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ASSESSMENT REPORT ON
BBEENNZZEENNEE FOR DEVELOPING
AMBIENT AIR QUALITY
OBJECTIVES
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ASSESSMENT REPORT ON
BENZENE
FOR DEVELOPING AMBIENT AIR QUALITY OBJECTIVES
Prepared by Toxico-Logic Consulting Inc.
for Alberta Environment
February 2006
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ISBN: 978-1-4601-0472-9 (Print) ISBN: 978-1-4601-0473-6 (Online) Web Site: http://www.environment.alberta.ca/
Although prepared with funding from Alberta Environment (AENV), the contents of this report/document do not necessarily reflect the views or policies of AENV, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
Any comments, questions, or suggestions regarding the content of this document may be directed to:
Air Policy Alberta Environment and Sustainable Resource Development 9th Floor, Oxbridge Place 9820 – 106th Street Edmonton, Alberta T5K 2J6
Additional copies of this document may be obtained by contacting:
Information Centre Alberta Environment and Sustainable Resource Development Phone: (780) 427-2700 Fax: (780) 422-4086 Email: env.infocent@gov.ab.ca
mailto:env.infocent@gov.ab.cahttp:http://www.environment.alberta.ca
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FOREWORD
Alberta Environment maintains Ambient Air Quality Objectives to support air quality
management in Alberta. Alberta Environment currently has ambient objectives for more than
thirty substances and five related parameters. These objectives are periodically updated and new
objectives are developed as required.
With the assistance of the Clean Air Strategic Alliance, a multi-stakeholder workshop was held
in October 2004 to set Alberta’s priorities for the next three years. Based on those
recommendations to Alberta Environment, a three-year work plan was developed to review four
existing objectives, and create three new objectives.
This document is one in a series of documents that presents the scientific assessment for these
substances.
Laura Blair
Project Manager
Air Policy
Assessment Report on Benzene for Developing Ambient Air Quality Objectives i
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ACKNOWLEDGEMENTS
The authors of this Assessment Report for Benzene would like to thank Laura Blair of the
Environmental Policy Branch of Alberta Environment for her input. Toxico-Logic Consulting
Inc. would also like to acknowledge and thank the following authors who participated in the
completion of this report:
Dr. Selma Guigard
Edmonton, Alberta
Dr. Warren Kindzierski
WBK & Associates Inc.
St. Albert, Alberta
Jason Schulz
Calgary, Alberta
Dr. John Vidmar
Edmonton, Alberta
Colleen Purtill
Toxico-Logic Consulting Inc.
Calgary, Alberta
Assessment Report on Benzene for Developing Ambient Air Quality Objectives ii
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TABLE OF CONTENTS
FOREWORD.................................................................................................................... i ACKNOWLEDGEMENTS............................................................................................... ii LIST OF TABLES ........................................................................................................... v LIST OF FIGURES.......................................................................................................... v ABBREVIATIONS AND ACRONYMS........................................................................... vi SUMMARY................................................................................................................... viii
1.0 INTRODUCTION .................................................................................................. 1
2.0 GENERAL SUBSTANCE INFORMATION........................................................... 3 2.1 Physical, Chemical and Biological Properties.......................................................3
2.2 Emissions Sources and Ambient Levels ...............................................................6
2.2.1 Natural Sources........................................................................................6
2.2.2 Anthropogenic Sources.............................................................................6
2.2.3 Ambient Levels .........................................................................................7
3.0 ATMOSPHERIC CHEMISTRY AND FATE.......................................................... 9
4.0 EFFECTS ON HUMANS AND ANIMALS .......................................................... 10 4.1 Overview of Chemical Disposition.....................................................................10
4.1.1 Absorption..............................................................................................10
4.1.2 Distribution ............................................................................................10
4.1.3 Metabolism.............................................................................................11
4.1.4 Elimination.............................................................................................13
4.1.5 Physiologically Based Pharmacokinetic (PBPK) Models........................14
4.1.6 Mechanism of Toxic Action.....................................................................15
4.2 Genotoxicity ......................................................................................................16
4.3 Acute Toxicity ...................................................................................................17
4.3.1 Acute Toxicity in Humans .......................................................................18
4.3.2 Acute Toxicity in Animals .......................................................................19
4.4 Subchronic and Chronic Toxicity .......................................................................22
4.4.1 Subchronic and Chronic Toxicity in Humans..........................................22
4.4.2 Subchronic and Chronic Toxicity in Animals ..........................................23
4.5 Developmental and Reproductive Toxicity.........................................................28
4.5.1 Developmental and Reproductive Toxicity in Humans ............................29
4.5.2 Developmental and Reproductive Toxicity in Animals.............................29
4.6 Carcinogenicity..................................................................................................33
4.6.1 Human Carcinogenicity Studies..............................................................33
4.6.2 Animal Carcinogenicity Studies..............................................................34
5.0 EFFECTS ON VEGETATION............................................................................. 36 5.1 Plant Uptake and Transformation of Benzene.....................................................36
Assessment Report on Benzene for Developing Ambient Air Quality Objectives iii
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6.0 EFFECTS ON MATERIALS............................................................................... 37
7.0 AIR SAMPLING AND ANALYTICAL METHODS.............................................. 38 7.1 Reference Methods ............................................................................................38
7.1.1 US EPA Compendium Method TO-1.......................................................38
7.1.2 US EPA Compendium Method TO-2.......................................................39
7.1.3 US EPA Compendium Method TO-14A...................................................39
7.1.4 US EPA Compendium Method TO-15.....................................................40
7.1.5 US EPA Compendium Method TO-17.....................................................40
7.1.6 NIOSH Method 1501 ..............................................................................41
7.1.7 NIOSH Method 2549 ..............................................................................41
7.1.8 NIOSH Method 3700 ..............................................................................41
7.1.9 NIOSH Method 3800 ..............................................................................42
7.1.10 OSHA Method 7 .....................................................................................42
7.1.11 OSHA Method 12....................................................................................42
7.1.12 OSHA Method 1005................................................................................43
7.2 Alternative, Emerging Technologies ..................................................................43
7.2.1 Passive Sampling....................................................................................43
7.2.2 Active Sampling......................................................................................44
7.2.3 Automated Samplers...............................................................................44
7.2.4 Differential Optical Absorption Spectroscopy.........................................45
8.0 AMBIENT OBJECTIVES IN OTHER JURISDICTIONS..................................... 48 8.1 Benzene Air Quality Guidelines and Objectives .................................................48
8.1.1 Canada...................................................................................................48
8.1.2 United States Air Quality Guidelines and Objectives ..............................48
8.1.3 International Air Quality Guidelines and Objectives...............................49
9.0 REFERENCES................................................................................................... 51
APPENDIX A ................................................................................................................ 61
APPENDIX B ................................................................................................................ 77
Assessment Report on Benzene for Developing Ambient Air Quality Objectives iv
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LIST OF TABLES
Table 1 Identification of Benzene (Lewis, 2004; Genium, 1999).......................................4
Table 2 Physical and Chemical Properties of Benzene ......................................................5
Table 3 Environmental Fate of Benzene............................................................................9
Table 4 On-site releases of Benzene in Canada and Alberta According to the NPRI
Database (in tonnes).............................................................................................7
Table 5 Acute Effects Following Human Exposure to Benzene.......................................18
Table 6 Acute Effects Following Animal Exposure to Benzene ......................................20
Table 7 Subchronic and Chronic Effects Reported Following Human (Occupational)
Exposure to Benzene..........................................................................................24
Table 8 Subchronic and Chronic Effects Following Animal Exposure to Benzene ..........26
Table 9 Reproductive and Developmental Effects Following Animal Exposure to Benzene
..........................................................................................................................31
Table 10 Cancer Effect Levels (CELs1) for Humans Exposed to Benzene.........................34
Table 11 Cancer Effect Levels (CELs1) for Animals Exposed to Benzene.........................35
Table 12 Advantages and Disadvantages of Sampling and Analytical Methods.................46
Table 13 Summary of Ambient Air Quality Objectives and Guidelines for Benzene .........50
LIST OF FIGURES
Figure 1 Metabolism of Benzene (ATSDR, 2005)............................................................12
Assessment Report on Benzene for Developing Ambient Air Quality Objectives v
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ABBREVIATIONS AND ACRONYMS
AENV Alberta Environment
ANLL Acute nonlymphocytic leukemia
ANR Agency of Natural Resources
ATSDR Agency for Toxic Substances and Disease Registry
BP British Petroleum
CAS Chemical Abstract Services
CASA Clean Air Strategic Alliance
CEQ Commission on Environmental Quality
CNS Central nervous system
CMS Carbon molecular sieve
d day
DEM Department of Environmental Management
DEP Department of Environmental Protection
DEQ Department of Environmental Quality
DES Department of Environmental Services
DNR Department of Natural Resources
DOAS Differential Optical Absorption Spectroscopy
DOE Department of Ecology
DOH Department of Health
EC Environment Canada
ECD Electron Capture Detector
ENR Environment and Natural Resources
EPHC Environment Protection and Heritage Council
FID Flame Ionization Detector
FTIR Fourier Transform Infrared Spectrometry
GC/MS Gas Chromatography/Mass Spectrometry
hr hour
HSDB Hazardous Substances Data Bank
IARC International Agency for Research on Cancer
IPCS International Programme on Chemical Safety
IRIS Integrated Risk Information System
LOAEL Lowest Observable Adverse Effect Level
mg m -3 milligram per cubic metre
MRL Minimum Risk Level
mo month
MOE Ontario Ministry of the Environment
NAPS National Air Pollution Surveillance Network
Assessment Report on Benzene for Developing Ambient Air Quality Objectives vi
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NIOSH National Institute for Occupational Safety and Health
NOAEL No Observable Adverse Effect Level
NPD Nitrogen-Phosphorous Detector
NPRI National Pollutant Release Inventory
OEHHA Office of Environmental Health Hazard Assessment (California)
OSHA Occupational Safety and Health Administration
PBPK Physiologically Based Pharmacokinetic Models
PID Photo-Ionization Detector
POI Point of Impingement
ppm part per million
RIVM Rijksinstituut Voor Volksgezondheid En Milieu (Netherlands National Institute of Public Health and the Environment)
RTECS Registry of Toxic Effects of Chemical Substances
STEL Short-Term Exposure Limit
TC05 Tumorigenic Concentration05
TDLAS Tunable Diode Laser Absorption System
TLV Threshold Limit Value
TWA Time Weighted Average
µg m -3
microgram per cubic metre
UN United Nations
US EPA United States Environmental Protection Agency
VOC Volatile Organic Compound
WHO World Health Organization
wk week
yr year
Assessment Report on Benzene for Developing Ambient Air Quality Objectives vii
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SUMMARY
Benzene is a clear, colourless, volatile, highly flammable liquid with a sweet aromatic odour.
It is primarily derived from petroleum and used in the manufacturing of chemical intermediates
and as an additive in gasoline. The historic use of benzene as a universal solvent and degreaser
was stopped in the early 1920s following reported deaths due to benzene exposure. The
majority of non-fuel use of benzene in the United States and Canada is attributed to chemical
manufacturing. The amount of benzene added to gasoline in Canada is regulated to below
1.5%.
Airborne benzene exists almost exclusively in the vapour phase and is transformed primarily by
reaction with hydroxyl radicals, resulting in a residence time ranging from 2 hours (at higher
hydroxyl radical concentrations) to 8 days (at lower hydroxyl radical concentrations). Benzene
occurs in petroleum at levels ranging from 1 to 4% and consequently may occur naturally in
water near petroleum and natural gas deposits. Natural sources of atmospheric emissions of
benzene include volcanoes, forest fires and plant volatiles. Major anthropogenic sources of
benzene in Canada include transportation, natural gas dehydrators, petroleum distribution and
refining, steel industry, chemical industry, and wood combustion. Vehicle emissions provide
the greatest anthropogenic contribution of benzene to the Canadian environment (over 80% in
urban areas).
In Canada, anthropogenic emissions of benzene are tracked by the Environment Canada
National Pollutant Release Inventory program. The industrial sectors that contribute to
benzene emissions in Alberta are principally the crude petroleum and natural gas sector
(~60%), the wood industries sector (~14%), the chemical and chemical products sector (~9%),
the petroleum products industries (~5%), and the refined petroleum and coal products sector
(~3%). Ambient air concentrations of benzene were reported for rural and urban sites in
Canada with annual mean benzene concentrations ranging from 0.6 to 5.5 µg m -3 in 2003 and from 0.2 to 1.9 µg m -3 in 2004. In Alberta, annual average ambient benzene concentrations measured in 2000 at three monitoring stations in urban areas (Edmonton and Calgary) ranged
from 2.05 to 2.21 µg m -3 .
Acute exposure to very high benzene concentrations (44,662,000 to 65,200,000 µg m -3) is fatal to animals and humans. Causes of death in humans include asphyxiation, respiratory arrest,
central nervous system (CNS) depression and cardiac collapse. Haematological, neurological,
and respiratory effects were reported in humans following acute exposure to non-lethal benzene
air concentrations (up to 978,000 µg m -3). Acute exposure of mice and rats to benzene (>33,000 µg m -3) decreased production of white and red blood cells, and reduced bone marrow cellularity. Chromosomal damage was induced in mice acutely exposed to 68,000 µg m -3
benzene.
Acute, subchronic and chronic exposure of animals to relatively low levels of benzene produces
measurable depression of one or more types of circulating blood cells which can produce
haematotoxic and immunotoxic effects. A more severe effect of benzene exposure is aplastic
anaemia in which the bone marrow is unable to function and stem cells do not mature. The
Assessment Report on Benzene for Developing Ambient Air Quality Objectives viii
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progression of aplastic anaemia can result in acute myelogenous leukemia. There are
inconclusive data to suggest that occupational exposure to benzene may result in reproductive
(menstrual disorders, reduced fertility) or developmental (chromosomal aberrations) toxicity in
humans, however, reproductive (ovary and testicular) and developmental (fetal mortality,
skeletal, and haematological effects) were observed following controlled exposures of animals
to high concentrations of benzene. The International Agency for Research on Cancer (IARC)
has classified benzene as a Group I human carcinogen. Although limited by confounding
exposures to other chemicals and lack of precise exposure monitoring, occupational studies
demonstrate a consistent increase in the risk of leukemia with exposure to benzene. Studies of
controlled animal exposure to benzene have also reported leukemia as well as non-Hodgkin’s
lymphoma, and tumours in the lung, liver, mammary gland, and Zymbal gland.
There were very few reports on the phytotoxicity of benzene on plants and those available
reported acute effects in plant species at benzene air concentrations in excess of 10,000,000 µg
m-3
. The available literature focused on the ability of plants to bioconcentrate benzene and the
utilization of plants for detoxification of atmospheric benzene. Blackberry, cucumber, and
apples were shown to accumulate benzene in the leaves and fruits with no phenotypic effects
following atmospheric exposure to 1,000 µg m-3
benzene. The removal of benzene from
ambient air was also demonstrated with several indoor plant species. Air-to-leaf transfer is the
major pathway of benzene uptake; once inside the plant benzene is metabolized to both organic
and amino acids.
The residence time for benzene in ambient air is too short to have substantial effects on
materials. Widely employed and accepted reference air monitoring methods for benzene have
been developed, tested and reported by the United States Environmental Protection Agency
(US EPA), National Institute of Occupational Safety and Health (NIOSH), and Occupational
Safety and Health Administration (OSHA). Standard collection methods include:
charcoal/glass/metal sorbent tubes; multi-bed adsorbent tubes; carbon molecular sieve (CMS)
adsorption; stainless steel canisters; Tedlar bags, and; direct reading sample pumps. Analysis
can be conducted by gas chromatography/mass spectrometry (GC/MS), flame ionization
detector (FID), nitrogen-phosphorous detector (NPD), electron capture detector (ECD), and
photo-ionization detector (PID). Emerging technologies for analyses include automatic
sampling using on-line GC/FID and Differential Optical Absorption Spectroscopy (DOAS), an
open path optical measuring technique.
An ambient (outdoor) objective of 30 µg m-3
as a 1-hr average has been developed for benzene
by Alberta Environment. British Columbia MOE, Manitoba Conservation, and Ontario MOE
currently do not have ambient air objective limits for benzene. Ambient air objectives for
benzene were identified from several international jurisdictions, including Australia, New
Zealand, Netherlands, UK, European Commission, and the WHO. Objectives ranged from 1 to
16 µg m-3
corresponding to an averaging time period of one year. Three jurisdictions (New
Zealand, UK, and European Commission) have committed to lowering their guidelines by
2010.
The US Agency for Toxic Substances and Disease Registry (ATSDR) has developed acute,
intermediate, and chronic minimal risk levels of 29, 19, and 10 µg m-3
for exposure to benzene
Assessment Report on Benzene for Developing Ambient Air Quality Objectives ix
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ranging in durations of
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1.0 INTRODUCTION
Alberta Ambient Air Quality Objectives (AAQO) are established by Alberta Environment under
Section 14 (1) of the Environmental Protection and Enhancement Act (EPEA) (AENV, 2007).
The purpose of this assessment report is to provide a review of scientific and technical
information to assist in evaluating the basis and background for an ambient air quality objective
for benzene. The following aspects were examined as part of the review:
• Physical-chemical properties and environmental fate;
• Existing and potential anthropogenic emissions sources in Alberta;
• Effects on humans, animals, and vegetation;
• Effects on materials and air monitoring techniques, and;
• Ambient air guidelines and objectives in other jurisdictions.
The physical and chemical properties identified for benzene include chemical structure,
molecular weight, melting and boiling points, water solubility, density, vapour density, organic
carbon partition coefficient, octanol water partition coefficient, vapour pressure, Henry's Law
constant, bioconcentration factor, and odour threshold. A discussion of the behaviour of benzene
in the environment was also presented. Existing and potential natural and anthropogenic sources
of benzene emissions in Alberta were examined. Benzene is a reportable substance on
Environment Canada’s National Pollutant Release Inventory.
Scientific information on the effects of benzene on humans, animals, and vegetation were
identified. Toxicity and epidemiology studies were located in peer reviewed evaluations by the
Agency for Toxic Substances and Disease Registry, the U.S. Environmental Protection Agency,
and the World Health Organization. The effects of benzene on vegetation were identified
following a comprehensive search of the Web of Science database and using data from the
Canadian Environmental Protection Act Priority List Substance Assessment Report for Benzene
and the Agency for Toxic Substances and Disease Registry.
There was a lack of literature for the effects of airborne benzene on materials as atmospheric
benzene reacts quickly with other chemicals and decomposes within a few days. Air sampling
and analytical methods for benzene used by regulatory agencies were identified and reviewed for
this assessment. The monitoring of benzene for regulatory purposes requires methods suitable to
measure very low concentrations with a sufficiently high accuracy. Widely employed and
accepted reference air monitoring methods for benzene reported by the United States
Environmental Protection Agency (US EPA), National Institute of Occupational Safety and
Health (NIOSH), and Occupational Safety and Health Administration (OSHA) were reviewed
and air monitoring methods used by Alberta Environment and Environment Canada identified.
A few unique and alternate technologies used to conduct point and line measurements of ambient
benzene concentrations were also identified from recent literature.
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 1
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Ambient air guidelines for benzene have been established by a number of jurisdictions in North
America, Europe, and Australia for different averaging time periods. The basis for how these
guidelines were developed and used by different jurisdictions was investigated in this report.
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 2
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2.0 GENERAL SUBSTANCE INFORMATION
2.1 Physical, Chemical and Biological Properties
Benzene is a clear, colourless, volatile, highly flammable liquid (O’Neil, 2006) with a
characteristic sweet aromatic odour (O’Neil, 2006; Genium, 1999). Benzene was first obtained
from the pyrolysis of coal; however, with the development of new technologies, benzene is now
primarily derived from petroleum (Folkins, 2005) by catalytic reforming, hydrodemethylation,
transalkylation or disproportionation of toluene and steam cracking of heavy naphthas or light
hydrocarbons (Fruscella, 2002).
In the past, benzene was primarily used as a universal solvent and degreaser (Fruscella, 2002).
With reported deaths due to benzene exposure in the early 1920s, benzene was replaced, for the
most part, by other solvents such as toluene and aliphatics (Fruscella, 2002). Benzene is now
commonly used in the manufacturing of chemical intermediates and as an additive in gasoline.
Approximately 86% of benzene use (non-fuel uses) in the United States is attributed to the
manufacturing of ethylbenzene (50%), cumene (24%) and cyclohexane (12%) (Fruscella, 2002).
In Canada, both produced and imported benzene are also primarily used for the manufacturing of
ethylbenzene (Health Canada, 2007). Ethylbenzene is mainly used to produce styrene, which is
in turn used to make plastics and elastomers (ATSDR, 2005). Cumene is used in the
manufacturing of phenol and acetone, which are in turn used to make resins, nylon intermediates,
pharmaceuticals, or in the case of acetone, as a solvent (ATSDR, 2005). Cyclohexane is used in
the manufacturing of nylon resins (ATSDR, 2005). Other non-fuel uses of benzene include the
manufacturing of aniline (6%), alkylbenzene (2%), chlorobenzene (1%) and other compounds
(5%) (Fruscella, 2002). Benzene is also a component of gasoline although the amount of benzene
in gasoline is regulated (Folkins, 2005). For example, in Canada, it is prohibited to supply
gasoline that contains benzene at a concentration greater than 1.0% by volume or to sell gasoline
that contains benzene at a concentration greater than 1.5% by volume (EC, 1998). Additional
uses of benzene include in photogravure printing and in veterinary medicine (Genium, 1999)
Table 1 provides a list of important identification numbers and common synonyms for benzene.
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 3
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Table 1 Identification of Benzene (Lewis, 2004; Genium, 1999)
Property Value
Formula C6H6
Structure
CAS Registry Number 71-43-2
RTECS number CY1400000
UN Number UN 1114
Common Synonyms/Trade names (6)annulene; benzeen; benzene; benzin; benzine; benzol1; benzol 90; benzole; benzolene; benzolo; bicarburet of hydrogen; carbon
oil; coal naphtha; cyclohexatriene; EPA Pesticide Chemical Code
008801; fenzen; mineral naphtha; motor benzol; NCI-C55276;
nitration benzene; phene; phenyl hydride; polystream;
pyrobenzol; pyrobenzole; RCRA waste number U019
1 name used to designate a compound or material containing benzene as its major component (Folkins, 2005; Fruscella, 2002)
The physical and chemical properties of benzene are summarized in Table 2.
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 4
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Table 2 Physical and Chemical Properties of Benzene
Property Value Reference
Molecular weight 78.1 g mol-1 Lide, 2007; Verschueren, 2001; O’Neil,
2006
Physical state Clear colourless volatile liquid Lide, 2007; Verschueren, 2001; O’Neil,
2006
Melting Point 5.49 ºC Lide, 2007; Verschueren, 2001; O’Neil,
2006
Boiling Point 80.09 ºC Lide, 2007; Verschueren, 2001; O’Neil,
2006
Density (liquid) 0.8765 g ml-1 (at 20ºC) Lide, 2007
Density (gas) 2.77 (air=1) Verschueren, 2001
Vapour pressure 12.7 kPa (at 25ºC) Lide, 2007
Solubility in water 1780 mg.L-1 (at 20ºC)
0.188 % w/w (at 23.5ºC)
Verschueren, 2001
Budavari, 1989
Solubility miscible with most organic
solvents1 IPCS, 1993
Henry’s Law Constant 5.55 10-3 atm.m3.mol-1 Mackay et al., 1979 (cited in SRC, 2007)
Octanol water partition coefficient
(log Kow)
Organic carbon partition coefficient
(Koc)
2.13
1.56 to 2.15
Koc 38 to 53 at 1.0 mg.L-1
log Koc 1.8 to 1.9
Sangster, 1989 (cited in Lide, 2007)
IPCS, 1993
Seip et al., 1986 (cited in Verschueren,
2001)
IPCS, 1993; Kenaga, 1980 (cited in
ATSDR, 2005)
Bioconcentration factor (log BCF) 0.48 to 1.49
1.48, 1.72
SRC, 2007
Veith and Kosian, 1982 (cited in
Verschueren, 2001)
Flash Point -11ºC Lide, 2007; O’Neil, 2006
Explosive limits 1.2 to 7.8% 1.4 (lower) to 8.0% (upper)
Lide, 2007 Lewis, 2000
Autoignition temperature 498ºC Lide, 2007
Odour threshold 4.68 ppm Verschueren, 2001
STEL 2.5 ppm Lide, 2007
TWA 0.5 ppm Lide, 2007
Conversion factors for vapour (at
25 °C and 101.3 kPa) 1 mg.m
-3= 0.307 ppm
1 ppm= 3.26 mg.m-3 Verschueren, 2001
1 see Lide (2007) for detailed list
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 5
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2.2 Emissions Sources and Ambient Levels
2.2.1 Natural Sources
Benzene occurs naturally in the environment (IPCS, 1993). Benzene occurs in petroleum at
levels ranging from 1 to 4% (IARC, 1989, cited in IPCS, 1993). As a result, benzene may also
occur naturally in water near petroleum and natural gas deposits (Reynolds and Harrison, 1982,
cited in IPCS, 1993). Atmospheric emissions of benzene from natural sources include volcanoes,
forest fires and plant volatiles (IARC, 1982 and Graedel, 1978, cited in Howard, 1990).
2.2.2 Anthropogenic Sources
Anthropogenic sources of benzene include the combustion of gasoline and diesel fuels for
vehicles and residential heating, emissions during benzene production, emissions during primary
iron and steel production, and emissions during gasoline marketing (Health Canada, 2007).
Environment Canada (EC) (2007a) lists the main sources of benzene emissions in Canada as
wood combustion, transportation, natural gas dehydrators, the steel industry, petroleum
distribution and refining; and the chemical industry, with transportation (more specifically
vehicle emissions) being the largest anthropogenic source to the environment (EC, 2004a).
According to Environment Canada (1998), in 1995, approximately 56% of Canadian benzene
emissions were from vehicles. More specifically, in urban areas, vehicles represented over 80%
of the benzene emissions (EC, 1998). Other anthropogenic sources include tobacco smoke,
wastewater treatment plants, the petrochemical and petroleum industries (Edgerton and Shah,
1992 as cited in ATSDR, 2005), landfill emissions, oil spills (Bennett, 1987, as cited in ATSDR,
2005; Hazardous Substances Data Bank (HSDB), 2005 as cited in ATSDR, 2005; Wood and
Porter 1987, as cited in ATSDR, 2005) and off-gases from particle board (Glass et al. 1986, as
cited in ATSDR, 2005). Benzene is also produced indirectly in coke ovens and during
nonferrous metal manufacturing, ore mining, wood processing, coal mining and textile
manufacturing (HSDB, 2007).
Industrial emissions of benzene in Canada are provided by the National Pollutant Release
Inventory. The data for on-site releases of benzene in Canada and more specifically for Alberta
since 1995 are summarized in Table 3 (EC, 2007b). More detailed emissions data are also
presented for Alberta for 2005 in Appendix A (EC, 2007c). The 2005 data were used since, at the
time of writing this report, the 2006 data were preliminary and unreviewed. Appendix table A-1
summarizes the benzene emissions to air, land and water and appendix table A-2 provides details
specifically related to air emissions of benzene.
The results in Appendix A show that, in Alberta, the NPRI reported emissions of benzene are
almost exclusively to air, and that these air emissions are predominantly the result of stack or
point source emissions and fugitive emissions. The industrial sectors that contribute to benzene
emissions in Alberta are principally the crude petroleum and natural gas sector (approximately
60% of the emissions), the wood industries sector (approximately 14%), the chemical and
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 6
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chemical products sector (approximately 9%), the petroleum products industries (approximately
5%), the refined petroleum and coal products sector (approximately 3%).
Table 3 On-site releases of Benzene in Canada and Alberta According to the NPRI
Database (in tonnes)
Canada Alberta
Benzene Benzene
Emissions Number of Facilities Emissions Number of Facilities
Year (in tonnes) Reporting (in tonnes) Reporting
2006 915.9 217 281.9 98
2005 975.6 252 255.6 108
2004 861.8 253 251.2 105
2003 995.3 252 257.6 112
2002 863.2 205 230.9 98
2001 1052.0 136 307.1 78
2000 1138.0 125 353.7 77
1999 1341.5 118 321.2 71
1998 1464.9 112 352.0 68
1997 1686.2 115 357.0 64
1996 2029.8 105 406.2 66
1995 2148.1 104 490.0 65
2.2.3 Ambient Levels
Extensive ambient air concentration data for benzene are presented in the HSDB (2007), ATSDR
(2005), EC (1993), IPCS (1993) and Howard (1990). Ambient benzene concentrations at several
rural and urban Canadian sites are available from the annual reports of the National Air Pollution
Surveillance (NAPS) Network (see http://www.etc-cte.ec.gc.ca/NAPS/index_e.html). Benzene
has been monitored as part of this program since 1989. In 2003, benzene concentrations were
reported for 52 sites (14 rural sites and 38 urban sites in 18 different cities) (EC, 2004b). Annual
mean benzene concentrations at the 38 urban sites ranged from 0.6 to 5.5 µg m -3, and, at 33 of the 38 urban sites, the annual mean concentration was below 2.0 µg m -3 (EC, 2004b). In 2004, annual mean benzene concentrations were reported for 27 sites (14 rural sites and 13 urban sites
in 10 different cities), and the concentrations ranged from 0.2 to 1.9 µg m -3 (EC, 2007d).
In a recent report summarizing NAPS Network data from 2001 and trends from 1990 to 2001,
EC (2004a) notes that the highest ambient air concentrations (median values) over the studied
time period were observed in Saint John, Oakville, Edmonton, Montreal and Vancouver, while
the lowest concentrations were observed in Peterborough, Sarnia, London, and Kitchener. The
high concentrations observed in Saint John, Oakville, Edmonton, Montreal and Vancouver were
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 7
http://www.etc-cte.ec.gc.ca/NAPS/index_e.html
-
attributed to the influence of nearby industries (refineries and others) emitting significant
amounts of benzene (EC, 2004a). Results from the NAPS Network data also showed a seasonal
variability of ambient benzene concentrations, with lower concentrations in the summer months
versus the winter months (EC, 2004a). EC (2004a) suggests that the lower concentrations of
benzene are most likely due to the presence of higher concentrations of oxidants and greater
mixing depths in the summer months (EC, 2004a). In considering the NAPS Network data over
the period of 1990 to 2003, EC (2004b) notes that urban annual mean benzene concentrations
decreased by 65% from 1990 to 2002 but increased slightly from 2002 to 2003 in 30 of the 38
urban sites. No explanation for this increase is provided. Rural annual mean benzene
concentrations remained relatively unchanged (of the order of 0.5 µg m -3) over the period of 1994 to 2002 (EC, 2004b). It should be noted that complete rural data were not available prior to
1994 and therefore were not considered in the trend analysis (EC, 2004b).
In Alberta, there are three monitoring stations that measure ambient air benzene concentrations
in urban areas: Edmonton East, Edmonton Central and Calgary Central (AENV, 2001). Benzene
ambient air concentrations are available from the Clean Air Strategic Alliance (CASA). CASA
(2007) presents the long-term trend for ambient air benzene concentrations in Alberta over the
period of 1991 to 2000. The data show that over this time period, the benzene concentrations
have decreased by 51% at the east Edmonton monitoring station and by 30% at the downtown
Calgary monitoring station. Data for the downtown Edmonton monitoring station were only
available for the period of 1992 to 2000 and indicate a 52% decrease in benzene concentrations
(CASA, 2007). Alberta Environment (AENV) (2001) presents similar data for ambient air
benzene concentrations over the period of 1995 to 2000 and states that the benzene
concentrations have decreased by 24%, 29% and 53% in Edmonton East, Edmonton Central and
Calgary Central, respectively (AENV, 2001). The annual average ambient benzene
concentrations in 2000 were 2.21, 2.19 and 2.05 µg m -3 in Edmonton East, Edmonton Central and Calgary Central, respectively (AENV, 2001).
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 8
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3.0 ATMOSPHERIC CHEMISTRY AND FATE
The environmental fate of benzene presented by Howard (1990) is summarized in Table 4.
Briefly, benzene emitted to air will exist almost exclusively in the vapour phase and will be
transformed primarily by reaction with hydroxyl radicals (ATSDR, 2005). Reaction with
photochemically produced hydroxyl radicals results in a benzene atmospheric residence time
ranging from approximately 2 hours (at higher hydroxyl radical concentrations characteristic of
polluted atmospheres) to 8 days (at lower hydroxyl radical concentrations) (ATSDR, 2005). A
detailed discussion is also presented in ATSDR (2005).
Table 4 Environmental Fate of Benzene
System Fate Reaction rates
Surface water • rapidly volatilizes • not expected to significantly absorb to
sediment, bioconcentrate in aquatic
organisms, or hydrolyze
• may biodegrade • may photodegrade in situtations where
biodegradation is not favoured (low
temperatures, low nutrient levels for
example)
• volatilization half-life ranging from 2.7 hours (in a river at 20ºC) to 5.2
hours (in a wind-wave tank)
• half-lives for evaporation from seawater of 3.1, 13 and 23 days in the
summer, winter and spring,
respectively with biodegradation
playing a major role in the spring and
summer
• biodegradation half-life of 16 days in a river test under aerobic conditions
• photodegradation half-life of 17 days
Soil • rapidly volatilizes at soil surface • half-life for volatilization (without • benzene that does not volatilize will be water evaporation) of 7.2 days at 1cm
highly to very highly mobile and may leach depth and 38 days at 10cm depth
into groundwater • 47% biodegradation in 10 weeks in a • may biodegrade silty soil
Groundwater • may biodegrade in shallow, aerobic groundwater
Air • • •
•
exists predominantly in the vapour phase
will not be subject to direct photolysis
will react with photochemically produced
hydroxyl radicals
will form products such as phenol,
•
•
half-life of 13.4 days by reaction with
photochemically produced hydroxyl
radicals
half-life of 4 to 6 hours by reaction in
polluted atmospheres with nitrogen
nitrophenols, nitrobenzene, formic acid and oxides or sulphur dioxide
• peroxyacetyl nitrate
will be removed from the atmosphere by rain
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 9
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4.0 EFFECTS ON HUMANS AND ANIMALS
The chemical disposition and adverse health effects reported following the inhalation of benzene
by humans and experimental animals were reviewed and are summarized below. Literature
sources identified for this review include the Agency for Toxic Substances and Disease Registry
(ATSDR, 2005), the U.S. Environmental Protection Agency (US EPA, 1998; 2002; IRIS, 2002),
and the World Health Organization (IPCS, 1993; WHO, 2000).
4.1 Overview of Chemical Disposition
Inhalation is the major route of human exposure to benzene (ATSDR, 2005). A summary of the
chemical disposition of benzene (absorption, distribution, metabolism and elimination) in
humans and animal systems following inhalation is provided below.
4.1.1 Absorption
Studies in mice, rats, and humans suggest that benzene is rapidly absorbed following inhalation
(IPCS, 1993; ATSDR, 2005). Approximately 50% of inhaled benzene (50 to 100 ppm; 163 to
326 mg m-3
) was absorbed following acute controlled exposure studies in humans (Nomiyama &
Nomiyama and Snyder et al., cited in IPCS, 1993). A higher absorption rate occurred during the
first 5 minutes of exposure to benzene with absorption dropping to approximately 50% following
prolonged exposure (15 minutes to 3 hours) (Srbova et al., cited in ATSDR, 2005; Nomiyama &
Nomiyama, cited in US EPA 2002). A recent study reported an average absorption of 64%
following exposure to benzene (32 to 69 ppm; 104 to 225 mg m-3
) produced from burning
cigarettes (Yu and Weisel, cited in ATSDR, 2005); however, this study was limited by a low
number (n=3) of exposed individuals.
Absorption was dose-dependent in acute inhalation studies conducted on rats and mice.
Increasing exposure to benzene from 10 to 100 ppm (33 to 326 mg m-3
) resulted in decreasing
retention, from 50 to 10% (Sabourin et al., cited in ATSDR, 2005). The uptake and retention of
inhaled benzene varied according to species, with mice absorbing and retaining a greater dose
than rats or monkeys as a result of a higher respiratory rate and faster metabolism (Henderson,
cited in US EPA 2002).
4.1.2 Distribution
Benzene distributes to fatty tissue throughout the body upon absorption into the bloodstream
(ATSDR, 2005). Animal studies suggest that the tissue distribution of benzene depended on
lipid content and the rate of blood perfusion of the tissues (IPCS, 1993; US EPA 2002; ATSDR,
2005). The inhalation exposure of pregnant animals to very high concentrations of benzene
(2,000 ppm; 6,520 mg m-3
) for 10 minutes resulted in the detection of benzene in lipid rich (brain
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 10
-
and fat) and perfused (liver and kidney) tissues as well as in the placenta and fetuses immediately
after exposure (Ghantous and Danielsson, cited in ATSDR, 2005).
Benzene was detected in the fat at levels of 16.4 mg% (where mg% equals mg of benzene per
100 mL of blood or mg per 100 g of tissue), in the bone marrow (3.8 mg%), blood (1.2 mg%)
and to a lesser extent in the kidney, lung, liver, brain, and spleen of rats exposed by inhalation for
6 hours to 500 ppm (1,630 mg m-3
). Concentrations of some benzene metabolites (e.g., phenol,
catechol, and hydroquinone) were higher in the bone marrow compared to the blood (Rickert et
al., cited in ATSDR, 2005).
Case studies of human individuals exposed to lethal benzene concentrations reported preferential
distribution in the brain (lipid rich), followed by the blood (plasma proteins) and liver (Tauber
and Winek & Collom, cited in ATSDR, 2005). Benzene will cross the placenta and was reported
in cord blood at concentrations equal to or greater than maternal blood concentrations (Dowty et
al., cited in ATSDR, 2005). Benzene has also been detected in samples of human breast milk
(Fabietti et al., cited in ATSDR, 2005).
4.1.3 Metabolism
The toxicity of benzene is attributed to multiple benzene metabolites yet the metabolism of
benzene is not thoroughly understood (US EPA, 2002). The data available suggests that benzene
metabolites produced in the liver are responsible for toxic effects in the bone marrow; however,
in vitro studies have demonstrated benzene metabolism can also occur within the bone marrow
itself (ATSDR, 2005).
The metabolic pathways reported for benzene are summarized in Figure 1. Benzene is initially
catalyzed by cytochrome P450 2E1 (CYP2E1) to form the epoxide benzene oxide (Lindstrom et
al., cited in ATSDR, 2005). Benzene oxide can then be metabolized via several alternative
pathways, the predominant pathway being nonenzymatic rearrangement to form phenol (Jerina et
al., cited in ATSDR, 2005). The epoxide may also react with glutathione to form S
phenyl-mercapturic acid (Nebert et al.; Sabourin et al.; Schafer et al.; Schlosser et al.; Schrenk et
al., and; van Sittert et al., cited in ATSDR, 2005). Benzene oxide can also form trans,trans
muconic acid via the highly reactive trans,trans-muconaldehyde (MUC) produced by an iron-
catalyzed, ring-opening reaction (Bleasdale et al.; Nebert et al.; Ross, and; Witz et al., cited in
ATSDR, 2005). Benzene oxide may also be acted on by epoxide hydrolase (EH) to form
benzene dihydrodiol (Nebert et al.; Snyder et al., cited in ATSDR, 2005), which is converted to
catechol by dihydrodiol dehydrogenase (DHDD) (Nebert et al.; Snyder et al., cited in ATSDR,
2005).
The major metabolic pathway for benzene is oxidation by CYP2E1 and rearrangement to form
phenol. Further oxidation of phenol by CYP2E1 produces catechol or hydroquinone; CYP2E1
catalysis of these products produces the reactive metabolite 1,2,4-benzenetriol. Alternatively,
catechol or hydroquinone can undergo oxidation by myeloperoxidase (MPO) to form 1,2- or 1,4
benzoquinone, respectively. These benzoquinones can be reduced back to catechol or
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 11
-
hydroquinone via NAD(P)H:quinone oxidoreductase (NQ01) (Nebert et al., cited in ATSDR,
2005).
Figure 1 Metabolism of Benzene (ATSDR, 2005)
The role of CYP2E1 in the metabolism and toxicity of benzene has been well documented in
mice studies. No signs of benzene toxicity (genotoxicity and cytotoxicity) were observed in
transgenic CYP2E1 mice that did not express hepatic CYP2E1 (Valentine et al., cited in
ATSDR, 2005). CYP2E1 is likely a major catalyst in benzene metabolism but other CYPs (e.g.,
CYP2B1 and CYP2F2) may also play a role (Gut et al.; Powley and Carlson; Sheets and
Carlson; Sheets et al.; Snyder et al., cited in ATSDR, 2005). Pretreatment of mice with CYP
inhibitors reduced benzene metabolite formation (Andrews et al.; Gill et al.; Ikeda et al., and;
Tuo et al., cited in ATSDR, 2005) and genotoxicity (Tuo et al., cited in ATSDR, 2005). In
contrast, induction of CYP increased the metabolism and clastogenicity (ability to cause
chromosomal breaks) of benzene (Gad-el-Karim et al., cited in ATSDR, 2005).
The majority of CYPs are located in the liver which is believed to be the primary site for benzene
metabolism (ATSDR, 2005). However, results of in vitro studies on human and animal
pulmonary microsomes (Powley and Carlson; Sheets et al., cited in ATSDR, 2005) and on bone
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 12
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marrow from rabbits (Andrews et al.; Schnier et al., cited in ATSDR, 2005), rats (Irons et al.
cited in ATSDR, 2005), and mice (Ganousis et al. cited in ATSDR, 2005) have indicated CYP-
catalyzed benzene metabolism can also occur in the lung and bone marrow, indicating the
potential for production of toxic metabolites at these locations.
Phenol is believed to be a major product of benzene metabolism; however, the administration of
phenol does not produce the same toxicity as benzene. Differences in urinary metabolites
produced by mice following oral exposure to phenol compared to benzene (e.g., less
hydroquinone produced from phenol administration compared to benzene administration) were
attributed to differences in the zonal distribution of metabolic enzymes within the liver (Kenyon
et al. cited in ATSDR, 2005). Enzymes capable of conjugating phenol for urinary excretion are
located in zone 1 (periportal area) of the liver, the first region to absorb xenobiotics. CYP
enzymes (including CYP2E1) are located in zone 3 (pericentral area) of the liver and metabolism
by these enzymes occurs only after a xenobiotic has passed through zone 1. Conjugation of
orally administered phenol would be extensive in zone 1 of the liver which would greatly reduce
the potential for oxidation of free phenol to hydroquinone by CYPs in zone 3. The metabolism
of orally administered benzene to phenol would not occur until zone 3 of the liver, where CYPs
are located. Unlike the conjugation and removal of phenol in zone 1 of the liver, phenol
produced in zone 3 by the metabolism of benzene is preferentially converted to hydroquinone
due to the high CYP content in this zone (Kenyon et al. cited in ATSDR, 2005).
It is likely that several metabolites are responsible for the toxic effects of benzene. Animal
studies have reported large variances in metabolite production between species (Sabourin et al.,
cited in ATSDR, 2005). There is still uncertainty as to which animal model best describes
benzene metabolism in humans as there is limited data available to define the proportion of
benzene metabolite production in humans (US EPA, 2002). Further details on studies of the
metabolism of benzene and associated toxicity can be found in ATSDR, 2005 and US EPA,
2002.
4.1.4 Elimination
Animal studies have reported that exposure to very high air concentrations of benzene (>850
ppm or 2,718 mg m-3
) saturates metabolic processes and results in the exhalation of greater
concentrations of unchanged benzene (48% in rats and 14% in mice). Exposure of animals to
lower air concentrations of benzene (10 ppm or 32 mg m-3
) resulted in the exhalation of lower
concentrations of unchanged benzene (
-
benzene for 8 hours or 99 ppm (316 mg m-3
) for 1 hour, Sherwood (cited in US EPA, 2002)
demonstrated a greater proportion of the inhaled benzene dose was excreted in the urine versus
exhalation. This is supported by occupational and cross-sectional studies which suggest that
benzene and benzene metabolites in urine are important biomarkers for benzene exposure.
4.1.5 Physiologically Based Pharmacokinetic (PBPK) Models
Physiologically based pharmacokinetic models (PBPK) utilize mathematical equations to
describe the uptake and disposition of a chemical substance, to predict chemical concentrations
in target tissues, and, to describe the relationship between target tissue dose and toxic end points
(ATSDR, 2005). The ability of these models to predict the dose-response characteristics of a
chemical is dependent on how accurately mechanisms for chemical absorption, transport, and
metabolism are described. In general, the models assume that biochemical processes identified
in animal models will simulate the human toxicological response (US EPA, 2002).
As described below, PBPK models have been developed and used to describe benzene
metabolism, to relate benzene metabolites to toxicity endpoints, and, to a limited extent, to
extrapolate data on benzene metabolism in animals to predict human metabolism of benzene
(ATSDR, 2005).
Medinsky and colleagues developed a multicompartmental PBPK model (blood, bone
marrow, fat, liver, lung, slowly-perfused tissues, and rapidly-perfused tissues) to describe the
absorption and distribution of benzene in the human, mouse, and rat (ATSDR, 2005). The model
has been used to predict benzene metabolite formation in rats and mice after inhalation
exposures. When compared to rats, mice were predicted to have a higher rate of benzene
metabolism and produce more hydroquinone glucuronide and muconic acid (metabolites
associated with toxic effects of benzene). Although this model has been used to simulate the
formation of major metabolites in mice, rats, and humans, it is limited by the assumption that all
metabolism occurs in the liver. The model also excludes bone marrow as a target tissue for
benzene metabolites (ATSDR, 2005). Sun and colleagues incorporated into the Medinsky model
the formation of haemoglobin adducts in the liver by benzene oxide following oral and inhalation
exposure of mice and rats to benzene (ATSDR, 2005). This model is limited in that it attributes
the formation of haemoglobin adducts to benzene oxide concentrations in the liver with no
consideration of potential haemoglobin adduct formation by other benzene metabolites (i.e.,
hydroquinone, phenol, muconaldehyde) (ATSDR, 2005).
Travis and colleagues also developed a multicompartmental PBPK model (blood, bone marrow,
fat, liver, lung, and other slowly- and rapidly-perfused tissues) to describe the absorption and
disposition of benzene in humans, mice, and rats (ATSDR, 2005). In this model benzene
metabolism is assumed to occur both in the liver and bone marrow. The model has been applied
to humans to predict benzene metabolism and benzene concentrations in expired air and blood
following inhalation exposures. An internal dose-response relationship for humans was derived
for benzene using this model (Cox, cited in ATSDR, 2005). The Travis et al. model was
extended by Fisher and colleagues to predict the partitioning of benzene into breast milk and
subsequent exposure of breast feeding infants (ATSDR, 2005). Sinclair and colleagues also
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 14
-
extended the Travis et al. model to include dermal absorption of benzene and first-order urinary
excretion of total benzene metabolites and phenol, in order to predict benzene levels in exhaled
air and urinary phenol concentrations following occupational exposure to benzene (ATSDR,
2005).
Bois and colleagues developed PBPK models for benzene which included metabolic pathways in
the liver and bone marrow, phenol conjugation in the lung and gastrointestinal tract, and
endogenous production of phenolic metabolites (ATSDR, 2005). Their model was used to
predict benzene and phenol metabolite formation in rats during inhalation exposures equivalent
to the OSHA PEL for benzene. The results suggest that dose rate (dose and time) is an important
factor in bone marrow toxicity as a greater amount of toxic metabolites (hydroquinone, catechol,
and muconaldehyde) were produced in rats exposed for 15 minutes to a 32 ppm (104 mg m-3
)
benzene compared to rats exposed for 8 hours to 1 ppm (3 mg m-3
) benzene (ATSDR, 2005).
Brown and colleagues developed a PBPK model for determining benzene concentrations in
blood following inhalation by humans; the model incorporates gender-specific partition
coefficients and predicts a higher blood:air partition coefficient and subsequently a higher
metabolic rate for benzene in females compared to males (ATSDR, 2005).
Cole and colleagues developed a multicompartmental PBPK model (blood, fat, liver, and other
slowly- and rapidly-perfused tissues) to describe the absorption and disposition of benzene in the
mouse following oral or inhalation exposures (ATSDR, 2005). This model included simulation
of the disposition of major metabolites; metabolic parameters were derived empirically from in
vitro studies versus model optimization. The model is limited by a lack of simulation of
metabolic processes in the bone marrow. Furthermore, data on tissue dosimetry for benzene
metabolites indicate the rat may be a better model for humans than the mouse (Seaton et al.,
cited in US EPA, 2002).
4.1.6 Mechanism of Toxic Action
Haematotoxicity and leukemia are considered to be the most critical effects of benzene exposure
and thus numerous studies have been conducted to determine the mechanisms by which benzene
produces these effects. Benzene also affects reproduction, development, and the nervous system;
however, the mechanism for these endpoints has not been studied in as much detail (ATSDR,
2005; IPCS, 1993; US EPA, 1998; 2002).
Studies conducted in mice and rats by Sammett et al. and Valentine et al. have shown that the
metabolism of benzene by CYP2E1 was necessary for the expression of haematotoxicity (US
EPA, 2002). The haematotoxicity of benzene has been attributed to the transport of phenolic
metabolites (phenol, catechol, hydroquinone, 1,2,4-benzenetriol, and 1,2- and 1,4-benzoquinone)
to the bone marrow and potentially the metabolism of benzene within the bone marrow (ATSDR,
2005). Phenolic metabolites in the bone marrow can be metabolized by myeloperoxidase to
form highly reactive semiquinone radicals and quinones that stimulate production of reactive
oxygen species and lead to DNA damage; damage to stem or early progenitor cells would be
expressed as hematopoietic and leukemogenic effects (Smith, cited in ATSDR, 2005).
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 15
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The US EPA (2002) cited several different mechanisms for benzene toxicity including: the
formation of covalent adducts with cell proteins and DNA; chromosomal aberrations; oxidative
stress/formation of reactive oxygen species in target tissues, and; the inhibition of cytokine IL-1
formation, which is essential for the development of blood cells (haematopoiesis).
4.2 Genotoxicity
Chromosomal aberrations were reported in peripheral blood lymphocytes and bone marrow
following occupational exposure (dermal and inhalation) to benzene (ATSDR, 2005). In
workers chronically exposed to benzene, Zhang and colleagues reported monosomy of
chromosomes 5, 7, and 8 and trisomy and/or tetrasomy of chromosomes 1, 5, 7, and 8 in
peripheral lymphocytes (mean time weighted average (TWA) exposure of 30 ppm or 98 mg m-3
benzene); Sasiadek et al. reported breaks in chromosomes 2, 4, and 9 gaps in chromosomes 1
and 2; Kasuba et al. reported dicentric chromosomes and unstable aberrations, and; Smith et al.
reported increased hyperploidy of chromosomes 8 and 21 and translocations between
chromosomes 8 and 21 (mean TWA exposure of 31 ppm or 102 mg m-3
benzene) (ATSDR,
2005).
A 10 year study (1990 to 2000) on the hprt loci of peripheral blood lymphocytes collected from
oil refinery workers exposed to benzene (annual peak concentrations from 1.5 to 43.8 ppm; 5 to
143 mg m-3
) reported a reduction in the incorporation of tritiated thymidine and an increase in
the frequency of mutations in the hprt loci, suggesting the potential for benzene to produce
mutations (Major et al., cited in ATSDR, 2005).
Liu et al. (cited in ATSDR, 2005) assessed DNA damage in peripheral blood lymphocytes from -3 -3
workers exposed to low (2.46 mg m or 0.78 ppm), medium (103 mg m or 32.2 ppm), or high
(424 mg m-3
or 133 ppm) benzene concentrations. Oxidative DNA damage (formation of 8
hydroxy-2-deoxyguanosine or 8-OHdG) and micronuclei formation increased in a dose-related
manner with increasing benzene concentrations. A dose-related increase in urinary levels of 8
OHdG and DNA single-strand breaks were reported for male gasoline station workers exposed to
breathing zone benzene concentrations ranging from 0.003 to 0.6 ppm (mean 0.13 ppm or 0.42
mg m -3
) by Nilsson et al. (cited in ATSDR, 2005). These studies suggest the induction of
reactive oxygen species and oxidative DNA damage by benzene metabolites (ATSDR, 2005).
Numerous in vivo mammalian studies have provided convincing evidence of the genotoxicity of
benzene (ATSDR, 2005). Chromosomal aberrations have been reported in bone marrow of
mice, rats, Chinese hamsters and rabbits (Tice et al.; Siou et al.; Meyne and Legator; Shelby and
Witt; Giver et al.; Styles and Richardson; Anderson and Richardson; Philip and Jensen; Fujie et
al.; Hoechst; Kissling and Speck; cited in ATSDR, 2005) and in spleen lymphocytes, lymphoid
cells, and myeloid cells of mice (Rithidech et al.; Au et al.; Giver et al., cited in ATSDR, 2005)
following in vivo exposure to benzene. Benzene exposure was also associated with an increase
in sister chromatid exchange in mice (bone marrow, lymphocytes, fetal liver cells) and rats
(lymphocytes) (Tice et al.; Erexson et al.; Sharma et al., cited in ATSDR, 2005).
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 16
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An increase in micronuclei frequency was reported in fetal liver cells, bone marrow, lung
fibroblasts, and peripheral and bone marrow erythrocytes of benzene exposed mice (Farris et al.;
Siou et al.; Erexson et al.; Healy et al.; Ranaldi et al.; Diaz et al.; Choy et al.; Barale et al.; Hite
et al.; Meyne and Legator; Au et al.; Harper et al.; Toft et al.; Ciranni et al.; Suzuki et al.;
Rithidech et al.; Luke et al., cited in ATSDR, 2005). The increase in micronuclei frequency in
erythrocytes was exposure-dependent and required exposure concentrations of 100 ppm (326 mg
m-3
) or greater; this response was not observed by Farris and colleagues at air concentrations of 1
or 10 ppm (3 to 33 mg m-3
) benzene (ATSDR, 2005).
In vivo exposure to benzene produced DNA mutations (spleen lymphocytes and lung tissue)
(Mullin et al.; Ward et al., cited in ATSDR, 2005) and strand breaks (peripheral blood
lymphocytes) (Tuo et al., cited in ATSDR, 2005) in mice, inhibited DNA and/or RNA synthesis
(bone marrow, liver mitochondria) in mice and rats (Lee et al; Kissling and Speck; Kalf et al.,
cited in ATSDR, 2005) and resulted in oxidative DNA damage in rats (Liu et al., cited in
ATSDR, 2005). Equivocal results were reported for the formation of DNA adducts following in
vivo exposure to benzene, with negative responses reported for mouse bone marrow and
mammary gland by Reddy et al. (ATSDR, 2005) and positive responses reported for mouse bone
marrow and white blood cells, and rat liver cells by Pathak et al.; Levay et al., and; Lutz and
Schlatter (ATSDR, 2005). One in vivo study in mice reported sperm head abnormality following
benzene exposure (Topham, cited in ATSDR, 2005).
In vitro studies of benzene confirm the results of in vivo genotoxicity studies and suggest that
genotoxicity is primarily the result of benzene metabolites (ATSDR, 2005). Several studies
reported positive results for gene mutation in Salmonella typhimurium (Glatt et al.; Kaden et al.;
Seixas et al., cited in ATSDR, 2005), sister chromatid exchange in human lymphocytes
(Morimoto, cited in ATSDR, 2005), altered DNA synthesis in rat hepatocytes (Glauert et al.,
cited in ATSDR, 2005), altered RNA synthesis in rat liver mitoplasts and rabbit and cat bone
marrow mitoplasts (Kalf et al., cited in ATSDR, 2005), and DNA adduct formation in rat liver
mitoplasts (Rushmore et al., cited in ATSDR, 2005) only in the presence of endogenous (within
the cell) or exogenous (added to the cellular preparation) metabolic activators of benzene.
In summary, benzene is considered a potent clastogen with evidence of numerical and structural
chromosomal aberrations, sister chromatid exchanges, and micronuclei following in vivo
exposure of experimental animals and humans. In vitro tests results suggest that benzene
metabolites are responsible for gene mutations, DNA adducts, and altered DNA and RNA
synthesis. Details on in vivo and in vitro studies of benzene genotoxicity are provided in
ATSDR, 2005.
4.3 Acute Toxicity
Acute exposure to very high benzene concentrations (44,662 to 65,200 mg m-3
) has been fatal to
animals and humans. Haematological (reduced blood cell count), neurological, and respiratory
effects occurred in humans following acute exposure to non-lethal benzene air concentrations (up
to 978 mg m-3
). The acute exposure of mice and rats to benzene decreased production of white
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 17
-
blood cells (leucocytes, granulocytes, and lymphocytes), red blood cell production (erythrocytes
and CFU-E), bone marrow cellularity, and induced chromosomal damage.
4.3.1 Acute Toxicity in Humans
Exposure of humans to 20,000 ppm (65,200 mg m-3
) benzene for 5 to 10 minutes is considered
fatal (Flury et al., cited in ATSDR, 2005). The cause of death from acute overexposure to
benzene has been reported to result from asphyxiation, respiratory arrest, CNS depression or
cardiac collapse (Avis and Hutton; Greenburg; Hamilton; Winck and Collom; Winck et al.; cited
in ATSDR, 2005). Brief exposure (30 minutes) to 300 ppm (978 mg m-3
) benzene produced
drowsiness, dizziness and headaches in exposed workers (Flury et al., cited in ATSDR, 2005).
Occupational exposure of males to benzene air concentrations >60 ppm (196 mg m-3
) for up to 3
weeks (2.5 to 8 hours/day) during the removal of residual fuel from shipyard tanks produced
respiratory effects (mucus membrane irritation and dyspnea), reduced blood cell counts
(leukocytes, erythrocytes, and thrombocytes), and neurological effects (dizziness, nausea,
headache, fatigue) (Midzenski et al., cited in ATSDR, 2005). Uncertainty in exposure levels and
duration, the potential for confounding exposures to other chemicals, and lack of corresponding
control groups, limit the use of data collected from an occupational setting; however, the ATSDR
has identified well conducted occupational studies with effects linked to specific benzene
exposure concentrations. Adverse health effects reported in well conducted human studies
following the acute inhalation of benzene and the air concentration at which they are predicted to
occur are summarized in Table 5.
Table 5 Acute Effects Following Human Exposure to Benzene
Effect Exposure Period Air Concentration
ppm (mg m-3
) Reference
1
Death 5 to 10 minutes 20,000 (65,200) Flury et al. 1928
Neurological: drowsiness,
dizziness, headaches 30 min 300 (978) Flury et al. 1928
Neurological: dizziness,
headaches, nausea, fatigue
(males)
1-21 d, 2.5-8 hr/d 60 (196) Midzenski et al.
1992
Respiratory: mucus membrane
irritation and dyspnea (males).
Hematological: leucopenia, anemia, and thrombocytopenia
(males).
1-21 d, 2.5-8 hr/d 60 (196) Midzenski et al.
1992
1cited in ATSDR, 2005
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 18
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4.3.2 Acute Toxicity in Animals
Acute inhalation of high benzene concentrations has resulted in death of experimental animals
with a 4 hour LC50 value of 13,700 ppm (44,662 mg m-3
) was reported for Sprague-Dawley rats
(Drew and Fouts, cited in ATSDR, 2005). Exposure of C57B1/6BNL mice to lower benzene air
concentrations (400 ppm or 1304 mg m-3
) for longer duration (2 weeks) did not cause death
(Cronkite et al., cited in ATSDR, 2005).
The acute exposure of mice and rats to benzene resulted in decreased production of white blood
cells (leucocytes, granulocytes, and lymphocytes), decreased red blood cell production
(erythrocytes and CFU-E), decreased bone marrow cellularity, and chromosomal damage
(ATSDR, 2005). The lowest observed adverse effect levels (LOAELs) for decreases in white
blood cells in mice or rats acutely exposed (6-24 hours/day for 1 to 14 days) to benzene ranged
from 10.2 to 400 ppm (33 to 1304 mg m-3
), while the no observed adverse effect levels
(NOAEL) for these responses ranged from 3 to 50 ppm (10 to 163 mg m-3
) benzene (Toft et al.;
Rosenthal and Snyder; Gill et al.; Wells and Nerland; Green et al.; Rozen et al.; Li et al.;
Cronkite et al.; Chertkov et al.; Ward et al.; Aoyama et al, cited in ATSDR, 2005). The
LOAEL values reported for decreased red blood cell production in mice acutely exposed (6
hours/day for 5 to 14 days) to benzene ranged from 10 to 400 ppm (33 to 1304 mg m-3
), while
the NOAELs for these responses in mice ranged from 25 to 30 ppm (82 to 98 mg m-3
) of benzene
(Dempster and Snyder; Rozen et al.; Cronkite et al.; Neun et al.; Ward et al., cited in ATSDR,
2005). LOAELs for decreased bone marrow cellularity in acutely exposed mice (6 to 24
hours/day for 1 to 14 days) ranged from 21 to 400 ppm (68 to 1304 mg m-3
)(Toft et al.; Gill et
al.; Green et al.; Cronkite et al.; Neun et al.; Chertkov et al., cited in ATSDR, 2005) with one
NOAEL of 9.9 ppm (32 mg m-3
) reported for this response in mice (Green et al., cited in
ATSDR, 2005).
An increased frequency of micronucleated polychromatic erythrocytes, indicative of
chromosomal damage, was reported in male NMRI mice following a series of experiments
conducted by Toft et al. (cited in ATSDR, 2005) exposing the mice to benzene for 8 to 24
hours/day over 1 to 14 days. A LOAEL of 21 ppm (68 mg m-3
) and NOAEL values ranging
from 10.5 to 14 ppm (34 to 46 mg m-3
) were reported for this response in mice (ATSDR, 2005).
A minimum risk level (MRL) for acute inhalation exposure (14 days or less) to benzene was
established by the ATSDR (2005) based on the lowest reported LOAEL (10.2 ppm or 33 mg m-3
)
for decreased white blood cell production in mice. Exposure of male C57B1/6J mice to 10.2
ppm (33 mg m-3
) benzene for 6 hours per day over 6 days resulted in decreased lymphocyte
production (Rozen et al., cited in ATSDR, 2005). An MRL of 0.009 ppm (29 µg m-3
) was
recommended based on this LOAEL following adjustment for intermittent exposure, conversion
to a human equivalent concentration, and division by a 300-fold uncertainty factor to account for
use of a LOAEL, extrapolation from animals to humans, and variations in human sensitivity.
This MRL is an estimate of daily human exposure to benzene that is likely to be without an
appreciable risk of adverse effects (non carcinogenic) over a continuous exposure period of 14
days or less (ATSDR, 2005). A summary of the acute effects of benzene inhalation in animals,
the exposure period and concentration at which they occurred, and the species studied is
provided in Table 6.
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 19
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Table 6 Acute Effects Following Animal Exposure to Benzene
Effect Exposure Period Air Concentration
ppm (mg m-3
) Species Reference
1
4 hr LC50 = 13,700 (44,662) Rat
Sprague-Dawley
Drew and Fouts,
1974 Death
2 weeks NOAEL = 400 (1304) Mouse C57B1/6BNL
Cronkite et al. 1985
1-10 d, 24 hr/d LOAEL = 21 (68) Mouse, male
NMRI Toft et al. 1982
1-12 d, 6 hr/d LOAEL = 30 (98)
NOAEL = 10 (33)
Mouse, male
C57B1/6
Rosenthal and
Snyder, 1985
2-8 d, 24 hr/d LOAEL = 100 (326) Mouse, male
C57B1/6 Gill et al. 1980
5 d, 6 hr/d LOAEL = 25 (82)
NOAEL = 3 (10)
Mouse, male
Swiss Webster
Wells and Nerland,
1991
5 d, 6 hr/d LOAEL = 103 (336)
NOAEL = 9.9 (32)
Mouse, male
CD-1 Green et al. 1981
6 d, 6 h/d LOAEL = 10.2 (33) Mouse, male
C57B1/6J Rozen et al.1984
7 d, 8 hr/d LOAEL = 100 (326)
NOAEL = 50 (163)
Rat, female
Wistar Li et al. 1986
11 d, 5 d/wk, 6 hr/d LOAEL = 400 (1304) Mouse, male
Hale-Stoner Cronkite et al., 1982
Decreased WBC:
leucopenia,
granulocytopenia,
lymphopenia.
2 wk, 5 d/wk, 6 hr/d LOAEL = 25 (82)
NOAEL = 10 (33)
Mouse
C57B1/6 BNL,
CBA/Ca
Cronkite et al. 1985;
1986
2 wk, 5 d/wk, 6 hr/d LOAEL = 300 (978) Mouse, male
DBA/2
Chertkov et al.,
1992
2 wk, 5 d/wk, 6 hr/d LOAEL = 300 (978)
NOAEL = 30 (98)
Rat, male
Sprague-Dawley
Mouse
CD-1
Ward et al., 1985
2 wk, 5 d/wk, 8 hr/d LOAEL = 21 (68)
NOAEL = 10.5 (34)
Mouse
NMRI Toft et al. 1982
14 d, 6 h/d LOAEL = 48 (156) Mouse, male
BALB/c Aoyama et al., 1986
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 20
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Table 6 Acute Effects Following Animal Exposure to Benzene (continued)
Air Concentration Effect Exposure Period -3 Species Reference
1
ppm (mg m )
Mouse Dempster and 5 d, 6 h/d LOAEL = 10 (33)
DBA/2J Snyder, 1991
Mouse, male 6 d, 6 h/d LOAEL = 100 (326) Rozen et al., 1984
C57B1/6J
Mouse, male Cronkite et al., Decreased RBC: 11 d , 5 d/wk, 6 hr/d LOAEL = 400 (1304)
Hale-Stoner 1982; 1989 anaemia, decreased
Mouse, male erythrocytes, reduced 2 wk, 4 d/wk, 6 h/d LOAEL = 300 (978) Swiss Webster, Neun et al., 1982 CFU-E.
C57B1/6J
LOAEL = 100 (326) Mouse 2 wk, 5 d/wk, 6 hr/d Cronkite et al., 1985
NOAEL = 25 (82) C57B1/6BNL
LOAEL = 300 (978) Mouse 2 wk, 5 d/wk, 6 hr/d Ward et al. 1985
NOAEL = 30 (98) CD-1
Mouse 1-10 d, 24 hr/d LOAEL = 21 (68) Toft et al. 1982
NMRI
Mouse, male 2-8 d, 24 hr/d LOAEL = 100 (326) Gill et al. 1980
C57B1/6
LOAEL = 103 (336) Mouse, male 5 d, 6 hr/d Green et al. 1981
NOAEL = 9.9 (32) CD-1 Decreased bone
Mouse, male marrow cellularity 11 d, 5 d/wk, 6 hr/d LOAEL = 400 (1304) Cronkite et al., 1982 Hale-Stoner
Mouse, male
2 wk, 4 d/wk, 6 h/d LOAEL = 300 (978) Swiss Webster, Neun et al., 1982
C57B1/6J
Mouse, male Chertkov et al., 2 wk, 5 d/wk, 6 hr/d LOAEL = 300 (978)
DBA/2 1992
Mouse, male Chromosomal: 1-10 d, 24 h/d LOAEL = 21 (68) Toft et al. 1982 NMRI increased frequency
of micronucleated Mouse, male 1 wk, 24 hr/d NOAEL = 14 (46) Toft et al. 1982
polychromatic NMRI erythrocytes (MN LOAEL = 21 (68) Mouse, male PCEs). 2 wk, 5 d/wk, 8 h/d Toft et al. 1982 NOAEL = 10.5 (34) NMRI
LC50: lethal concentration to 50% of the exposed study population 1cited in ATSDR, 2005
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 21
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4.4 Subchronic and Chronic Toxicity
Similar to the effects reported following acute exposures, subchronic and chronic exposure to
relatively low levels of benzene produced measurable depression of one or more circulating
blood cells, resulting in haematotoxic and immunotoxic effects. Subchronic and chronic studies
in humans and animals have reported pancytopenia or the reduction in number of all major blood
cells, including leukocytes (white blood cells), erythrocytes (red blood cells), and thrombocytes
(platelets). Blood cells are produced by the bone marrow and therefore pancytopenia is a
condition that results from the inability of the bone marrow to adequately produce mature blood
cells. A more severe effect of benzene exposure is aplastic anaemia in which the bone marrow is
unable to function and stem cells do not mature. The progression of aplastic anaemia can result
in acute myelogenous leukemia, or cancer of the myeloid line of white blood cells (ATSDR,
2005).
The ability of benzene to induce carcinogenic effects via the same mechanism as haematotoxic
and immunotoxic effects has not yet been demonstrated. It has been well demonstrated in human
and animal studies that chronic exposure to benzene depressed bone marrow function however,
there is no suitable animal model for the induction of leukemia following benzene exposure.
Furthermore, benzene-induced haematotoxicity/immunotoxicity leads to health effects apart
from potential induction of leukemia (US EPA, 2002).
4.4.1 Subchronic and Chronic Toxicity in Humans
Pancytopenia was reported in workers occupationally exposed to benzene concentrations ranging
from 3 to 210 ppm (10 to 685 mg m-3
) over periods of 4 months to 3 years (Askoy and Erdrem;
Askoy et al.; Doskin; Erf and Rhoads, Rothman et al., cited in ATSDR, 2005). Decreased
production of white blood cells (leucocytes and lymphocytes) occurred in workers
occupationally exposed for 1 to 21 years to benzene concentrations ranging from 0.57 to 75 ppm
(1.86 to 245 mg m-3
)(Cody et al.; Xia et al.; Tsai et al.; Kipen et al.; Qu et al.; Rothman et al.,
cited in ATSDR, 2005). Decreased red blood cell counts and anaemia were reported following
subchronic and chronic occupational exposure to benzene concentrations ranging from 2.26 to 29
ppm (7.37 to 95 mg m-3
) (Yin et al.; Goldwater; Greenburg et al.; Tsai et al.; Kipen et al.; Qu et
al., cited in ATSDR, 2005).
There was a lack of observed adverse effects on blood cells in male refinery workers exposed to
0.53 ppm (1.73 mg m-3
) benzene for 1-21 years (Tsai et al., cited in ATSDR, 2005). This
exposure level was selected by the California Office of Environmental Health Hazard
Assessment and adjusted for continuous exposure and variation in human sensitivity to develop a
chronic reference exposure level (REL) of 0.02 ppm or 60 µg m-3
(OEHHA, 1999).
The study reporting the lowest air concentration at which white blood cell (lymphocyte) levels
were reduced was selected by the ATSDR (2005) for the development of the minimum risk level
(MRL) for chronic inhalation exposure (>365 days) to benzene. Significant decreases in B-
lymphocyte counts were reported for male shoe manufacturing workers in Tianjin, China
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 22
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exposed to 0.57 ppm (1.86 mg m-3
) benzene for an average of 6.1 years (Lan et al., cited in
ATSDR, 2005). A chronic MRL of 0.003 ppm (0.01 mg m-3
) was determined using benchmark
dose (BMD) modeling and adjusting from occupational to continuous exposure. A 10-fold
uncertainty factor was also applied to account for variations in human sensitivity (ATSDR,
2005).
The US EPA developed a Reference Concentration (RfC) also based on a study reporting
decreased lymphocyte counts following occupational exposure to 7.6 ppm (24 mg m-3
) benzene
(Rothman et al., cited in US EPA, 2002). The US EPA used benchmark dose modeling and
adjusted for human variability, subchronic-to-chronic exposures, and database deficiencies to
arrive at an RfC of 30 µg m-3
for lifetime chronic human exposure to benzene (US EPA, 2002).
The California OEHHA, the ATSDR, and the US EPA have all developed chronic exposure
guidelines for benzene based on effects (or lack thereof) on blood cell counts following
occupational exposures. However, the US EPA (2002) cautions that there is inherent uncertainty
as to when a change in a parameter that has inherent variability, such as hematologic parameters,
will translate into an adverse effect.
Selected key effects reported in humans following subchronic and chronic inhalation exposure to
benzene and the air concentrations at which these effects occurred are summarized in Table 7.
4.4.2 Subchronic and Chronic Toxicity in Animals
Subchronic and chronic exposure of rats and mice to 200 or 300 ppm (652 to 978 mg m-3
)
benzene resulted in death or a shortened lifespan (Maltoni et al.; Cronkite et al.; Farris et al.;
Green et al.; Snyder et al., cited in ATSDR, 2005). Pancytopenia occurred in mice
subchronically exposed (13 weeks) to 300 ppm (978 mg m-3
) benzene (Ward et al., cited in
ATSDR, 2005) and chronically exposed (lifetime) to 100 ppm (326 mg m-3
) benzene (Snyder et
al., cited in ATSDR, 2005). A NOAEL of 30 ppm (98 mg m-3
) was reported for pancytopenia in
mice following subchronic exposure to benzene (Ward et al. cited in ATSDR, 2005).
The lowest LOAELs reported for decreases in white blood cell count (leukocytes, granulocytes,
and/or lymphocytes) following subchronic or chronic benzene exposure ranged from 100 to 400
ppm (326 to 1304 mg m-3
) in mice (Cronkite et al.; Green et al.; Farris et al.; Toft et al.; Cronkite
et al.; Green et al.; Snyder et al., cited in ATSDR, 2005) and from 100 to 500 ppm (326 to 1630
mg m -3
) in rats (Dow; Ward et al.; Wolf et al.; Snyder et al., cited in ATSDR, 2005). LOAELs
of 80, 88 and 100 ppm (261, 287, and 326 mg m-3
) were reported for decreased white blood cell
counts in chronically exposed rabbits, guinea pigs and Duroc Jersey pigs, respectively (Wolf et
al.; Dow, cited in ATSDR, 2005).
LOAEL values for reductions in red blood cell counts in mice subchronically or chronically
exposed to benzene ranged from 10 to 400 ppm (33 to 1304 mg m-3
) benzene (Baarson et al.;
Vacha et al.; Farris et al.; Toft et al.; Plappert et al.; Seidel et al.; Cronkite et al.; Luke et al.;
Green et al.; Snyder et al., cited in ATSDR, 2005). NOAEL values ranging from 9.6 to 100 ppm
(31 to 326 mg m-3
) were reported for reduced red blood cell counts following subchronic and
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 23
-
chronic exposure of mice to benzene (Farris et al.; Toft et al.; Plappert et al.; Green et al., cited
in ATSDR, 2005).
Table 7 Subchronic and Chronic Effects Reported Following Human (Occupational)
Exposure to Benzene
Effects Reported Exposure Period Air Concentration
ppm (mg m-3
) Reference
1
4 mo – 1 yr 150 (489) Askoy and Erdem, 1978
4 mo – 1 yr 210 (685) Askoy et al. 1972
Pancytopenia: decreased
RBC, WBC and
platelets.
1 – 3 yr
Chronic
(not specified)
6.3 yr (average)
3 (10)
24 (78)
31 (101)
Doskin, 1971
Erf and Rhoads, 1939
Rothman et al. 1996a;
1996b
Decreased WBC:
leucopenia, lymphopenia..
1 yr
> 1 yr
1 – 21 yr
1 – 25 yr
4.5 – 9.7 yr
6.1 yr (average)
6.3 yr (average)
40 (130)
0.69 (2.25)
NOAEL = 0.53 (1.73)
75 (245)
2.26 (7.4)
0.57 (1.86)
7.6 (24)
Cody et al. 1983
Xia et al. 1995
Tsai et al. 1983
Kipen et al. 1989
Qu et al. 2002; 2003
Lan et al, 2004
Rothman et al. 1996a;
1996b
3.5 mo – 19 yr 29 (95) Yin et al. 1987
0.5 to 5 yr 11 (36) Goldwater 1941;
Greenburg et al. 1939
Decreased RBC 1 – 21 yr NOAEL = 0.53 (1.73) Tsai et al. 1983
1 – 25 yr 75 (245) Kipen et al. 1989
4.5 – 9.7 yr 2.26 (7.37) Qu et al. 2002; 2003
1cited in ATSDR, 2005
A reduction in bone marrow cellularity was reported for mice and rats subchronically and
chronically exposed to benzene air concentrations ranging from 100 to 400 ppm (326 to 1304 mg
m-3
) (Farris et al.; Cronkite et al.; Ward et al.; Cronkite et al.; Snyder et al., cited in ATSDR,
2005) with NOAELs for this response reported to range from 10 to 30 ppm (33 to 98 mg m-3
)
benzene (Farris et al.; Toft et al.; Ward et al.; Cronkite et al., cited in ATSDR, 2005). In
Assessment Report on Benzene for Developing Ambient Air Quality Objectives 24
-
contrast, granulocytic hyperplasia (increased WBC production) was induced in the bone marrow
of mice subchronically exposed (16 weeks) to 300 ppm (978 mg m-3
) benzene (Farris et al., cited
in ATSDR, 2005).
A decrease in spleen cells and
top related