where it will break down primarily through reaction
with hydroxyl radicals. Concentrations likely to occur in aquatic systems are
expected to be far lower than of concern, and this expectation is supported by
reported international monitoring data. A low aquatic risk is therefore predicted.
Additionally, the short atmospheric lifetime of benzene indicates concentrations
will not occur at levels harmful to the atmosphere. While widespread transport
within the troposphere is possible, the chemical is not expected to reach the
stratosphere and therefore would not have an influence on global warming or ozone
depletion.
Due to the low expected exposure to the terrestrial compartment, a low
environmental risk is predicted to terrestrial organisms.
As such, the findings in this assessment have not identified any significant risk to
the environment resulting from exposure to benzene.
20.2 Health effects
Benzene is well absorbed by the inhalation and oral routes in all animal species
tested. It is also absorbed through the skin, although in practice skin contact is
unlikely to result in significant absorption because of the rapid evaporation of the
chemical. In humans, the absorption of benzene by the inhalation route is maximal
within minutes of exposure and subsequently declines to a constant level, with 20-
80% of the inhaled dose being retained after short-term exposure to air levels in the
Benzene 199
order of 1-100 ppm. In the body, benzene accumulates in lipid-rich tissues such as
the brain. It also reaches the liver, where it is first metabolised by CYP2E1-
mediated hydroxylation of the aromatic ring. Subsequent oxidations take place in
several organs and result in a series of polyphenols and, to a lesser extent, cleavage
of the ring, with a variety of metabolites occurring in the urine within 2 h of
exposure. Benzene is also eliminated unchanged with exhaled air, particularly at
higher exposure levels that saturate the enzymes which convert it to water-soluble
metabolites.
Benzene is not highly acutely toxic to experimental animals. By repeated exposure,
the main manifestations of benzene toxicity are CNS depression,
immunosuppression, bone marrow depression, degenerative lesions of the gonads,
and foetal growth retardation. Benzene also causes damage to genetic material
(DNA, chromosomes); increases the incidence of lymphoma in mice strains where
this is a common spontaneous tumour type; and induces malignant tumours in the
mouth, nasal cavities, lung alveoli, Harderian, Zymbal, preputial and mammary
glands, and the ovary. However, a valid animal model for benzene-induced
leukaemia has not been identified.
The reported lethal dose in humans is 20,000 ppm by inhalation for 5-10 min, or
125 mg/kg by ingestion. The most significant acute effects are irritation of the skin,
eyes and respiratory system at benzene vapour concentrations >33 ppm and
progressive CNS depression at concentrations 250 ppm.
It is well documented through epidemiological studies that the critical human
health effects from repeated exposure to benzene are bone marrow depression and
leukaemia, specifically AML (ANLL). There are also observations showing an
association between long-term benzene exposure and the risk for lymphoma (NHL,
MM), although the evidence is not as conclusive as it is for leukaemia.
Furthermore, structural and numerical chromosome aberrations have been detected
in peripheral blood cells of workers exposed to high benzene levels.
For bone marrow depression, a NOAEL has not been determined, but occupational
studies with various limitations indicate that it is likely to be >0.5 ppm. Based on
current human data, 7.6 ppm (TWA8) is considered the best estimate for a LOAEL
which may be close to the threshold for blood count changes in otherwise healthy
workers. No threshold has been established for the genotoxic and carcinogenic
effects of benzene. However, the available epidemiological evidence shows that the
risk of leukaemia increases with exposure and is significantly elevated at
cumulative exposures >50 ppm-years, corresponding to >1.25 ppm (TWA8) over a
working life of 40 years.
Experimental studies indicate that the toxic effects of benzene on the bone marrow
are due to several secondary metabolites that are formed locally in relatively high
concentrations. These metabolites act in an additive or synergistic manner to
disrupt a range of mechanisms that regulate blood stem cell division and maturation
and cause other cell damage through a combination of genetic and non-genetic
changes. Damaged cells are usually eliminated, but may on occasion possess
activated oncogenes or have lost tumour suppressor genes, which could enable
them to proliferate as clonal lines of leukaemic cells.
The kinetics and metabolism of benzene are similar in men and women. There are
no data on age-related differences. However, there is likely to be substantial
variations in the sensitivity of an individual to the toxic effects of the chemical as
both genetic polymorphisms and lifestyle factors may modulate the expression or
Priority Existing Chemical Number 21
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activity of several enzymes involved in the biotransformation of benzene to toxic
metabolites.
20.3 Public exposure and health risks
The benzene content in consumer products is nil or negligible, except for tobacco
smoke and petrol. Mainstream tobacco smoke contains about 50 (range: 3-60) 礸
benzene per cigarette, corresponding to an intake of 0.89 mg benzene/day in the
average smoker (17.8 cigarettes/day). This is equivalent to the intake from
continuous inhalation of ambient air containing 12.5 ppb of the chemical. Although
the general public may have skin contact with petrol and inhale petrol vapours, for
example, during refuelling at self-service stations, such exposures would be
infrequent and of short duration and thus have little impact on total intake. Benzene
has been detected in human breast milk, however, there are no good data on
secretion levels of benzene in breast milk. Benzene has not been detected in
Australian drinking water and overseas studies have, in general, found benzene
levels in food to be very low. As such, the predominant pathway for public
exposure to benzene is the inhalation of ambient air in the microenvironments
where people spend most of their time, that is, the home, the school or workplace,
outdoors and in vehicles on the road.
For the purposes of this assessment, an estimated benzene level in outdoor urban
air was predicted based upon releases to the atmospheric air column above a model
city with a population of 300,000 and a population density approaching 2500
people/km2 (similar to Sydney). This gave a value of 3.4 ppb, which is comparable
to individual results measured in various Australian urban centres. Based on a
review of the available Australian and overseas data, the concentration of benzene
in indoor air in urban homes and non-residential buildings such as schools and
offices was estimated at 1.4 times the outdoor air concentration, or 4.8 ppb.
Average benzene exposures resulting from urban transport activities, such as the
use of cars (15-48 ppb) and buses and trams (7.5 ppb), were also estimated.
Contamination with ETS was estimated to augment exposures in indoor/in-vehicle
microenvironments by 1.2 ppb. Overall exposure levels were then calculated by
factoring in the length of time various age groups within the general population are
likely to spend in the relevant microenvironments.
The results of this exercise indicate that the lifetime weighted 24-h exposure to
benzene in the general urban population is 5.2 ppb in non-ETS exposed persons,
6.1 ppb in passive smokers exposed to ETS at home, at work and in their cars and
15.2 ppb in the average smoker.
Benzene emissions to the urban atmosphere will tend to reduce over time as older
petrol vehicles with higher emissions are removed from the fleet (EA, 2000c).
Under the Fuel Quality Standards Act 2000, the Commonwealth will establish
national standards prescribing a range of characteristics for petrol and diesel. These
will include a maximum content of benzene in petrol of 1% (v/v) from January 1
2006 and standards for other relevant quality parameters such as the content of
aromatics, which are predicted to result in a further reduction in benzene emissions
(EA, 2000c). As 85% of benzene in both outdoor and indoor air in the model used
for this assessment is due to petrol engine exhaust fumes, renewal of the car fleet
and implementation of the proposed fuel quality standards would clearly lead to a
downward revision of the estimated levels of exposure among the general
population.
Benzene 201
Based upon the occupational LOAEL for bone marrow depression corrected for the
difference between working hours and chronological time and on the conservative
nature of the assessed exposure, adverse health effects from benzene-induced
haematotoxicity are not expected to present a significant public health risk.
Based upon low-dose extrapolation of relevant quantitative risk estimates, the
excess lifetime risk of benzene-induced leukaemia is 2/100,000 population per 1
ppb benzene in the air breathed. In the Australian model city mentioned above, the
average exposure was estimated at 5.2 ppb corresponding to an excess lifetime risk
of benzene-induced leukaemia in the order of 1/10,000, which is at the maximum
permissible level for any single carcinogenic substance according to Dutch and US
authorities. This estimate, however, is based on substantial uncertainties in the
exposure assessment. Personal and ambient exposure monitoring of representative
samples of the Australian population would enable validation of this estimate.
Further indoor/outdoor air monitoring data, including in rural areas, would also be
helpful in refining the assessment of benzene-associated risks to human health.
Nevertheless, as benzene is an established human carcinogen for which no safe
level of exposure has been established, any increase in public exposure should be
avoided and, where practicable, measures should be taken to reduce exposure.
Given the extensive contribution of vehicle exhaust to ambient benzene levels,
reductions in total benzene emitted by vehicles would be effective in lowering
public exposure to benzene. A reduction in benzene levels in petrol from 3% to 1%,
as proposed in the Fuel Quality Standards, will likely result in significantly
lowering benzene exposure in the general population. Measures to reduce
environmental tobacco smoke in enclosed public areas should also be continued. A
range of lifestyle choices can also be made by individuals to reduce their exposure
to benzene, including minimising the time spent in a vehicle in heavy traffic,
avoidance of ETS and managing air flow in the home to minimise indoor benzene
levels. As high indoor levels of benzene have been found in houses with direct
access from attached garages, indoor levels may be reduced by ensuring that
doorways are adequately sealed and fitted with automatic door closers.
In one study in the UK, mean benzene levels in fatty foods sold at petrol stations
and roadside stalls were in the order of 10 to 20 ng/g. Other studies in both
Germany and the UK did not detect elevated levels. The possibility of elevated
benzene levels in food sold at sites with elevated ambient benzene levels should be
referred to ANZFA and to State Health Departments for their consideration.
Australia, unlike a number of other countries, does not have an ambient air standard
for benzene. It is important that such a standard be set, so that the results of
monitoring studies can be considered and action taken where appropriate.
The development of a National Environment Protection Measure (NEPM) which
sets ambient standards for air toxics is to be considered by the National
Environment Protection Council (NEPC) in June 2001. Should the development of
the NEPM proceed, it is expected that it will be completed in December 2002.
20.4 Occupational exposure and health risks
Inhalation of vapours is the predominant route of occupational exposure to
benzene, although significant skin absorption may occur in workers having
prolonged skin contact with benzene or benzene-containing liquids such as petrol.
Priority Existing Chemical Number 21
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Exposure occurs principally in the petroleum, chemical, coal gas, coal tar and
associated industries which use, produce, store, distribute or otherwise handle high
volume streams or products containing benzene at concentrations that range from
0.1% in crude oil to 99% in chemical feedstock. In these industries, exposure is
generally controlled by full containment in enclosed systems located in naturally
ventilated, outdoor facilities. As such, the main sources of exposure are fugitive
emissions from pumps and seals, transfers between closed systems resulting in
drips, spills and/or vapour displacement, and sampling, dipping, cleaning and
maintenance operations that require open access to the closed system. Various
engineering controls are also in place, as are safe work practices and the use of PPE
in situations where air levels above 1-2 ppm benzene or skin contact with the
chemical may occur.
The number of potentially exposed workers in these industries is not known with
certainty, but is probably in the order of 25,000-35,000 in the petroleum industry
and 700-800 in the chemical, coal gas and coal tar industries. It is estimated that
current long-term occupational exposure levels are <0.1 ppm in the upstream
petroleum industry; <0.5 ppm in the chemical industry (except < 0.7 ppm for
maintenance workers in phenol plants); <0.7 ppm in the down-stream petroleum
industry; and 0.7 ppm in coke oven, coal gas by-product and coal tar workers in
the steel and associated industries. Higher individual full shift exposure levels have
been measured in reformer operators (up to 54 ppm), distribution terminal workers
(up to 7.9 ppm), workers involved in ship to shore transfer of benzene feedstock
(up to 5.6 ppm), chemical plant engineers (up to 1.5 ppm) and coal gas by-product
plant operators (up to 11 ppm), but are not expected to be of regular or frequent
occurrence. The highest short-term exposure reported is 12 ppm during ship to
shore transfer of benzene feedstock.
Furthermore, it is estimated that around 600 workers are potentially exposed to
benzene vapour in laboratories where minor quantities of the chemical are used for
research or analytical purposes. The predominant control measure in these
workplaces is the confinement of all handling procedures to a fume cupboard.
Based on an inherently conservative model, the average long-term occupational
exposure level in these workers is predicted to range from 0.25-0.5 ppm, although
short-term exposures may reach 10-20 ppm.
Finally, workplace environments may contain benzene air concentrations that
exceed those of normal ambient or indoor air because of contamination with petrol
vapours, engine exhaust or tobacco smoke. There are no control measures in these
workplaces that specifically target benzene, however, ventilation and air
purification systems in use for other reasons may also reduce the concentration of
benzene in the workers' breathing zone.
Occupations potentially exposed to petrol vapours and engine exhaust include in
the order of 100,000-400,000 vehicle mechanics, professional users of petrol-
fuelled implements such as gardeners and loggers, and people who work in the
immediate vicinity of busy roads, such as professional drivers, road labourers, staff
at fast-food outlets, toll collectors and traffic wardens. Overseas data indicate that
vehicle mechanics and professional users of petrol-fuelled implements have long-
term occupational exposure levels <0.2 ppm benzene. Based on a modelled
Australian urban environment, exposure levels are estimated at 7-48 ppb in the case
of professions whose workplace environment is on or near heavily trafficked roads.
In the case of vehicle mechanics, tasks that require the fuel system to be broken
Benzene 203
open may entail short-term exposure levels 15 ppm benzene, in addition to skin
contact with the chemical.
Occupations potentially exposed to environmental tobacco smoke include up to
150,000 workers in the clubs and pubs, taverns and bars industries, whose long-
term occupational exposure levels are estimated at 8-21 ppb.
The impact of fuel quality standards on ambient benzene levels has been discussed
in Section 20.3 above. A mandatory reduction of the concentration of benzene in
petrol from current levels to 1% is likely to result in a substantial reduction in the
average occupational exposure levels in workers exposed to petrol fumes, such as
petrol distribution workers and vehicle mechanics. The reduction in exposure is
likely to be approximately proportional to the reduction in benzene content, that is,
2- to 3-fold. The predicted reduction in vehicle emissions of benzene would also
reduce the occupational exposure of professional drivers and similar road or
roadside workers to the chemical. As non-benzene aromatics in fuel can cause
around 70-80% of the exhaust benzene formed and some also forms from other
hydrocarbons, it is difficult to quantify the extent of the reduction in occupational
exposure.
The banning of smoking in all enclosed public areas would reduce benzene
exposure in the hospitality industry to background levels.
The occupational risk characterisation does not give cause for concern about acute
health effects from exposure to benzene.
With regard to chronic exposure to benzene, it cannot be excluded that cases of
mild bone marrow depression may occur at the exposure levels encountered in the
downstream petroleum, coal gas by-product, coal tar distillation and chemical
industries. However, such cases would be picked up by the prescribed health
surveillance and are expected to be reversible upon cessation of exposure.
There is concern about leukaemia in all workers with repeated occupational
exposure to benzene. Although no threshold has been established for the genotoxic
and carcinogenic effects of benzene, the risk for leukaemia is proportional to
cumulative exposure. Therefore, exposure should be controlled to the highest
practicable standard.
In workplaces where benzene or benzene-containing streams are contained in fully
enclosed systems, particular attention should be paid to engineering control
techniques and operating procedures aimed at reducing fugitive emissions from
pumps and seals as well as drips, spills and vapour displacement during transfers
between closed systems, and to improvements which eliminate the need to break
open the closed system for the purposes of sampling, dipping and cleaning. In
workplaces where benzene or benzene-containing products are not contained in
closed systems, such as laboratories and car repair shops, particular attention
should be paid to safe work practices and the availability of good local exhaust
ventilation. Where skin contact with benzene or petrol may occur, workers should
wear appropriate PPE, including benzene-resistant gloves.
As benzene is flammable and classified as a dangerous good, it should be stored,
handled, labelled and transported in accordance with state and territory dangerous
goods legislation.
The current national occupational exposure standard of 5 ppm (TWA8) should be
revised as 5 ppm is close to the human LOAEL for bone marrow toxicity (7.6 ppm)
Priority Existing Chemical Number 21
204
and higher than the level at which there is statistically significant evidence of an
increased risk for leukaemia (1.25 ppm). Furthermore, the exposure data collected
from Australian workplaces for this assessment indicate that it is technically
feasible to keep exposures below 0.5 ppm (TWA8).
The NOHSC List of Designated Hazardous Substances (NOHSC, 1999b) classifies
benzene as flammable (R11), a carcinogen in Category 1 (R45) and toxic by
prolonged exposure through inhalation, in contact with skin and if swallowed
(R48/23/24/25). This classification has been adopted from the European Union
where it has remained unchanged since 1967 (although currently under review). In
accordance with the NOHSC Approved Criteria for Classifying Hazardous
Substances (NOHSC, 1999a), this assessment has reviewed the classification of
benzene, and amended the above classification to include the following risk
phrases: `Irritating to eyes, respiratory system and skin' (R36/37/38) and `Possible
risk of irreversible effects' (R40, that is, a mutagenic substance in Category 3).
Additional safety phrases are not considered warranted, given the prescribed
labelling of all mixtures containing 0.1% benzene with S53: `Avoid exposure ?br>
obtain special instructions before use'.
20.5 Data gaps
For the purposes of risk assessment, the most significant data gaps are as follows:
epidemiological data permitting the establishment of an appropriate human
?br>
NOAEL for bone marrow depression;
epidemiological data on the additional risk for leukaemia at benzene exposure
?br>
levels that fall within the range experienced by the general population;
data on whether various subpopulations are more susceptible to adverse health
?br>
effects of benzene exposure; and
personal and ambient monitoring data on the benzene exposure of a
?br>
representative cross-section of the Australian population.
In addition, further research is needed to determine if benzene is a germ cell
mutagen and could cause reproductive effects and contribute to the risk for breast
cancer in humans.
Benzene 205
21. Recommendations
Preamble
This section provides the recommendations arising from the assessment of benzene.
The critical issues, summarised below, have been taken into consideration in
formulating these recommendations:
benzene is a known human genotoxic carcinogen for which there is no known
?br>
safe level of exposure;
occupational exposure to benzene occurs during its manufacture and through
?br>
the use of benzene-containing products, particularly petroleum products;
the main sources of public exposure to benzene are the use of petrol and diesel
?br>
fuelled equipment, smoking and releases from industrial processes;
the best available LOAEL value for non-carcinogenic effects in humans is 7.6
?br>
ppm for haematotoxicity;
a statistically significant increased risk for leukaemia has been measured at and
?br>
above 1.25 ppm (TWA8) in occupational studies;
the estimated excess lifetime risk of benzene-induced leukaemia is 2/100,000
?br>
population per 1 ppb benzene in air;
the current Australian exposure standard is set at 5 ppm (16 mg/m3) TWA8; and
?br>
best practice must be implemented to minimise occupational and public
?br>
exposure to benzene.
Recommendation 1: NOHSC occupational hazard classification
Benzene is currently listed in the NOHSC List of Designated Hazardous
Substances (NOHSC, 1999b) with the following classification:
R11 Highly flammable
R45 May cause cancer, Carcinogen Category 1
R48/23/24/25 Toxic: Danger of serious damage to health by prolonged
exposure through inhalation, in contact with skin and if
swallowed
This assessment has amended the above classification to include the following:
R36/37/38 Irritating to eyes, respiratory system and skin
R40 Possible risks of irreversible effects, Mutagen Category 3
Recommended safety phrases include:
S45 In case of accident or if you feel unwell, seek medical advice immediately
(show the label whenever possible).
S53 Avoid exposure ?obtain special instructions before use.
Priority Existing Chemical Number 21
206
It is recommended that suppliers and employers take note of this amendment and
that it be taken up in the NOHSC List of Designated Hazardous Substances as soon
as possible.
Based on the cut-off concentration levels tabulated in the NOHSC List of
Designated Hazardous Substances (NOHSC, 1999b), risk phrase R36/37/38
applies to liquid mixtures containing 20% and gaseous mixtures containing 5%
benzene, whereas R40 applies to all mixtures containing 1% benzene.
MSDS, labels and training materials should be amended accordingly and where
appropriate provide relevant information about the irritant and mutagenic effects of
benzene.
Recommendation 2: National occupational exposure standard
It is recommended that NOHSC lower the occupational exposure standard for
benzene with urgency. Given benzene is a human carcinogen and noting that
exposures below 0.5 ppm (TWA8) for the majority of workers, NICNAS
recommends that the standard be lowered to 0.5 ppm (TWA8).
However, industry has raised concerns that lowering the standard below 1 ppm
(TWA8) is not practicable. The NOHSC exposure standard setting process requires
a statutory period of public comment, where practicability data may be submitted.
Therefore, it is recommended that NOHSC consult on a proposal to lower the
exposure standard to 0.5 ppm (TWA8), including seeking information on
practicability. In the interim, it is recommended that companies immediately adopt
1 ppm (TWA8) as an internal standard.
Recommendation 3: Workplace control measures
a) Engineering controls and safe work practices: It is recommended that benzene
is eliminated or substituted with less hazardous chemicals in industrial processes
wherever practicable. In workplaces where this is not practicable, employers
should strive for further improvements in current workplace control measures and
utilise best available technology to minimise worker exposure to benzene, wherever
this is technically and economically feasible.
In workplaces where benzene or benzene-containing streams are contained in
?br>
fully enclosed systems, particular attention should be paid to engineering
control techniques and operating procedures aimed at reducing fugitive
emissions from pumps and seals as well as drips, spills and vapour
displacement during transfers between closed systems;
Improvements that eliminate the need to break open the closed system for the
?br>
purposes of sampling, dipping, maintenance and cleaning;
In workplaces where benzene or benzene-containing products are not contained
?br>
in closed systems, such as laboratories and car repair shops, particular attention
should be paid to safe work practices and the availability of good local exhaust
ventilation;
Where skin contact with benzene or petrol may occur, workers should wear
?br>
appropriate personal protective equipment, including benzene-resistant gloves;
and
Benzene 207
In workplace environments contaminated due to petrol vapour, vehicle exhaust
?br>
or tobacco smoke, measures should be implemented to reduce exposure levels
as low as possible, such as good local exhaust ventilation and air purification
system.
b) Exposure monitoring:
Personal monitoring should be conducted where a workplace assessment
?br>
indicates that there is a significant risk to health.
Health surveillance should be conducted in accordance with the 1995
?br>
amendment to Schedule 3 of the NOHSC National Model Regulations for the
Control of Workplace Hazardous Substances (NOHSC, 1994b) listing benzene
as a hazardous substance for which health surveillance is required where there
is a significant health risk to workers from exposure to the chemical (NOHSC,
1995b). The health surveillance must include a baseline blood sample for
haematological profile, as further detailed in the specific health surveillance
guideline for benzene (NOHSC, 1996b).
It is recommended that the State and Territory occupational health and safety
?br>
authorities review the compliance of larger workplaces in the petroleum,
chemical (benzene-related), coal gas by-product and coal tar industries with the
requirements for personal exposure monitoring and health surveillance. State
and Territory authorities should also review compliance of workplaces with
respect to scheduled carcinogenic substances, major hazard facilities and
dangerous good legislation.
Given the very large number of small workplaces with the potential for
?br>
occupational exposure to benzene contained in petrol, it is recommended that
relevant industry organisations such as the Australian Institute of Petroleum
and the Institute of Automotive Mechanical Engineers develop programs aimed
at improving control measures in petrol stations and car repair shops. NICNAS
will prepare a Safety Information Sheet for benzene, aimed primarily at
workers, which can be distributed to workplaces. It is recommended that
industry and State jurisdictions distribute this information widely.
Recommendation 4: Public health recommendations
a) Public health authorities should update their advice on how to minimise
exposure to benzene. For example, indoor air levels of benzene in houses with
attached garages may be reduced by ensuring that internal garage doorways are
adequately sealed and fitted with automatic door closures.
b) Public health authorities should continue to seek measures to reduce
environmental tobacco smoke in enclosed public areas.
c) This assessment report will be forwarded to the Australia New Zealand Food
Authority and to State Health Departments for their consideration with respect to
levels of benzene in foods sold in areas with high ambient benzene levels, such as
roadside shops or stalls or petrol stations.
d) To more accurately estimate the risk to the public, personal and ambient air
monitoring data should be collected. The data should focus on those scenarios
where the greatest uncertainties exist, such as indoor air levels, urban air levels and
air levels near potential industrial point sources. The Department of Environmental
Priority Existing Chemical Number 21
208
Protection (Western Australia) in association with the University of Western
Australia, Murdoch University, CSIRO, EPA Victoria, NSW EPA, SA EPA,
Flinders University, Monash University and NSW Health is currently conducting
an air monitoring study for the Living Cities ?Air Toxics Program, which will
provide some of these data.
e) It is recommended that an ambient air standard for benzene be set. The findings
of this report will be provided to the National Environment Protection Council so
that they may be taken into account when considering benzene in the context of
developing a National Environment Protection Measure (NEPM) for air toxics.
f) It is recommended that government authorities improve public health cancer
registers to include information on occupation and workplace factors and
identification of leukaemia type.
Benzene 209
22. Secondary Notification
Under Section 65 of the Industrial Chemicals (notification and Assessment) Act
1989, secondary notification of benzene may be required where an introducer of the
chemical becomes aware of circumstances that may warrant a reassessment of its
hazards and risks. Specific circumstances include:
the function or use of benzene has increased, or is likely to change,
?br>
significantly;
the amount of benzene introduced into Australia has increased, or is likely to
?br>
increase, significantly;
the method of manufacture of the chemical in Australia has changed, or is
?br>
likely to change, in a way that may result in an increased risk of adverse health
effects or adverse environmental effects; and
additional information has become available to the introducers as to the adverse
?br>
health effects or adverse environmental effects of the chemical.
The Director (Chemicals Notification and Assessment) must be notified within 28
days of the manufacturer/importer becoming aware of any of the above or other
circumstances prescribed under Section 65 of the Act.
Priority Existing Chemical Number 21
210
Appendix 1
Sample Material Safety Data Sheet
for Benzene
Date of issue Page of Total
8 December 2000 1 7
Benzene is classified as Hazardous according to the National
Occupational Health and Safety Commission's Approved Criteria for
Classifying Hazardous Substances [NOHSC:1008(1999)].
Company details
Company name
Address
State Postcode
Telephone number Emergency telephone number
Facsimile number Telex number
Identification
Product name
Benzene
Other names
Benzol; cyclohexatriene
Manufacturer's product code
UN number
1144
Dangerous goods class and subsidiary risk
Class 3
Hazchem code
3WE
Poisons Schedule number
Schedule 7
Use
Laboratory reagent
Benzene 211
Page of Total
2 7
Physical description and properties
Appearance
Colourless liquid
Boiling point Melting point
80.1癈 5.5癈
Vapour pressure
12.6 kPa at 25癈
Specific gravity
0.87 at 25癈 (water = 1)
Flashpoint
-11癈 (closed cup)
Flammability limits
1.4-7.9%
Solubility in water
1.8 g/L at 25癈
Other properties
Odour: Sweet, aromatic
Odour threshold: 0.8-160 ppm (average: 2 ppm)
Vapour density: 2.8 (relative to air = 1)
Autoignition temperature: 560癈
Ingredients
Chemical entity CAS Number Proportion
Benzene 71-43-2
Priority Existing Chemical Number 21
212
Page of Total
3 7
Health hazard information
HEALTH EFFECTS
Acute:
Inhalation: Irritating to respiratory system (including mouth, nose and
throat) at 30-60 ppm. Dizziness and headache progressing to drowsiness and
unconsciousness at 250-3000 ppm. Inhalation at 20,000 ppm may be fatal
within 5-10 minutes.
Skin: Liquid and vapour irritating to skin. Readily absorbed through skin.
Eye: Liquid and vapour cause eye irritation.
Swallowed: The lowest reported fatal dose is 10 mL. Smaller doses can
cause dizziness and headache progressing to drowsiness and
unconsciousness. Severe lung damage can occur if drawn into the lungs
(aspirated) during swallowing or vomiting.
Chronic:
Skin: No evidence of sensitisation in animals or humans.
Inhalation: Prolonged or repeated exposure can cause decreased bone marrow
production of blood cells, severe blood disorders and leukaemia (cancer of
the white blood cells). Damage to the chromosomes of white blood cells has
been observed at high concentrations.
Other information:
Benzene is secreted in breast milk.
Risk phrases:
Highly flammable
R11
May cause cancer (Carcinogen Category 1
R45
R48/23/24/25 Toxic: Danger of serious damage to health by prolonged
exposure through inhalation, in contact with skin and if swallowed
Irritating to eyes, respiratory system and skin
R36/37/38
Possible risk of irreversible effects (Mutagen Category 3)
R40
FIRST AID
Inhalation: Remove from exposure to fresh air immediately. If breathing
with difficulty, give oxygen. If not breathing, clear airways and apply
artificial respiration. Call a doctor.
Skin: Remove contaminated clothing and wash skin thoroughly. Seek medical
attention if irritation develops.
Eye: Irrigate immediately with copious quantities of water for at least 15
minutes. Seek medical attention.
Swallowed: Do not give anything by mouth if victim is losing
consciousness, unconscious or convulsing. Do not induce vomiting, give a
glass of water. If breathing with difficulty, give oxygen. If not
breathing, clear airways and apply artificial respiration. Call a doctor.
FIRST AID FACILITIES
An emergency safety shower and eye wash station should be available in the
immediate work area.
ADVICE TO DOCTOR
Treatment is symptomatic and supportive. No specific antidote.
Benzene 213
Page of Total
4 7
Precautions for use
EXPOSURE STANDARD
Australian Exposure Standard: 5 ppm (16 mg/m3)TWA,
Carcinogen Category 1 (known human carcinogen).
ENGINEERING CONTROLS
Control airborne concentrations well below the exposure standard.
Use only in flameproof fume cupboard or with good local exhaust
ventilation.
Cover working surfaces with an absorbent material backed by
plastic and replace at regular intervals and immediately a
spillage occurs.
Do not decant into plastic containers that may be permeable to
benzene, or from large bottles into measuring cylinders or beakers
as splashing or spills may occur.
PERSONAL PROTECTION
Wear long-sleeved protective clothing, safety glasses and benzene
resistant gloves in accordance with manufacturer's recommendation.
A respirator with full-face protection may be required where
engineering controls are inadequate, such as in the case of
spills.
FLAMMABILITY
Highly flammable. Vapour may form explosive mixtures with air.
Avoid all sources of ignition.
Vapour is heavier than air and may travel along the ground to a
source of ignition and flash back.
Priority Existing Chemical Number 21
214
Page of Total
5 7
Safe handling information
STORAGE AND TRANSPORT
Regulated dangerous goods in Class 3, Packaging Group III.
Store in screw-capped, unbreakable, chemically resistant container
in locked flammable liquids/poisons cupboard in a ventilated
storage room.
SPILLS AND DISPOSAL
Small spills can be cleaned up with absorbent material. Wear
appropriate personal protective equipment to prevent skin and eye
contamination and, if necessary, a respirator with full-face
protection. Collect contaminated material in sealable containers
for disposal in accordance with all Local, State and Federal
regulations at an approved waste disposal facility.
Do not allow the substance to enter drains and waterways.
In the case of large spills, evacuate the area, shut off all
possible sources of ignition and follow institutional emergency
procedures.
Prior to disposal, keep contaminated pipette tips in ventilated
fume cupboard until completely dry.
Dispose of at an approved waste disposal facility in accordance
with all Local, State and Federal regulations.
FIRE/EXPLOSION HAZARD
Highly flammable. Vapour may form explosive mixtures with air.
Carbon monoxide may be released in a fire involving benzene.
Fire fighters should wear self-contained breathing apparatus and
complete protective clothing. For fires, foam, carbon dioxide or
dry chemical extinguishing media may be used.
Benzene 215
Page of Total
6 7
Other information
ANIMAL TOXICITY DATA
Acute (inhalation) LD50(4h): 13,700 ppm (rat).
Acute (oral) LD50: 810-9900 mg/kg (rat).
Acute (dermal) LD50: >8200 mg/kg (rabbit).
Repeated dose toxicity: Benzene has been shown to cause central
nervous system depression, immunosuppression and bone marrow
depression in mice and rats.
Fertility effects: High doses can have toxic effects on the testes
and ovaries in mice. Data on reproductive capacity are
inconclusive.
Developmental toxicity: In rats and mice exposed to 100-500 ppm
during pregnancy, benzene causes foetal growth retardation. There
is no evidence of birth defects.
Lactation effects: No data.
Genetic toxicity: Benzene is positive in several test systems.
Carcinogenicity: Benzene has been shown to induce malignant
tumours in several organs in rats and mice.
ENVIRONMENTAL DATA
Acute (mg/L):
Selenastrum capricornutum (alga) 72-h EC50 29
Daphnia magna 48-h EC50 >100
18.4
Ceriodaphnia dubia (water flea) 24-h EC50
Scylla serata (crab species) 96-h LC50 3.7-7.7
Pimephales promelas (fathead minnow) 96-h LC50 12.6-24.6
28.6
Poecilia reticulata (guppy) 96-h LC50
Oncorhynchus mykiss (rainbow trout) 96-h LC50 5.3-9.2
5.8
Morone saxatilis (striped bass) 96-h LC50
Chronic:
The lowest recorded no observed effect concentration is 0.17 mg/L
in Cancer magister (Dungeness crab).
FURTHER INFORMATION
National Health and Medical Research Council: Guidelines for
laboratory personnel working with carcinogenic or highly toxic
chemicals (Australian Government Publishing Service, 1990).
Guidelines for Health Surveillance: Benzene (NOHSC, 1996).
National Industrial Chemicals Notification and Assessment Scheme:
Full Public Report ?Priority Existing Chemical No. XX ?Benzene
(NICNAS, 2001).
Priority Existing Chemical Number 21
216
Page of Total
7 7
Contact point
Contact name Telephone number
Position title
Address
State Postcode Country
Benzene 217
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