BENZENE
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Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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ATSDR/TP-88/03
TOXICOLOGICAL PROFILE FOR
BENZENE
Date Published — May 1989
Prepared by:
Oak Ridge National Laboratory
under DOE Interagency Agreement No. 18S7-B026-A1
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. 1857-B026-A1
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DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans."
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
iii
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Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement Is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.-
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
James 0. Mason, M.D., Dr. P.H.
Assistant Surgeon General
Administrator, ATSDR
iv
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-«« iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS BENZENE? 1
1.2 HOW MIGHT I BE EXPOSED TO BENZENE? 1
1.3 HOW DOES BENZENE GET INTO MY BODY? 1
1.4 HOW CAN BENZENE AFFECT MY HEALTH? 2
1.4.1 Brief Exposure at High Levels 2
1.4.2 Long-Term Exposures at Various Levels 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE
IF I HAVE BEEN EXPOSED TO BENZENE? 2
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH? 3
2. HEALTH EFFECTS SUMMARY 7
2.1 INTRODUCTION 7
2.2 LEVELS OF SIGNIFICANT EXPOSURE 8
2.2.1 Key Studies and Graphical Presentations 8
2.2.1.1 Lethality 8
2.2.1.2 Systemic/target organ toxicity 13
2.2.1.3 Developmental toxicity 15
2.2.1.4 Reproductive toxicity 16
2.2.1.5 Careinogenieity 16
2.2.2 Biological Monitoring as a Measure of
Exposure and Effects 17
2.2.2.1 Monitoring of exposure 17
2.2.2.2 Monitoring of effects 20
2.2.3 Environmental Levels as Indicators of
Exposure and Effects 20
2.2.3.1 Levels found in the environment 20
2.2.3.2 Human exposure potential 21
2.3 ADEQUACY OF DATABASE 21
2.3.1 Introduction 21
2.3.2 Health Effect End Points 22
2.3.2.1 Introduction and graphic summary 22
2.3.2.2 Descriptions of highlights of graphs 25
2.3.2.3 Summary of relevant ongoing research 25
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Contents
2.3.3 Other Information Needed for Human
Health Assessment 28
2.3.3.1 Pharmacokinetics and mechanisms of action .. 28
2.3.3.2 Monitoring of human biological samples 29
2.3.3.3 Environmental considerations 30
3. CHEMICAL AND PHYSICAL INFORMATION 31
3.1 CHEMICAL IDENTITY ' [ ' ' 31
3 .2 PHYSICAL AND CHEMICAL PROPERTIES '.'.'.'.'.'.'.'.'.'.'.'.'.'.'. '. . . 31
4. TOXICOLOGICAL DATA 35
4.1 OVERVIEW ' ' .' ' ] 35
4.2 TOXICOKINETICS '.'.'.'.'.'.'.'.'.'.'.'.'."".'. 35
4.2.1 Overview 35
4.2.2 Absorption 36
4.2.2.1 Inhalation 36
4.2.2.2 Oral '.'.'.'.'.'..'. 37
4.2.2.3 Dermal \\ 37
4.2.3 Distribution '.'.'.'.'.'. 38
4.2.3.1 Inhalation 38
4.2.3.2 Other routes of exposure 39
4.2.4 Metabolism "j 39
4.2.5 Excretion 43
4.2.5.1 Inhalation '.'.'.'.'. 43
4.2.5.2 Oral '.'.'.'.'. 44
4.2.5.3 Dermal 44
4. 3 TOXICITY '.'.'.'.'.'.'.'.'.'.'.'. 44
4.3.1 Lethality and Decreased Longevity 44
4.3.1.1 Overview 44
4.3.1.2 Inhalation 46
4.3.1.3 Oral ' 47
4.3.1.4 Dermal '.'.'.'.'.'. 47
4.3.2 Systemic/Target Organ Toxicity 47
4.3.2.1 Hematotoxicity 47
4.3.2.2 Immunotoxicity 54
4.3.2.3 Neurotoxicity 57
4.3.2.4 Dermal toxicity 58
4.3.2.5 Ocular toxicity 58
4.3.3 Developmental Toxicity 59
4.3.3.1 Overview 59
4.3.3.2 Inhalation 59
4.3.3.3 Oral |. 63
4.3.3.4 Dermal 63
4.3.3.5 Injection 63
4.3.3.6 General discussion 64
4.3.4 Reproductive Toxicity 64
4.3.4.1 Overview 64
4.3.4.2 Inhalation 65
4.3.4.3 Oral 65
4.3.4.4 Dermal 65
4.3.4.5 Injection 66
4.3.4.6 General discussion 66
vi
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Concents
4.3.5 Genotoxlcity 66
4.3.5.1 Overview 66
4.3.5.2 Human 66
4.3.5.3 Animal 67
4.3.5.4 In vitro 70
4.3.5.5 General discussion 70
4.3.6 Carcinogenicity 73
4.3.6.1 Overview 73
4.3.6.2 Inhalation 73
4.3.6.3 Oral 85
4.3.6.4 Dermal 91
4.3.6.5 General discussion 91
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL 95
5.1 OVERVIEW ". 95
5.2 PRODUCTION 95
5.3 IMPORT 96
5.4 USE 96
5.5 DISPOSAL 96
6. ENVIRONMENTAL FATE 99
6.1 OVERVIEW 99
6.2 RELEASES TO THE ENVIRONMENT 99
6.3 ENVIRONMENTAL FATE 102
6.3.1 Transport 102
6.3.2 Transformation and Degradation 103
6.3.2.1 Chemical degradation 103
6.3.2.2 Biodegradation 104
7. POTENTIAL FOR HUMAN EXPOSURE 105
7 .1 OVERVIEW 105
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 105
7.2.1 Air 105
7.2.2 Water 108
7.2.3 Soil 108
7.2.4 Other 108
7. 3 OCCUPATIONAL EXPOSURES 110
7.4 POPULATIONS AT HIGH RISK 110
8. ANALYTICAL METHODS 113
8.1 ENVIRONMENTAL MEDIA 113
8.1.1 Air 113
8.1.1.1 Sample collection and preparation 113
8.1.1.2 Methods 113
8.1.2 Water 118
8.1.2.1 Sample collection and preparation 118
8.1.2.2 Methods 118
8.1.3 Soil 118
8.1.3.1 Sample collection and preparation 118
8.1.3.2 Methods 118
8.1.4 Food 118
8.1.4.1 Sample collection and preparation 118
8.1.4.2 Methods 118
vil
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Concencs
8.2 BIOMEDICAL SAMPLES 119
8.2.1 Fluids/Exudates '.'.'.'.'.'.'.'.'.'.'.'.'...'." 119
8.2.1.1 Sample preparation 119
8.2.1.2 Methods '.'.'.'.. 119
8.2.2 Tissues 120
8.2.2.1 Sample preparation 120
8.2.2.2 Methods 120
9. REGULATORY AND ADVISORY STATUS 121
9.1 INTERNATIONAL ','.',', i2i
9. 2 NATIONAL 121
9.2.1 Regulations 121
9.2.1.1 Media-specific 121
9.2.1.2 Hazard ranking ' 121
9.2.1.3 Emission and effluent regulations 123
9.2.1.4 Consumer products regulations 124
9.2.2 Advisory Guidance 124
9.2.2.1 Media-specific '.'.'.'.'.'.'.'.'.'. 124
9.2.3 Data Analysis 125
9.2.3.1 Carcinogenic potency 125
9.3 STATE "'' 125
9.3.1 Regulations 125
9.3.1.1 Media-specific '.'.'.'.'.'.'.'.'.'.'.'. 125
9.3.2 Advisory Guidance 126
10. REFERENCES 12y
11. GLOSSARY 169
APPENDIX: PEER REVIEW 173
viii
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LIST OF FIGURES
1.1 Health effects from breathing benzene 4
1.2 Health effects from ingesting benzene 5
2.1 Effects of benzene-- inhalation exposure 9
2.2 Effects of benzene--oral exposure 10
2.3 Levels of significant exposure for benzene-- inhalation 11
2.4 Levels of significant exposure for benzene--oral 12
2.5 Correlation of urinary phenol levels and atmospheric
benzene concentrations in workers occupationally exposed
in a rubber coating plant 19
2.6 Availability of information on health effects of benzene
(human data) 23
2.7 Availability of information on health effects of benzene
(animal data) 24
4.1 Biotransformation of benzene 41
4.2 Urinary metabolites of benzene 45
ix
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LIST OF TABLES
3.1 Chemical Identity of benzene 32
3.2 Physical and chemical properties of benzene 33
4.1 Summary of results of some teratological studies on
benzene in the mouse and rabbit 61
4.2 Teratology studies on inhaled benzene in rats 62
4.3 In vivo genotoxicity studies of benzene 68
4.4 In vitro genotoxicity studies of benzene 71
4.5 Case studies of workers occupationally exposed to benzene .... 74
4.6 Epidemiological studies of workers exposed to benzene 77
4.7 Carcinogenicity review studies of occupationally
exposed workers 81
4.8 Summary of animal inhalation carcinogenicity experiments 86
4.9 Carcinogenic-related end points observed in animals
exposed to benzene by inhalation 87
4.10 Summary of animal oral/gavage carcinogenicity experiments .... 88
4.11 Carcinogenicity-related end points observed in animals
exposed to benzene by gavage 90
5.1 Disposal of petroleum industry wastes containing benzene 97
6.1 Annual emissions of benzene to air from various sources
in the United States 100
6.2 Annual emissions of benzene to water in the United States .... 100
6.3 Benzene concentrations in wastewaters 101
7.1 Benzene levels in air samples 106
7.2 Benzene levels in water samples 109
7.3 Number of employees exposed to benzene (by exposure
levels and by industry divisions) Ill
8.1 Analytical methods for measuring benzene levels in air 114
8.2 Analytical methods for measuring benzene levels
in water and soil 116
8.3 Analytical methods for measuring benzene levels in biological
samples and food 117
9.1 Regulations and advisory guidance for benzene 122
XL
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS BENZENE?
Benzene is a naturally occurring substance produced by volcanoes
and forest fires and present in many plants and animals, but benzene is
also a major industrial chemical made from coal and oil. As a pure
chemical, benzene is a clear, colorless liquid. In industry, benzene is
used to make other chemicals, as well as some types of plastics,
detergents, and pesticides. It is also a component of gasoline.
1.2 HOV MIGHT I BE EXPOSED TO BENZENE?
The three main types of exposure to benzene are environmental,
consumer product, and occupational. Without question, the greatest
possibility for high-level exposures is in the workplace. However most
people are exposed to benzene in tobacco smoke and automobile exhaust.
Benzene has been found in at least 337 of 1,177 National Priorities
List (NPL) hazardous waste sites. Other environmental sources of benzene
include gasoline (filling) stations, vehicle exhaust fumes, tobacco
smoke, underground storage tanks that leak, wastewater from industries
that use benzene, chemical spills, groundwater next to landfills
containing benzene, and possibly some food products that contain benzene
naturally. In addition, certain industries may.release benzene into the
surrounding air. These include ethylbenzene- and styrene-production
facilities, petroleum refineries, chemical manufacturing plants, and
recovery plants for coke oven by-products. People living near such
industries may be exposed to benzene in the surrounding air.
Consumer products containing benzene include glues, adhesives,
household cleaning products, paint strippers, some art supplies, tobacco
smoke, and gasoline.
Occupational exposure to benzene can occur in the rubber industry;
oil refineries; chemical plants; the shoe manufacturing industry; and
gasoline storage, shipment, and retail stations.
1.3 HOV DOES BENZENE GET INTO MY BODY?
Because benzene evaporates very quickly, the most common exposure
to benzene comes from breathing air containing benzene.
Very small amounts of benzene are found in some foods, such as
canned beef, and in contaminated drinking water.
Although benzene can enter through the skin, very few individuals
come in contact with liquid benzene, except possibly through contact
with benzene-containing products such as gasoline.
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2 Section 1
1.4 UOV CAN BENZENE AFFECT MY HEALTH?
Benzene is harmful, especially to the tissues that form blood
cells. How benzene affects your health would depend on how much you are
exposed to and how long you are exposed to it.
1.4.1 Brief Exposure at High Levels
Death may occur in humans and animals after brief oral or
inhalation exposures to high levels of benzene; however, the main
effects of these types of exposures are drowsiness, dizziness, and
headaches. These symptoms disappear after exposure stops.
1.4.2 Long-Term Exposures at Various Levels
From overwhelming human evidence and supporting animal studies,
benzene is known to be a human carcinogen. Leukemia (cancer of the
tissues that form the white blood cells) and subsequent death from
cancer have occurred in some workers exposed to benzene for periods of
less than 5 and up to 30 years. Long-term exposures to benzene may
affect normal blood production, possibly resulting in severe anemia and
internal bleeding.
In addition, human and animal studies indicate that benzene is
harmful to the immune system, increasing the chance for infections and
perhaps lowering the body's defense against tumors. Exposure to benzene
has also been linked with genetic changes in humans and animals.
Animal studies indicate that benzene has adverse effects on unborn
animals. These effects include low birth weight, delayed bone formation,
and bone marrow damage. Some of these effects occur at benzene levels as
low as 10 parts of benzene per million parts of air (ppm). Although
benzene has been reported to have harmful effects on animal
reproduction, the evidence for human reproductive effects, such as
spontaneous abortion or miscarriage, is too limited to form a clear link
with benzene.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE
BEEN EXPOSED TO BENZENE?
Benzene can be measured in the blood and the breath. The body
changes benzene to a chemical called phenol, which can be measured in
the urine. Amounts of benzene (in blood) and phenol (in urine) cannot be
used as yet to predict what degree of harmful health effects may occur.
The meaning of benzene and phenol measurements in blood and urine
should be viewed carefully for several reasons: 1) phenol occurs
naturally in urine, and urinary amounts of phenol would have to be much
higher than usual before any measurement was meaningful; 2) present test
methods are limited and raise doubts about the blood level values found
in some laboratories; 3) because smoking can raise the background level
of benzene in the blood, smoking habits must be considered when
evaluating exposure to benzene; 4) benzene disappears rapidly from the
blood and measurements may be accurate only for recent exposures;
5) average amounts of benzene found in the body have not been determined
for the general population.
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Public Health Statement 3
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
The graphs on the following pages show the relationship between
exposure to benzene and known health effects. Effects in animals are
shown on the left side, effects in humans on the right. The first
column, called "short-term exposure," refers to known health effects in
laboratory animals and humans from exposure to benzene for 14 days or
less. The second column, "long-term exposure," refers to benzene
exposures of more than 14 days.
In the first set of graphs, labeled "Health effects from breathing
benzene" (Fig. 1.1), exposure is measured in parts of benzene per
million parts of air (ppm). The number of cases of cancer that could
occur after breathing 1 ppm benzene for a lifetime has been estimated to
be 260 persons in a population of 10 thousand, or 260 thousand persons
in a population of 10 million individuals. It should be noted that these
risk values are plausible upper-limit estimates. Actual risk levels are
unlikely to be higher and may be even lower.
The levels marked on the graphs as "minimal risk for effects other
than cancer" show estimates of levels of exposure at which no adverse
effects are expected to occur. These levels are based on animal studies,
but some uncertainty still exists.
In the second set of graphs, the same relationship is shown for the
known "Health effects from ingesting benzene" (Fig. 1.2). Exposures are
measured in milligrams of benzene per kilogram of body weight (mg/kg).
Although not enough information was available to estimate health effects
from absorbing benzene through the skin, benzene is known to enter
through the skin; this does not mean there is no possibility of a
hazard.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH?
The Environmental Protection Agency (EPA) set the maximum
permissible level in drinking water at 5 parts of benzene per billion
parts of water (ppb). Because benzene can cause leukemia, EPA
established an ultimate goal of 0 ppb for benzene in drinking water and
in ambient water such as rivers and lakes. EPA realizes that this goal
may be-unattainable and has estimated how much benzene in ambient water
would be associated with one additional cancer case for every 100,000
persons (6.6 ppb benzene), one case for every 1 million persons (0.66
ppb benzene), and one case for every 10 million persons (0.066 ppb
benzene).
Although more people are exposed to benzene outside the workplace
than in the workplace, the highest levels of benzene exposures occur in
the workplace.
The National Institute for Occupational Safety and Health (NIOSH)
has recommended an occupational exposure limit in air of 0.1 part of
benzene per million parts of air (ppm). The Occupational Safety and
Health Administration's (OSHA) legally enforceable limit is an average
of 1.0 ppm over the standard 8-hour workday.
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Seccion 1
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
CONC IN
AIR
(Ppm)
EFFECTS
IN
HUMANS
EFFECTS
IN
ANIMALS
CONC IN
AIR
(ppm)
EFFECTS
IN
HUMANS
100.000
-DEATH
DEATH -
•10.000
1.000
100000
10.000
1.000
EFFECTS ON
OFFSPRING
EFFECTS ON
BLOOD-
FORMING
EFFECTS ON4-'
IMMUNE I
SYSTEM
ru
. 1
EFFECT ON
REPRODUCTION.
LEUKEMIA
0 1(
1 f DROWSINESS
i t . .« » & * j». .^
f •< HEADACHE
> [ DIZZINESS
0 1
10
BLOOD-
FORMING
ORGANS
10
01
0 01-
MINIMAL RISK
.FOR EFFECTS
OTHER THAN
CANCER
01
001
MINIMAL RISK FOR
• EFFECTS OTHER
THAN CANCER
Fig. 1.1. Healtb effects from breathing benzene.
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Public Health Statement
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS EFFECTS
IN OOSE IN
ANIMALS (mg/kg/day) HUMANS
10.
11
1
1
000
DO
I0 DEATH
3
0
EFFECTS
IN
ANIMALS
DOSE
(mg/kg/day)
10.000
1000
100
CANCER
LOW WHITE
BLOOD CELL
COUNT
I 10
01 01
Fig. 1.2. Health effects from ingesting benzene.
EFFECTS
IN
HUMANS
QUANTITATIVE DATA
WERE NOT AVAILABLE
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2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to benzene. The purpose of this section is to
present levels of significant exposure for benzene based on key
toxicological studies, epidemiological investigations, and environmental
exposure data. The information presented in this section is critically
evaluated and discussed in Sect. 4, Toxicological Data, and Sect. 7,
Potential for Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of benzene and (2) a
summarized depiction of significant exposure levels associated with
various adverse health effects. This section also includes information
on the levels of benzene that have been monitored in human fluids and
tissues and information about levels of benzene found in environmental
media and their association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt clinical findings in exposed
persons or with the identification of persons with the potential to
develop such disease may be interested in levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health officials
and project managers concerned with response actions at Superfund sites
may want information on levels of exposure associated with more subtle
effects in humans or animals (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse-Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels) are of interest to
health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies on exposure to benzene in the scientific literature and displays
these data in three-dimensional graphs consistent with the format in
Sect. 2.2. The purpose of this section is to suggest where there might
be insufficient information to establish levels of significant human
exposure. These areas will be considered by the Agency for Toxic
Substances and Disease Registry (ATSDR), EPA, and the National
Toxicology Program (NTP) of the U.S. Public Health Service in order to
develop a research agenda for benzene.
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8 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
To help public health professionals address Che needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of exposure--
inhalation, ingestion, and dermal--and then by toxicological end points
that are categorized into six general areas--lethality, systemic/target
organ toxicity, developmental toxicity, reproductive toxicity, genetic
toxicity, and carcinogenicity. The data are discussed in terras of three
exposure periods--acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type is
a "thermometer11 graph. It provides a graphical summary of the human and
animal toxicological end points (and levels of exposure) for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing NOAELs and
LOAELs reflect the actual doses (levels of exposure) used in the key
studies. No adjustments for exposure duration or intermittent exposure
protocol were made.
Adjustments reflecting the uncertainty of extrapolating animal data
to humans, intraspecies variations, and differences between experimental
vs actual human exposure conditions were considered when estimates of
levels posing minimal risk to human health were made for noncancer end
points. These minimal risk levels were derived for the most sensitive
noncancer end point for each exposure duration by applying uncertainty
factors. These levels are shown on the graphs as a broken line starting
from the actual dose (level of exposure) and ending with a concave-
curved line at its terminus. Although methods have been established to
derive these minimal risk levels (Barnes et al. 1987), shortcomings
exist in the techniques that reduce the confidence in the projected
estimates. Also shown on the graphs under the cancer end point are low-
level risks (1(T4 to 10'7) reported by EPA. In addition, the actual dose
(level of exposure) associated with the tumor incidence is plotted.
2.2.1 Key Studies and Graphical Presentations
For benzene, the "thermometer" graphs for inhalation exposure are
shown in Fig. 2.1 and those for oral exposure are shown in Fig. 2.2. The
corresponding LSE graphs are shown in Figs. 2.3 and 2.4. Data were not
found for deriving LOAELs and NOAELs based on the toxic effects of
benzene via dermal absorption.
2.2.1.1 Lethality
Inhalation. Acute lethality data in humans are limited to case
studies, mostly of victims of inhalation toxicity, in which exposure
levels are generally not known but have been estimated to be 19,000 to
20,000 ppm for 5 to 10 min (Sandmeyer 1981). These data suggest a
possible range for the LOAEL for acute lethality in humans. In the rat,
the LOAEL for an LCso value can be estimated to be 13,700 ppm for a 4-h
exposure (Drew and Fouts 1974). A slightly higher mortality rate (4/6)
has been reported for a 4-h exposure to 16,000 ppm (Smyth et al. 1962).
These data are indicative of relatively low acute toxicity.
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Health Effects Summary 9
4NIVWLS
Cpni
10000
1000
'SO")
.00000
RAT .Cw «•> COS'NUOLS
1000 -
-I
• RABBIT DEVELOPMENTAL TOXICITV \ 3 OAVS CONTINUOUS
• MOUSE LYMPWOMA 16 WEEKS INTERMITTENT
• MOUSE REPRODUCTIVE TOXIC.TV • 3 WEE
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10 Section 2
ANIMALS
(mg/kg/day)
10000 i-
1000
100
10
HUMANS
(mg/kg/day)
10000 |-
1.000
• RAT LD,
100
• RAT. CARCINOGENICITY. 103 WEEKS. INTERMITTENT
• MOUSE. CARCINOGENICITY. 103 WEEKS. INTERMITTENT
- • RAT HEMATOTOXICITY. 6 MONTHS. INTERMTTTENT
10
O RAT. HEMATOTOXICITY. 6 MONTHS. INTERMITTENT
• LOAEL IN ANIMALS A LOAEL IN HUMANS
O NOAEL IN ANIMALS
Fig. 2.2. Effects of benzene—oral exposure.
1L-
OEATH
-------
Health Effaces Summary 1L
ACUTE
(SI4 DAYS)
INTERMEDIATE
(15-364 DAYS)
DEVELOP- TARGET
LETHALITY MENTAL ORGAN
TARGET REPRO-
ORGAN CANCER DUCTION
(ppm)
100000
10.000
1.000
100
10
01
001
0001
00001
0 00001
0 000001
r
(BONE
• m MARROW)
. (CNS)
r
m (BONE MARROW) 9 m
• m
• m (BONE MARROW)
CHRONIC
(2365 DAYS)
CANCER
10~* -i
,-S-
10
10~6 ~
10
,-7-1
ESTIMATED
UPPER-BOUND
HUMAN CANCER
RISK LEVELS
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
A LOAEL FOR HUMANS
A NOAEL FOR HUMANS
r RAT
m MOUSE
n RABBIT
MINIMAL RISK
FOR EFFECTS
OTHER THAN
CANCER
Fig. 2.3. Levels of significant exposure for benzene—inhalation.
-------
12 Section 2
(mg/kg/day)
10000 i-
1.000
100
10
0 1
001
0001
00001
000001 -
0 000001 •-
ACUTE
(S14DAYS)
LETHALITY
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
A LOAEL FOR HUMANS
INTERMEDIATE
(15-364 DAYS)
TARGET ORGAN
r (BONE MARROW)
CHRONIC
(^365 DAYS)
CANCER
RAT
10-41
-5-
10
10-6-
-7-1
ESTIMATED
UPPER-BOUND
HUMAN CANCER
RISK LEVELS
10
MINIMAL RISK
FOR EFFECTS
OTHER THAN
CANCER
Fig. 2.4. Lereb of significant exposure for benzene—oral.
-------
Health Effects Summary 13
Oral. Oral lethal doses for humans have been estimated at 10 mL
(8.8 g) (Thienes and Haley 1972, as reported in Sandmeyer 1981), 9 to
12 g (Von Oettingen 1940, as reported in Sandmeyer 1981), and 30 g
(Moeschlin 1965, as reported in Sandmeyer 1981). After conversion to
milligrams per kilogram (for a 70-kg adult), a range of 128 to 428 mg/kg
can be estimated for oral lethal exposures in humans. On Figs. 2.2 and
2.4, 128 mg/kg is plotted as an estimated LOAEL for lethality in humans.
For the rat, the lowest LDSO found in the literature was 930 mg/kg; this
value is plotted on Figs. 2.2 and 2.4 as a LOAEL for LD50 in animals.
Dermal. No data were found for lethality of benzene in humans or
animals by dermal exposure.
2.2.1.2 Systemic/target organ tozicity
The most sensitive target systems for benzene toxicity are the
hematopoietic and the immune systems. The nervous system is also
important in the context of acute toxicity.
Numerous studies in animals have shown that benzene-induced bone
marrow depression is the result of damage to the pluripotential stem
cells and/or the early proliferating committed cells in either erythroid
(red cell) or myeloid (white cell) lines (Toft et al. 1982, Green et.
al. 1981). These alterations can occur during short-term exposures to
-10 ppm benzene. Similar adverse effects have also been observed in some
workers exposed to low levels of benzene for short time periods. Because
bone marrow depression is generally associated with long-term exposure,
a "sensitization phenomenon," occurring in a particularly susceptible
population, has been proposed as a possible reason for the effects
observed following low-level, short-term exposures (Aksoy et al. 1976,
Ikeda 1964). These short-term effects may also be related to the
accumulation of benzene (metabolized in the liver and in the bone
marrow) and its putative toxic metabolites in the bone marrow (Rickert
et al. 1979; Irons et al. 1980a,b)
Inhalation, acute. LOAELs and NOAELs have been derived for what
appear to be the most sensitive parameters of hematotoxicity,
immunotoxicity, and neurotoxicity.
Toft et al. (1982) exposed NMRI mice intermittently for 8 h/day,
5 days/week, for 2 weeks to benzene concentrations ranging from 1 to
200 ppm. The LOAELs in this study were 50 ppm (P £ 0.05) for decreased
bone marrow cellularity (decreased number of nucleated cells/tibia) and
21 ppm (P £ 0.05) for decreases in the number of granulopoietic stem
cells in the marrow of the tibia. With the same doses administered
continuously, the LOAEL was 21 ppm for both parameters. NOAELs were not
clear in this study.
The effects in the bone marrow are reflected in the peripheral
blood cell counts. Li et al. (1986) examined the effect of benzene and
other solvent vapors on peripheral blood leukocytes and leukocyte
alkaline phosphatase levels in female Wistar rats. The animals were
exposed to 0, 20, 50, 100, 300, 1,000, or 3,000 ppm benzene, 8 h/day for
7 days, and leukocyte enzyme activities and leukocyte counts were
determined. The leukocyte counts were depressed significantly (based on
nonoverlapping standard deviations) at 50 ppm (LOAEL) and not
-------
14 Section 2
significantly at 20 ppm (NOAEL). At 300 ppm, the enzyme levels were
significantly increased (P < 0.01) (LOAEL), and at 100 ppm the levels
were increased but not significantly (P > 0.10) (NOAEL). There were no
effects at SO ppm.
Rozen et al. (1984) observed dose-dependent depressions of
peripheral red blood cell (RBC) and lymphocyte counts in CS7B16 male
mice exposed to benzene concentrations of 0, 10.2, 31.0, 100, or 301 ppm
6 h/day for 6 days. The LOAEL for RBC depression was 100 ppm; the NOAEL
was 30 ppm. Lymphocyte counts were depressed at all levels (P < 0.05);
thus the LOAEL for lymphocyte depression was 10.2 ppm. These results are
consistent with the observation that, of the erythroid, myeloid, and
lymphoid blood cell lineages, the lymphoid line appears to be the most
sensitive to benzene toxicity (Goldstein 1977, Irons et al. 1979).
Lymphocytes play an important role in the immune response.
To measure cellular immunity in mice, a function dependent on
lymphocyte populations, Rosenthal and Snyder (1985) tested host
resistance to the bacterium Listeria aonocytogenes during 12 days
(6 h/day) of exposure to benzene. The benzene concentrations tested were
10, 30, 100, and 300 ppm. The numbers of bacteria in the host spleens
increased significantly (P s 0.05) at 30 ppm (LOAEL) or greater; there
was an effect at 10 ppm, but it was not statistically significant
(NOAEL).
Based on data presented by Gerarde (1959, 1960) and Von Oettingen
(1940, as reported in Sandmeyer 1981), Sandmeyer (1981) correlated the
signs and symptoms of acute benzene toxicity in humans via inhalation
with concentration and duration of exposure: 1.5 ppm was the olfactory
threshold; 25 ppm for 480 min had no obvious effect, even though benzene
was detectable in the blood; 50 to 150 ppm for 300 min produced
headache, dizziness, and lassitude; 500 ppm for 60 min produced
headache; 1,500 ppm for 60 min caused signs of illness; 3,000 ppm was
tolerated for 30 min to 1 h; 7,500 ppm induced signs of toxicity in
30 min to 1 h; and 19,000 to 20,000 ppm for 5 to 10 min may be fatal.
At inhalation exposures of less than 100 ppm, men and women absorb
-50% of the dose in 4 h (Nomiyama 1974a,b, both as reported in IARC
1982). However, this fraction absorbed appears to increase with
decreasing dose.
Inhalation, Intermediate. CD-I mice were exposed to 1, 10, 30, and
300 ppm benzene vapor 6 h/day, 5 days/week, for 13 weeks (Ward et al.
1985). Interim examination on day 28 of the study revealed statistically
significant (P < 0.05) hematological changes in the males and females of
the 300-ppm group. These changes included decreased erythrocyte and
leukocyte counts. Treatment-related changes were not observed at lower
concentrations. The LOAEL for these effects is, therefore, 300 ppm, the
NOAEL 30 ppm.
Inhalation, chronic. Data were not sufficient to derive LOAELs and
NOAELs.
Oral, acute. No data were found from which to derive LOAELs and
NOAELs.
-------
Health Effects Summary L5
Oral, intermediate. Wolf et al. (1956) conducted a 6-month study
in Wistar rats using benzene doses of 0, 1, 10, SO, and 100 mg/kg/day
and evaluated hematological parameters. Leukopenia was a dose-related
effect which was slight at 10 mg/kg/day and not observed at 1 mg/kg/day.
The data were not treated statistically. A LOAEL of 10 mg/kg/day and a
NOAEL of 1 mg/kg/day were identified for this study.
Oral, chronic. Data were not found from which to derive LOAELs and
NOAELs.
Dermal. No data were found for hematological effects via dermal
exposure for acute, intermediate, or chronic exposure.
2.2.1.3 Developmental toxicity
A number of investigations have evaluated the
developmental/maternal toxicity of benzene in animals. They have
demonstrated that benzene is not teratogenic but does cause maternal
toxicity and embryo/fetotoxicity, sometimes at levels as low as 10 ppm.
As will be briefly discussed in the following paragraphs, the
determination of minimal risk from current information has many
uncertainties.
Inhalation. With respect to decreased fetal weight and skeletal
variations, only the data for inhalation exposures are adequate to
determine LOAELS and NOAELS and minimal risk levels.
The study of Ungvary and Tatrai (1985) demonstrates dose-dependent
fetotoxic effects in mice exposed on days 6 to 15 of gestation and
rabbits exposed on days 7 to 20 of gestation to benzene concentrations
of 156 and 313 ppm. In both cases, exposure was continuous (24 h/day).
The LOAEL for fetal weight and skeletal variations in rabbits was
313 ppm, and the NOAEL was 156 ppm. For mice, the LOAEL is estimated Co
be 156 ppm, but lower concentrations were not tested. The study appeared
to be well conducted, but the use of only two concentrations limits the
conclusions that can be reached.
Kuna and Kapp (1981) tested three concentrations of benzene on
pregnant rats 7 h/day, during days 6 to 15 of gestation. The LOAEL for
fetal weight and skeletal variations was 50 ppm, and the NOAEL was
10 ppm. The investigators stated that the chemical showed potential, but
not statistically significant, teratogenicity at 500 ppm.
Oral. No data were found from which to derive LOAEL and NOAEL
values for oral developmental toxicity; however, Seidenberg et al.
(1986) observed reduced fetal body weights in the offspring of mice that
were given 1,300 mg/kg of benzene per day by gavage on gestation days 8
to 12. In addition, Nawrot and Staples (1979) reported an increase in
resorptlons in pregnant CD-I mice given oral doses of 0.5 or
1.0 mLAg/day (both of which were maternally toxic), but not at
0.3 mLAg/day.
Dermal. No data were found for dermal developmental toxicity.
-------
16 Section 2
2.2.1.4 Reproductive toxicity
Inhalation. Ward et al. (1985) exposed mice to benzene
concentrations of 1, 10, 30, or 300 ppm for 13 weeks. A LOAEL of 300 ppra
was noted for histopathological changes in the ovaries (bilateral cysts)
and testes (atrophy/degeneration, decrease in spermatozoa, moderate
increase in abnormal sperm forms). The NOAEL for these effects was
30 ppm. The difference between the values considered to be the NOAEL and
the LOAEL was tenfold; more closely spaced doses could reveal these
values to be closer.
Oral. Data from which to derive LOAELs and NOAELs for reproductive
toxicity by oral administration of benzene were not found.
Dermal. Data were not found for reproductive toxicity of benzene.
2.2.1.5 Carcinogenicicy
Inhalation. Benzene is considered to be a human carcinogen by EPA,
OSHA, the World Health Organization (WHO), and the International Agency
for Research on Cancer (IARC).
The EPA (1986) has reviewed the human and animal carcinogenicity
data on benzene, and this report should be consulted for data of
interest (e.g., q.* values for each of the oral and inhalation animal
studies reviewed). The following paragraph is a summary of the EPA
calculations of unit risk values for leukemia based on human
epidemiological studies. It should be noted that these values are
estimates of human risk, since the true human risk at low doses cannot
be accurately identified.
The potency of benzene has been estimated based on three separate
epidemiological studies (Rinsky et al. 1981; Ott et al. 1978; Wong et
al. 1983, as reported in EPA 1986). Giving equal weight to cumulative
dose and weighted cumulative dose, as well as relative and absolute
model forms, EPA estimated a risk value of 2.6 x 10*2 for leukemia due
to a lifetime exposure of 1 ppm benzene in the air (EPA 1986). Based on
this value, the exposure levels associated with individual lifetime
upper-bound risks of ID""*, 10*^, 10*6, an
-------
Health Effects Summary L7
In another case history, a chemical plant worker died of "acute
myelogenous leukemia" at age 51, 15 years after being exposed for an
18-month period to benzene concentrations of less than 2 ppm, time-
weighted average (TWA) (Ott et al. 1978). These two data points are
indicated in Fig. 2.3.
In animal studies it is noteworthy that, in one bioassay,
relatively short-term exposure to benzene (300 ppm for only 16 weeks)
was leukemogenic in mice 1.5 years later (Cronkite 1986). This duration
of exposure is less than that for the usual chronic carcinogenicity
bioassay, and, to indicate this fact, the data point has been placed in
the intermediate-exposure category in Fig. 2.3.
Oral. There are no oral exposure data for benzene carcinogenicity
in humans; however, the oral dose levels associated with specific
carcinogenic risks can be extrapolated by converting the risk value of
2.6 x 10'2 for an inhalation exposure of 1 ppm to 2.9 x 10'2 for an oral
exposure of 1 mg/kg/day and assuming identical levels of absorption of
benzene into the body. Using the method described in EPA (1986), the
dose levels associated with individual upper-bound estimates of risk of
10'4, 10'5, 10'6, and 10'7 have been calculated to be 3.6 x 10'3,
3.6 x 10 *4, 3.6 x 10-5. and 3.6 x 10"6 mgAg/day, respectively. (These
values are partially based upon Rinsky 1981 data. The Rinsky 1987 data
have not been evaluated by EPA.)
Rats administered benzene by gavage at doses of 25, 50, and
100 mg/kg/day for 103 weeks developed tumors of the zymbal gland and the
mouth at 50 mg/kg/day (NTP 1986). Mice treated similarly developed
lymphoma at 25 mg/kg/day. Other types of tumors observed in this study
are described in a later section.
Dermal. Data were not found for the carcinogenicity of benzene
administered by the dermal route, except for many skin painting studies
in which benzene was used as a vehicle and was negative for
carcinogenicity.
2.2.2 Biological Monitoring as a Measure of Exposure and Effects
Biological monitoring for benzene is complicated by the
difficulties in establishing precise correlations between the monitoring
end points, the equivalent exposure levels, and the ultimate toxic
effects. Most monitoring end points provide only a rough estimate of
exposure because of the potentially wide variability in background
levels. Current methods lack sensitivity at levels corresponding to
exposures below about 10 ppm (inhalation exposure). New methods would
have to be developed before biological monitoring could be used to
identify minimal effect levels.
Biological monitoring can be based on indirect indicators of
exposure as determined by measurements of benzene or benzene metabolites
in biological media, or it can be based on measurements of biological
effects induced by benzene.
2.2.2.1 Monitoring of exposure
In monitoring for benzene exposure, both selective and nonselective
end points have been used. Nonselective end points provide only a rough
-------
18 Section 2
estimate of exposure. One such nonselective test is the urinary sulfate
ratio test, which is based on the premise that with increasing exposure
there will be an increase in benzene metabolites conjugated with sulfate
moieties. Estimates of benzene exposure can be made by comparing the
ratio of inorganic to organic sulfates in the urine. Inorganic sulfate
levels amounting to 80 to 95% of total urinary sulfates are considered
normal background, 70 to 80% indicate some exposure to benzene, 60 to
70% indicate a dangerous level of exposure, and 0 to 60% indicate an
extremely hazardous exposure (Hammond and Herman 1960). Urinary sulfate
levels are, however, quite variable, and they have not been used to
identify exposure levels associated with minimal toxic effects.
As a urinary metabolite of benzene, phenol provides a more specific
indicator of exposure than do urinary sulfates. Phenol measurements have
routinely been used for monitoring occupational exposures (NIOSH 1974),
and there is evidence that urinary phenol levels can be correlated with
exposure levels (Pagnotto et al. 1961, see Fig. 2.5). Inoue et al.
(1986) reported a good correlation between occupational benzene
exposures and urinary phenol levels when expressed in terms of
creatinine excretion. The calculated mean correlation coefficient was
0.891. After reviewing the available data, NIOSH (1974) concluded that a
urinary phenol level of 75 mg/L provided a good correlation with an 8-h
TWA exposure to 10 ppm. However, according to studies reported on by
Lauwerijs (1979, as reported in van Sittert and de Jong 1985), this
exposure level corresponds to a urinary phenol level of 45 to 50 mg/L.
For exposures to 25 ppm benzene, urinary phenol levels of 100 to as high
as 200 mg/L have been reported (Sandmeyer 1981, NIOSH 1974).
Correlating urinary phenol with benzene exposure is complicated by
potentially high background levels in nonexposed persons. Lauwerijs
(1979, as reported in van Sittert and de Jong 1985) reported that
nonexposed persons had urinary phenol levels of about 20 mg/L, and in
studies cited by NIOSH (1974), levels ranging from 5 to 42 mg/L have
been measured in nonexposed persons. Because of such high background
levels, benzene exposures of 5 ppm or less would be difficult to monitor
by measuring urinary phenol levels, and consequently, correlations
between phenol levels and no-observed-effect levels (NOELS) or NOAELS
would not be possible for effects occurring in this dose range.
Preliminary results of studies in which determinations of benzene
in blood were compared with those of phenol in the urine shoved that
blood levels of benzene are more reliable for assessing both exposure
and uptake of benzene (Braier er al. 1981). However, because of the
short half-life of benzene in the blood and the observations in animal
studies that the rate of disappearance of benzene from the blood varies
according to the number of times the animal has been exposed (C. A.
Snyder et al. 1981c), blood levels of benzene may not be useful except
for recent exposures (Goldstein 1986).
Urinary phenol excretions can be increased by exogenous non-
benzene sources such as dietary protein (Folin and Denis 1915);
medicines that contain phenylsalicylate (Pepto-Bismol* and Chloraseptic*
lozenges) (Kociba et al. 1976); aspirin (Fishbeck et al. 1975); and
calamine lotion and phenol-camphor-liquid petrolatum preparations
(Ruedemann and Deichmann 1953).
-------
Health Effects Summary
19
700 -
600 -
£ 500 -
O
z
111
X
Q.
z
cc
400 -
300 -
200 -
100
SPREADERS O
SATURATORS •
CHURN MEN 9
10 20 30 40 50 60 70 80
ATMOSPHERIC BENZENE (ppm)
90
100
•According to NIOSH (1974), values given represent both phenol and parcresol. Phenol alone
would result in values lower than indicated.
Source: Pagnotto et al. 1961.
Fig. 2.5. Correlation of urinary phenol levels and atmospheric benzene concentrations in workers
occnpatioomlly exposed in a rubber coating plant.
-------
20 Section 2
Because benzene is partially excreted in expired air, breath levels
have been used as a measure of exposure. In a review of several
occupational exposure studies, NIOSH (1974) reported that the benzene
concentration in the breath was 2 ppm immediately following a 4.5-h
exposure to 25 ppm and 60 to 70 ppm following 1- to 4-h exposures to
100 ppm. In studies on humans, Hunter (1968) found that benzene could be
detected in expired air 24 h after a 100-ppm exposure and suggested that
it might be possible to back-extrapolate to the concentration in the
inspired air. However, the amount of benzene lost in expired air will
vary not only with the dose, but also with the extent of metabolism in
the body. Consequently, levels in the breath may not be proportional to
the dose.
Little data are available correlating breath levels with exposures
to very low concentrations of benzene in the air. Comparative studies of
residents in urban and rural areas have revealed higher levels of
benzene in the expired air of urban dwellers (Wester et al. 1986). For
nonsmokers, benzene breath levels were 2.5 ± 0.8 ppb in the urban area
and 1.8 ± 0.2 ppb in the rural area. However, in both cases breath
levels were higher than ambient air levels (1.4 ± 0.1 and 1.0 ± 0.1 ppb,
respectively), suggesting that other sources of exposure were occurring.
One early animal study found that a linear relationship existed
between the equilibrium concentration of benzene in the blood and the
concentration in the air (Schrenk et al. 1941). A steady-state
concentration was reached in a few hours. Because blood levels generally
decrease rapidly following exposure, monitoring would have to be
conducted during exposure. No information was found correlating effects
with blood levels. However, blood levels would be expected to provide a
more accurate assessment of internal dose and, thus, a more accurate
prediction of target organ effects than other monitoring end points.
2.2.2.2 Monitoring of effects
In addition to using benzene and benzene metabolite levels for
monitoring purposes, various biological indices might also be used to
measure low-level exposures. Monitoring of benzene workers has inr uded
monthly blood counts, with workers being removed from areas of po?. -ntial
exposure when white blood cell (WBC) counts fell below 5,000 or RBC
counts fellbelow 4.000,000 (ITII 1975). Van Sittert and de Jong (1985)
have suggested that, for some compounds such as benzene, the biological
end points of chromosomal aberrations in peripheral lymphocytes and
sister chromatid exchanges (SCEs) could be used as monitoring end
points.
2.2.3 Environmental Levels as Indicators of Exposure and Effects
2.2.3.1 Levels found in the environment
Benzene is ubiquitous in the environment, and a large segment of
the U.S. population is undoubtedly exposed, but levels are ordinarily
quite low compared with occupational exposure levels. There are no data
documenting health effects as a result of environmental exposure to
benzene, including consumption of certain foods known to contain
benzene.
-------
Health Effects Summary 21
2.2.3.2 Human exposure potential
For the majority of the U.S. population, the most likely route of
exposure to benzene is inhalation. Furthermore, there is a much greater
risk of developing health effects from occupational exposure to benzene.
The manner of benzene disposal at waste sites will determine the most
significant route of human exposure. If it is buried, then the most
likely route will be through consumption of contaminated water supplies.
Whether the benzene reaches the groundwater will depend on many factors
(e.g., groundwater depth, soil type, bacterial population, and amount of
rainfall). If benzene is disposed of in such a manner that it comes into
contact with air, inhalation then becomes an important exposure route.
Dermal absorption through contact with surface soils is not expected to
be significant, because of benzene's relatively high volatility.
Regardless of the exposure route, the most important factor
affecting toxicity is systemic absorption. Only a portion of the dose of
a chemical to which one is exposed is systemically absorbed, and unless
local irritation at the route of entry is significant, this is the
fraction of concern. Toxicity studies with benzene have shown that
pulmonary irritation is not a problem except at very high exposure
levels, and the fraction systemically absorbed as a result of inhalation
may be less than 50% of the exposure concentration. The breathing rate
can be an important factor, since more benzene will be inhaled during
heavy labor than during rest.
Because some, if not most, health effects of benzene are thought to
be due to the formation of its metabolites, its toxicokinetic pattern is
of interest. The fraction of the amount systemically absorbed that
undergoes biotransformation to reactive metabolites determines the
magnitude of the toxic response.
2.3 ADEQUACY OF DATABASE
2.3.1 Introduction
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of
significant human exposure for the substance and the
associated acute, subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and
chronic health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans."
-------
22 Section 2
This section Identifies gaps In current knowledge relevant to
developing levels of significant exposure for benzene. Such gaps are
Identified for certain health effects end points (lethality,
systemic/target organ toxicity, developmental toxiclty, reproductive
toxiclty, and carcinogenicity) reviewed In Sect. 2.2 of this profile In
developing levels of significant exposure for benzene, and for other
areas such as human biological monitoring and mechanisms of toxicity.
The present section briefly summarizes the availability of existing
human and animal data, identifies data gaps, and summarizes research in
progress that may fill such gaps.
Specific research programs for obtaining data needed to develop
levels of significant exposure for benzene will be developed by ATSDR,
NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs. 2.6 and 2.7, respectively.
The bars of full height indicate that there are data to meet at
least one of the following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or a "probable human carcinogen" by both
EPA and IARC (qualitative), and the data are sufficient to derive a
cancer potency factor (quantitative).
3. For animal carcinogenicity, a substance causes a statistically
significant number of tumors in at least one species and the data
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause this
health effect via this exposure route.
Bars of half height indicate that "some" information for the end
point exists but does not meet any of these criteria.
The absence of a column indicates that no information exists for
that end point and route.
Figures 2.6 and 2.7 summarize the adequacy of the existing database
for the end points of benzene toxicity that include lethality,
systemic/target organ toxicity, developmental toxicity, reproductive
toxicity, and carcinogenicity. Figure 2.6 represents human data;
Fig. 2.7 represents animal data. Each figure depicts the adequacy of the
available data for these effects by the inhalation, oral, and dermal
routes of exposure. The information on systemic effects is divided
according to exposure duration. Acute exposure refers to exposures
lasting 14 days or less; intermediate exposure refers to exposures
-------
HUMAN DATA
SUFFICIENT
INFORMATION*
V SOME
^INFORMATION
J
NO
INFORMATION
DERMAL
n
sr
0>
0
LETHALITY ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOOENICITY
Z . __/ TOXICITV TOXICITY
SYSTEMIC TOXICITV
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points
g. 2.6. Availability of information on health effects of benzene (human data).
-------
ANIMAL DATA
SUFFICIENT
INFORMATION'
05
r>
Q
NO
SOME
INFORMATION
NO
INFORMATION
INHALATION
DERMAL
LETHALITY
ACUTE
INTERMEDIATE
CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOGENIC!! Y
.—/ TOXICITY TOXICITY
SYSTEMIC TOXICITY
'Sufficient information exists to meet at least one of the criteria tor cancer or noncancer end points.
Fig. 2.7. Availability of information on health effects of benzene (animal data).
-------
Health Effects Summary 25
lasting 15 Co 364 days; and chronic exposure refers to exposures of
1 year or longer.
2.3.2.2 Descriptions of highlights of graphs
Figure 2.6 shows that there are no human studies that qualify as
adequate for determining NOAELs, LOAELs, and FELs for benzene.
Inhalation carcinogenicity data are considered to be adequate by the EPA
for the estimation of a unit risk. Some data exist in the area of
lethality by the inhalation and oral routes, and some data exist for
acute and chronic systemic effects by the route of inhalation; however,
these are not sufficient for establishing NOAELs, LOAELs, and FELs. No
data were available for any systemic effects resulting from dermal
exposure; no data were available for systemic, developmental,
reproductive, or carcinogenic effects resulting from oral exposure; and
no data were available for systemic (intermediate exposure),
developmental, or reproductive effects resulting from inhalation
exposure to benzene.
Figure 2.7 shows that adequate animal studies are available from
which to determine NOAELs, LOAELs, and FELs for systemic effects (acute
exposure) and developmental toxicity via inhalation and for systemic
effects (intermediate exposure) via oral exposure. Oral and inhalation
carcinogenicity data for benzene-exposed animals are adequate for
determining unit risk estimates for humans. Some data exist for
lethality by both the inhalation and oral routes, for reproductive
effects by inhalation, and for developmental toxicity via oral exposure,
but none are sufficient to determine NOAELs, LOAELs, and FELs for
noncarcinogenic effects. No data were available from which to determine
NOAELs, LOAELs, and FELs for systemic effects (acute and chronic) and
reproductive toxicity by the oral route and for systemic effects
(chronic) by inhalation. No data were available for any parameters of
toxicity induced by dermal exposure.
2.3.2.3 Summary of relevant ongoing research
The following information regarding ongoing research on benzene
toxicity was taken from the DIALOG (SSIE Current Research or Federal
Research in Progress) 1987 printouts:
B. D. Goldstein (Rutgers Medical School) will study the role of
muconaldehyde, an intermediate in benzene metabolism, in benzene
toxicity. Three isomers of muconaldehyde will be synthesized; the
recovery of muconaldehyde from biological systems will be accomplished
using chemical and analytical techniques, the possible formation of
muconaldehyde in an in vitro mouse liver microsome system will be
studied, and the toxicity of muconaldehyde will be evaluated.
0. A. Meyer et al. (National Institute of Environmental Health
Sciences) will identify methods sensitive to the neurobehavioral effects
of exposure to benzene during development and will attempt to
characterize any long-term neurobehavioral deficits following exposure
of rats to benzene during the postnatal period of development.
M. T. O'Berg (E. I. du Pont de Nemours & Company) is conducting a
retrospective cohort study of 2,000 workers exposed to benzene between
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26 Section 2
1910 and 1976. Mortality of the cohort will be compared with expectation
based on the U.S. population as well as the entire work force of the Du
Pont Company, with particular attention to cancer, especially leukemia.
Another epidemiological study of benzene-exposed workers, performed
by N. K. Weaver et al. (American Petroleum Institute), is in progress.
The study focuses on workers in petroleum operations. If primary studies
reveal excess mortality from specific diseases, especially leukemia,
further studies will be performed to determine latency periods, dose
relationships, and host factors.
S. Lamm (Tabershaw Occupational Medicine Associates) is conducting
a historical epidemiological mortality study on chemical workers
involved in the production and use of benzene within the last 30 years
to measure the risk of illness or death in the exposed, compared with an
unexposed, population.
R. Snyder et al. (Thomas Jefferson University) are currently
studying mechanisms of benzene toxicity [i.e., benzene metabolism
(disposition) in three strains of mice that have exhibited different
sensitivities to the bone marrow depressant effects of benzene, the
mechanism by which benzene inhibits cell replication in the regenerating
rat liver, and the effects of benzene and its metabolites on bone marrow
cells in culture]. R. Snyder is studying the effect of benzene on the
production of cell growth factors (hematopoietic factors).
G. F. Kalf (Thomas Jefferson University) is using an in vitro
liquid culture system to study hematopoiesis and, in particular, the
ability of the stromal microenvironment to support hematopoiesis
following exposure to benzene. From these studies the investigator may
determine whether the site of benzene toxicity is the marrow adherent
layer, whether the target cell in the adherent layer is the macrophage,
whether toxicity results from the inhibition of growth factor production,
and whether hydroquinone and p-benzoquinone represent the toxic species.
D. E. Nerland and H. E. Hurst (University of Louisville School of
Medicine) will study the effects of phenolic metabolites of benzene,
such as resorcinol, hydroquinone, and quinol. on erythropoiesis; the
immediate precursor of catechol, benzene dihydrodiol, will be tested for
bone marrow toxicity and certain pharmacokinetic properties.
D. E. Nerland will also examine benzene metabolism and toxicity in
mice, rats, and guinea pigs exposed to low levels of benzene. Alpha and
beta interferon titers will be measured in mice to help determine
whether immunotoxicity is expressed prior to hemotoxicity.
S. W. Burchiel (University of New Mexico) will use flow cytometry
and immunofluorescence to study the effects of several chemicals,
including benzene, on murine bone marrow, spleen, and peripheral blood
cells, particularly as these parameters apply to immunotoxicity.
A. C. Upton (New York University Medical Center) is conducting
studies which include development of an animal model for the
carcinogenesis of inhaled benzene or benzene in combination with known
leukemogenic agents in rats and mice.
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Health Effects Summary 27
R. Miday et al. (EPA, Cincinnati) are evaluating potential adverse
health effects in 35 persons exposed to well water contaminated with
benzene (8 ppm).
N. S. Legator (University of Texas Medical Branch at Galveston) is
conducting dominant lethal tests and cytogenetic analyses on mice
exposed to benzene by topical application or intramuscular injection
The following information regarding ongoing research on benzene
toxicity was obtained from Life Systems, Inc.:
C. A. Snyder (New York University) is investigating the hematotoxic
effects of inhaled benzene at concentrations encountered in actual
environmental settings. Low-level exposures and sensitive hematopoietic
cell assays will be used to explore: (1) the nature of the dose and
temporal responses of low benzene concentrations. (2) whether precursor
cell toxicity observed at low concentrations foreshadows more extensive
hematopoietic damage, (3) the extent to which the toxic effects produced
at low concentrations of benzene are reversible, and (4) whether benzene
toxicity will be more severe if the hematopoietic system is given
additional stress.
S. W. Burcheil (University of New Mexico) is conducting studies to
examine the effects of benzene and other toxic substances on murine,
bone marrow, spleen, and peripheral blood cells using computer-based
multiparameter flow cytometry and immunofluorescence. This will provide
significant insights into the differential effects of benzene on immune
systems.
D. Uierda (West Virginia University) is investigating the cellular
mechanisms of toxicity of benzene and benzene metabolites and bone
marrow immuno/hematopoiesis. The polyhydroxy metabolites of benzene to
be studied include benzoquinone, benzenetriol, catechol, hydroquinone,
and phenol. A primary objective is to examine the relationship between
the in vivo and in vitro effects of benzene metabolites on bone marrow
precursor cell proliferation and differentiation.
The following information regarding ongoing research in the area of
benzene carcinogenicity was obtained from Dynamac Corporation:
The Chemical Industry Institute for Toxicology (CUT) indicated in
their 1986 annual report that a joint American Petroleum Institute/CIIT
research program has been initiated to study the mechanisms of benzene-
induced leukemia in mice. Although chronic exposure to 100 ppm benzene
is believed to result in bone marrow damage and increased incidence of
leukemia in man, the significance of exposures to low levels of benzene
is not known. This study may help to clarify the relevance of the mouse
model in the assessment of human risk and may provide sensitive end
points for use as biological monitors of excess human exposure to
benzene.
The benzene metabolite hydroquinone is being tested for
carcinogenicity. The compound has been administered by gavage to rats
and mice in a 2-year NTP bioassay; currently the study is undergoing
quality assessment.
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28 Section 2
In addition to the above, other ongoing research projects on
benzene have been reported for this profile: E. P. Cronkite (Brookhaven
National Laboratory) is studying benzene leukemocarcinogenesis in mice,
and T. M. Fliedner and Seidl (University of Ulm, Federal Republic of
Germany) are studying carcinogenesis and other effects of inhaled
benzene in mice, as well as tissue distribution and excretion.
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Pharmacokineti.es and mechanisms of action
The proposed mechanisms of action for human and animal
toxicity/carcinogenicity are not fully understood on either the cellular
or molecular level; however, the subject has been studied extensively,
and several theories- have been postulated.
The database concerning absorption, distribution, metabolism, and
excretion of benzene in laboratory animals is extensive. Human data are
more limited, particularly for oral absorption, tissue distribution, and
metabolism. Additional information would be helpful in clarifying the
metabolism of benzene in bone marrow, as would pharmacokinetic data
concerning the binding of benzene metabolites to various tissues (i.e.,
how long are the metabolites bound to tissues?).
The following information regarding ongoing research on benzene
pharmacokinetics was taken from a computer printout from the DIALOG
(SSIE) (1987) database:
The percutaneous absorption of benzene will be assessed by I. H.
Blank et al. (Massachusetts General Hospital) using human cadaver
stratum corneum in vitro, human skin in vivo, and monkey skin in vivo
and in vitro.
R. E. Billings (SRI International) is studying the hepatic
formation and toxicity of catechol metabolites of aromatic compounds,
including benzene. The objective of the project is to (1) identify and
characterize the specific enzymes involved in catechol formation and
(2) examine the mechanism of catechol formation and toxicity in isolated
hepatocytes, in perfused liver, and in vivo in rabbits and mice.
The following information regarding ongoing research on benzene
pharmacokinetics was taken from a toxicological profile on benzene by
Life Systems, Inc., whose sources were the TOXLINE and CRISP databases
and the National Institutes of Health:
R. E. Peterson (University of Wisconsin) has proposed a study of
the prediction of metabolic pathways for benzene and other toxic
chemicals in rats and mice relative to the fact that there is an
inhibition of the metabolism related to the mixed-function oxidase
enzyme system.
R. Snyder (Rutgers, State University of New Jersey) is
investigating the relationship between the production of metabolites of
benzene and the epidemiology of benzene - induced bone marrow depression
and leukemia in mice, rats, and rabbits. The complete pathway of benzene
metabolism will be investigated.
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Health Effaces Summary 29
V. F. Thomas (University of Miami) will study the kinetics of
uptake, distribution, and elimination of benzene and other toxic
chemicals in man and in rats. Mathematical modeling will be used as a
tool.
In addition to the above, it has been reported that N. Abraham (New
York Medical College) is studying the metabolism of benzene.
2.3.3.2 Monitoring of human biological samples
Analytical methodologies exist for monitoring benzene levels in
expired breath and blood (see Sect. 8, Analytical Methods). These
techniques, particularly gas chromatography/mass spectrometry (GC/MS)
and gas chromatography/photoionization detection (GC/PID), have limits
of sensitivity in the sub-parts-per-billion range. However, to date,
little information is available to correlate these monitoring end points
with NOAELs or LOAELs for specific biological effects.
Urinary phenol levels have also been used as an index of benzene
exposure, particularly for occupational monitoring. At benzene levels of
5 ppm and higher, there appears to be a linear correlation between
exposure and phenol level; however, at lower exposures this correlation
can be obscured by potentially high background levels of urinary phenol
in unexposed individuals. Urinary phenol levels have not been used to
identify minimal adverse effect levels.
Biological end points can be used to monitor benzene exposures.
Blood cell counts have been used as an indicator of high occupational
exposures, but not for NOAEL or LOAEL determinations. Another biological
end point that has been suggested is chromosomal aberrations in
lymphocytes; however, quantitative data are lacking.
The following information on ongoing research on biological
monitoring for benzene exposure was obtained from searches of the SSIE
Current Research Data Base' and the Federal Research in Progress Data
Base on the DIALOG system.
W. B. Coates, N. K. Weaver, and C. R. Stack (Hazelton Laboratory,
Vienna, Virginia) are conducting 5-day acute inhalation studies on rats
and mice to validate clinical procedures to be used in later long-term
studies. The current study focuses primarily on changes in blood
chemistry that may be early indicators of benzene-induced toxicity.
D. E. Nerland (University of Louisville, Kentucky) is conducting
experiments on mice to determine whether benzene is immunotoxic.
Alpha/beta and gamma interferon titers will be quantified in animals
exposed to low concentrations of benzene. Quantification of interferon
production may provide a rapid method of screening workers exposed to
benzene.
G. A. Ansari (University of Texas, Galveston) is conducting studies
on rats and in vitro studies with human plasma to determine whether
plasma proteins (in terms of their biological activity, concentration,
and covalent modification) can be used as markers of chemical exposure.
Benzene is one of the model compounds being used in the study.
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30 Section 2
2.3.3.3 Environmental considerations
Analytical methodology. The analytical methodologies of gas
chromatography (GC) coupled with flame ionization detection (FID),
photoionization detection (PID), or mass spectrometry (MS) provide for a
sufficient level of sensitivity (0.1 ppb and below) in measuring
environmental concentrations of benzene. GC/MS provides the greatest
Level of specificity but is generally not as sensitive as GC/FID or GC/PID.
Bioavailability from environmental media. The database concerning
che bioavaliability of benzene from food and environmental media is
good. Benzene levels have been documented in food, air, soil, and water,
and human uptake from all but soil is considered very possible. Soil is
primarily an indirect source of benzene exposure via contaminated
groundwater.
Environmental transport and fate. The environmental transport and
fate of benzene are relatively well understood. Additional information
concerning the leaching of benzene from various soil types with varying
amounts of rainfall and differing microbial populations would, however,
be helpful.
Interactions with other common cocontaminants. Some studies have
been conducted on the interaction of benzene with other chemicals, both
in vivo and in the environment. Toluene, Arochlor-1254, phenobarbital,
and ethanol are known to alter the metabolism and toxicity of benzene.
These findings indicate that benzene metabolites, rather than benzene
itself, are the primary toxic agents in hematotoxicity and
immunotoxicity. Other than the reaction of benzene with active
atmospheric species, such as ozone and hydroxy radicals, reactions with
nitrogen oxides and sulfur dioxide have been investigated. Undoubtedly,
although information concerning the reaction of benzene with chemicals
other than those noted above does exist, it is unlikely that information
is available concerning the reaction with all the compounds with which
benzene will be found.
Ongoing research. No information was found concerning ongoing
research.
-------
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
The chemical formula, structure, synonyms, and identification
numbers for benzene are listed in Table 3.1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
The most important physical and chemical properties of benzene are
given in Table 3.2.
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32
Section 3
TiMeJ.l. Chemical identity of benzene
Value
References
Chemical name
Synonyms
Trade name
Chemical formula
Wiswesser line notation
Chemical structure
Benzene
Annulene. benzeen. benzen. benzm.
benzine, benzol, benzole, bicarburet
of hydrogen, carbon oil, coal naphtha.
cyclohexatnene, fenzen. mineral
naphtha, motor benzol. NCI-C55276,
nitration benzene, phene, phenyl
hydride, pyrobenzol. pyrobenzole
Polysirean
RH
I Oth C I Chem Abstr
RTECS 1986. Oiemlme
1987. Wmdholz et al
1976. HSDB 1987
IARC 1982
RTECS 1987. as reported
in HSDB 1987
c=cx
H-C C-H
\x '/
p-s
H H
Identification numbers
CAS Registry No 71-43-2
NIOSH RTECS No CY-1400000
EPA RCRA Hazardous Waste No. UOI9
OHM-TADS No 7216601
DOT/UN/NA/IMCO Shipping No Benzene 1114
STCCNo. 4908110
Hazardous Substances Data Bank No. 35
10th C I Chem Abstr
Tatken and Lewis 1983
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
-------
Chemical and Physical Information 33
Table 3.2. Physical and chemical properties of
Property
Molecular weight
Physical state
Odor
Odor threshold
Taste threshold
Melting point
Boiling point
Density"
Conversion factors
Solubility
Water
Nonaqueous solvents
Alcohol
Ether
Chloroform
Carbon disulflde
Acetone
Oils
Partition coefficient (log P)
(octanol/water)
Partition coefficient (log P)
(blood/air)
Vapor pressure
Viscosity
Heat capacity
Surface tension
Liquid-water interfacial tension
Latent heat of vaporization
Ratio of specific heats of vapor
Critical temperature
Critical pressure
Critical density
Soil adsorption coefficient (AToc)
Refractive index (nD:o)
Value
78 11
Clear colorless liquid
Rhombic prisms
Aromatic
4 68 ppm
05-45 mg/L
55'C
80 1"C at 760 mm Hg
0 8765 g/cm3
1 ppm — 3 26 mg/m3 at 20° C
1 mg/m3 — 0 31 ppm
0072%(wt/wt)at22°C
820 mg/L at 22°C
1000 mg/L at 25°C
1787 mg/L at 25°C
Miscible
Miscible
Miscible
Miscible
Miscible
Miscible
1 56-2.15
78
45 53 torr at IO°C
95 18 torr at 25°C
182.8 torr at 40.0°C
0125atmat 25°C
0.654 centipoue at 20° C
0 2499 cal/g/°C at 25°C
28 9 dyn/cm at 20° C
(0.0289 newton/m)
35 0 dyn/cm at 20°C
(00289 newton/m)
169 BTU/Ib
1061
289 5*C
48 7 atm
0 304 g/mL
0 3-100 (see Sect 22)
1 5011
References
Weast et al 1985
Windholz et al 1983
Weast et al. 1985
NFPA 1986
Weiss 1980
EPA 1975. as reported in
HSDB 1987
Weast et al 1985
Weast etal 1985
Weast etal 1985
Verschueren 1983
Jackman 1975
Chiou et al. 1977
Krasnoshchekova and Gubergnts
1975, as reported in CHEMFATE 1987
Chiou et al. 1982
Windholz et al. 1983
Windholz et al. 1983
Windholz et al. 1983
Windholz et al. 1983
Windholz et al. 1983
Windholz et al. 1983
Leo etal. 1971
Sato and Nakajuna 1979
Zwolinski and Wilhoit 1971. as
reported in CHEMFATE 1987
Thibodeaiu 1981
Jackman 1975
Jackman 1975
Weiss 1980
Weiss 1980
Weiss 1980
Weiss 1980
Jackman 1975
Jackman 1973
Jackman 1975
Rogers et al. 1980
Weast et al. 1985
-------
34 Section 3
Table 3.2 (continued)
Property
UV absorption coefficient
(in water)
Sadtler reference number
Flash point
Autoignition temperature
Flammable limits
Burning rate
Heat of combustion
Vapor-air density
Vapor volume
Evaporation rate
Evaporation halflife
(from water)
Henry's law constant
Reactivity in water
OH Radical - Rate constant
Value
7000 L/mol-cm at 200 nm
220 L/mol-cm at 255 nm
6402 (IR. prism)
1 36 (IR. grating)
1765 (UV)
3429 (NMR)
I2°F
1044-F
1 3% (lower limit)
7 1% (upper limit)
6 0 mm/mm
-17.406 Btu/lb
1 4 at 100-F
37ft3
( 1 gal evapor )
2 8 (ether - 1 )
27h
3-5 h
5.5 X I0~3 atm m3/mol
31 X I010 L/mol-s
References
Setzlcorn and Huddleston 1965
Weast et al 1979, as
reported in HSDB 1987
NF7A 1986
NFPA 1986
NFPA 1986
Weiss 1980
Weiss 1980
NFPA 1986
AAI 1980
AAI 1980
Thomas 1982
Mackay and Leinonen 1975.
Mackay and Yeun 1983
Mackay and Leinonen 1975
Anbar and Neta 1967
Halfhfe
Photodegradation in air
Reactivity in air
OH Radical • Rate constant
Halflife
O3 Radical - Rate constant
Halflife
Rate constant
Halflife
O(3P) Radical • Rate constant
078 X 1010 L/mol-s (25°C)
0 71 year
No direct photolysis; does not
absorb at 290 nm or longer
0.8 X 10~l2cm3/mcul-s(27eC)
0 13 X 10~" cm3/mcul-s (25'C)
0.114 X I0~" cm3/meul-s (2S°C)
24 5 days
0.7 X 10~22 cm3/mcul.i (24"C)
ca. 90 yean
0.7 X 10~22cm3/mcul-t(24aC)
126 yean
0.20 X I0~13 cm3/mcul-s (27"C)
Dorfman and Adams 1973, as
reported in CHEMFATE 1987
Anbar and Neta 1967
Howard and Durkin 1975. as
reported in CHEMFATE 1987
Cox et al. 1980
Gaffney and Levine 1979
Lorcaz and Zellner 1983a
Coxctal. 1980
Pitts et al. 1979
Pate et al. 1976
Hampton 1980, as
reported in CHEMFATE 1987
" Relative density Ratio of absolute density of benzene at 20°C to absolute density of water at 4°C.
Data originally reported as cm /raol-s.
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35
4. TOXICOLOGICAL DATA
4.1 OVERVIEW
Benzene is volatile and lipid-soluble and can be absorbed into che
body following ingestion, inhalation, and dermal contact. Available data
from both animal and human studies indicate that after absorption
benzene must undergo metabolic transformation to exert its toxic
effects. Metabolism of benzene occurs primarily in the liver; however,
the enzymes necessary for metabolism are also present in the bone
marrow, the putative organ of toxicity. The lymphoid system is another
target organ of benzene toxicity. It has been demonstrated
experimentally that the benzene metabolites benzene oxide, hydroquinone,
phenol, catechol, and trans,trans-mucondialdehyde can produce
hematotoxic effects. The metabolites hydroquinone, p-benzoquinone,
phenol, and catechol are known to cause lymphoid suppression.
In humans, the hematotoxicity of benzene is characterized by
pancytopenia (a decrease in various circulating blood cells), a
condition that reflects hypoplasia of the bone marrow. Some individuals
surviving bone marrow depression have developed myelogenous leukemia.
Benzene may also induce immunosuppression or sensitization.
In addition to hematotoxicity and immunotoxicity, benzene can cause
neurotoxic effects (drowsiness, dizziness, headache, vertigo, delirium.
and loss of consciousness). Animal studies indicate that benzene is noc
teratogenic, but it has caused increased incidences of resorptions,
reduced fetal weight, skeletal variations, and altered fetal
hematopoiesis. Benzene is genotoxic, causing structural and numeric
chromosome aberrations, SCEs, and induction of micronuclei; however, it
has rarely been shown to cause gene mutations. The carcinogenicity of
benzene has been demonstrated in rats and mice. Epidemiological studies
suggest that long-term low-level exposure to benzene is carcinogenic in
humans. Based on such evidence, EPA and IARC have classified benzene as
a human carcinogen (leukemogen).
4.2 TOZICOKINETICS
4.2.1 Overview
Following absorption into the body through ingestion, inhalation,
or dermal contact, benzene is widely distributed to tissues, with the
relative uptake dependent on the perfusion rate of the tissues by blood
For example, accumulation in fat is slow because of low perfusion, buc
the total potential uptake is high in these tissues because of the high
lipid solubility of benzene.
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36 Section 4
Metabolism of benzene occurs primarily in the liver, where it is
converted to benzene oxide, an unstable intermediate which forms phenol.
There is also evidence that phenol is formed from benzene by a direct
insertion mechanism without proceeding through a benzene oxide
intermediate. Other metabolites include catechol, hydroquinone, and
conjugated phenolic compounds. The primary oxidation of benzene is
catalyzed by enzymes of the cytochrome oxidase system, which occur
primarily in the liver but are also found in bone marrow.
Benzene is excreted both unchanged via the lungs and as metabolites
in the urine. Phenol and its conjugated sulfates and glucuronides are
excreted in the urine, with unconjugated phenol the major urinary
metabolite. The rate and percentage of excretion via the lungs are
dependent on exposure dose and route.
4.2.2 Absorpt ion
4.2.2.1 Inhalation
Human. Data regarding the inhalation absorption of benzene by
humans consistently suggest a lung absorption factor of about 50% for
continuous doses of 50 to 100 ppm for several hours (IARC 1982; Nomiyama
and Nomiyama 1974a,b; Sato and Nakajima 1979; R. Snyder et al. 1981;
Hunter 1968; Srbova et al. 1950). Nomiyama and Nomiyama (1974a,b)
exposed men and women to benzene at 52 to 62 ppm for 4 h and estimated
respiratory retention and uptake as a function of time during the
exposure period. Respiratory uptake (the difference between the
concentration of benzene in inhaled and exhaled air expressed as
percentage of the concentration in inhaled air) was measured at 47%,
with little difference between men and women. Respiratory retention (the
difference between respiratory uptake and excretion) was estimated at
30% of the inhaled dose. Absorption was greatest in the first 5 min and
reached a constant level somewhere between 15 min (Srbova et al. 1950)
and 3 h (Nomiyama and Nomiyama 1974a,b) of continuous exposure. Complete
saturation of body tissues and fluids may require several days (Gerarde
1963).
Animal. Inhalation studies with laboratory animals cor:inn that
benzene is rapidly absorbed through the lungs, although uptake is not
complete. Schrenk et al. (1941) found that the initial absorption of
benzene in dogs was nearly complete within 30 min, reaching an
equilibrium within several hours, and that a linear relationship existed
between the concentration in air and the equilibrium concentration in
blood.
An inhalation study with rats and mice recently presented at the
Society of Toxicology meeting (Sabourin et al. 1986) indicated that
uptake is inversely proportional to the exposure concentration. The
percentage of inhaled benzene that was absorbed and retained during a
6-h exposure period decreased from 33% to 15% in rats and from 50% to
10% in mice as the exposure concentration was increased from about 10 to
1,000 ppm.
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Toxicologies! Data 37
4.2.2.2 Oral
Human. Although definitive scientific data are not available on
oral absorption of benzene, case studies of accidental or intentional
poisoning indicate that benzene is readily and rapidly absorbed by the
oral route. Estimated oral doses ranging from 9 to 30 g have been fatal
in humans (Sandmeyer 1981). In addition, information gained from animal
studies (Parke and Williams 1953, Sabourin et al. 1986) indicates that
humans would absorb benzene with relatively high efficiency.
Animal. Benzene appears to be efficiently absorbed following oral
dosing. Parke and Williams (1953) were among the first to demonstrate
oral absorption of benzene. After ^C-labeled benzene was administered
orally to rabbits (0.34 to 0.5 g/kg), the total radioactivity eliminated
in exhaled air and urine accounted for -90% of the administered dose.
Recent data from the NTP (Sabourin et al. 1986) also indicate that
virtually all of an oral dose of benzene (0.5 to 150 mg/kg) is absorbed
by rats and mice.
4.2.2.3 Dermal
Human. Benzene can be absorbed through the skin, but the rate of
absorption is generally lower than that for inhalation exposure. No
studies were located regarding the cutaneous absorption of benzene
vapor. A recent investigation on the in vitro permeability of human skin
indicated that exposure of excised skin to benzene resulted in the
absorption of 0.17 mg/cm2 after 0.5 h and 1.92 mg/cm2 after 13.5 h
(Loden 1986). The initial absorption was in good agreement with an in
vivo study by Hanke et al. (1961), which showed that complete saturation
of a human forearm with benzene results in an hourly absorption of
0.4 mg/cm2. This rate of absorption was equal to 2% and 2 to 3% of that
of ethylbenzene and toluene, respectively (Dutkiewicz and Tyras 1967,
1968).
Franz (1984) demonstrated, in vivo, that 0.023 ± 0.022% of the
benzene applied to human skin was absorbed; the remainder of the applied
dose quickly volatilized and was lost to the atmosphere. In vitro, the
total absorption of applied benzene was 0.1% for human skin, with peak
absorption occurring at 15-40 min. Total absorption increased 10-100
times when progressively larger doses, which persisted on the skin for
up to 3 h, were applied. Thus, it appears that a major factor
controlling the percutaneous absorption of benzene is its contact time
with the skin.
Blank and McAuliffe (1985) calculated that an adult working in
ambient air containing 10 ppm benzene would absorb 7.5 /*L/h from
inhalation and 1.5 pL/h from whole-body (2 m2) exposure. They also
estimated that 100 cm2 of smooth and bare skin in contact with gasoline
containing 5% benzene would absorb 7.0 jjL/h. Blank and McAuliffe (1985)
noted that, because of the complex fate of benzene in the body, it is
difficult to relate quantitatively the amount of benzene in the body or
excreta to the amount penetrating the skin. Because of the degree of
water solubility of benzene, these authors propose that diffusion
through the stratum corneum is the rate-limiting step for dermal
absorption.
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38 Section 4
Based on skin absorption studies with mice (Susten et al. 1985),
NIOSH calculated that a worker exposed to benzene as a result of skin
contact with petroleum naphtha, a solvent commonly used in tire
manufacturing, could absorb -6 mg of benzene through intact skin. This
amount absorbed was compared with an estimated 14 mg of benzene absorbed
as a result of inhalation of 1 ppm for an 8-h day. Absorption through
abraded skin was estimated to be 5.3 times higher than through intact
skin (OSHA 1985). A similar calculation was performed by Johnson (1979,
as reported in Susten et al. 1985), based on data from a study by
Maibach and Anjo (1981) in which a rubber solvent containing 0.35%
benzene was applied repeatedly to the forearms of rhesus monkeys. From
these data, Johnson calculated that -0.4 to 0.9 mg of benzene would be
absorbed through the skin of rubber workers with one palm in contact
with the solvent 30 times a day. If Johnson had based his estimates on
contact with two palms 150 times per day as did Susten et al. (1985), 4
to 9 mg per day could be absorbed (compared to 6 mg per day calculated
by Susten et al.).
Animal. In rhesus monkeys and hairless mice, dermal absorption was
<1% following a single direct application of liquid benzene (Maibach and
Anjo 1981, Susten et al. 1985). Multiple applications as well as
application to stripped skin resulted in greater skin penetration
(Maibach and Anjo 1981). For the monkey and mini-pig, total in vivo
dermal absorptions were 0.14 and 0.09%, respectively, of the applied
dose; total in vitro absorptions were 0.19 and 0.23%, respectively
(Franz 1984). The total absorption of benzene in each of these animals
was approximately twofold higher than that of man.
4.2.3 Distribution
4.2.3.1 Inhalation
Human. An early study indicates that humans exposed to high doses
of benzene (6,000 ppm) absorb -30% into the blood; over half of the
absorbed portion is translocated into bone marrow, adipose tissue, and
liver (Ouvoir et al. 1946). Benzene is relatively insoluble in body
fluids; however, because of its high lipid solubility, it may be stored
and accumulated in fatty tissues (Sandmeyer 1981). Sato et al. (1975)
showed that the amount of body fat influences the toxicokinetics of
benzene. In experimental human inhalation exposures, the benzene
concentration in blood was consistently lower in females than in males.
Elimination was slower in females and attributed primarily to the
relatively higher fat content (Sato et al. 1975).
Tissue levels of benzene have been reported in cases of both
accidental and intentional exposure. Tauber (1970) reported levels of
0.38 mg% in blood (mg% - mg per 100 mL of blood or mg per 100 g of
tissue), 1.38 mg% in the brain, and 0.26 mg% in the liver of a worker
who died from exposure to high air concentrations of the chemical.
Autopsies from individuals who died after "sniffing" different materials
containing benzene revealed a range of concentrations in various
tissues: blood, 0.094 to 6.4 mg%; brain, 1.38 to 3.9 mg%; liver, 0.26 to
1.6 mg%; kidney, 0.55 mg%; urine 0.06 mg%; bile, 1.1 mg%; fat, 2.23 mg%;
and stomach, 1.0 mg% (Winek et al. 1967, Uinek and Collom 1971).
-------
Toxicological Data 39
Animal. A series of inhalation studies conducted with dogs
(Schrenk et al. 1941) indicate that benzene is rapidly distributed
throughout the body. Fat, bone marrow, and urine contained about 20
times the concentration of benzene in blood; benzene levels in muscles
and organs were one to three times that in blood; and RBCs contained
about twice the amount of benzene found in plasma.
Following inhalation exposure of rats to 500 ppm, benzene levels
reached a steady-state concentration within 6 h in blood (11.5 Mg/g),
bone marrow (37.7 j*g/g) , and fat (164.4 /*g/g). Lower concentrations were
found in kidney, lung, liver, brain, and spleen. Phenol, catechol, and
hydroquinone were detected in blood and bone marrow following 6 h of
exposure to benzene, with levels in bone marrow exceeding the respective
levels in blood. The levels of phenol in blood and bone marrow decreased
much more rapidly after exposure ceased than did those of catechol or
hydroquinone, suggesting the possibility of accumulation of the latter
two compounds (Rickert et al. 1979).
Sato et al. (1974) noted that benzene was stored longer and
eliminated more slowly in female and male rats with large body fat
content than in lean animals.
The relative uptake in tissues appears to be dependent on the
perfusion rate of tissues by blood. Following a 10-min inhalation
exposure of pregnant mice, benzene was found to be present in lipid-rich
tissues, such as brain and fat, and in well-perfused tissues, such as
liver and kidney. Benzene was also found in the placenta and fetuses
immediately following inhalation of benzene (Ghantous and Danielsson
1986).
C. A. Snyder (1987) notes that bioaccumulation and rates of
elimination of benzene are expected to be different from those of its
metabolites, due to differences in physical and chemical properties.
Benzene is nonpolar, neutral, and lipid soluble, while the metabolites
are polar, acidic, and water soluble. Reflecting these differences are
studies which show that the bone marrow/blood gradient for benzene in
rats and mice is 3 to 4 (Rickert et al. 1979; C. A. Snyder et al. 1977,
as reported in C.A. Snyder 1987), while that of phenol is about 0.3
(Greenlee et al. 1981). The bone marrow/blood gradient for catechol and
hydroquinone, two other benzene metabolites, is about three times
smaller than that for benzene (Greenlee et al. 1981).
4.2.3.2 Other routes of exposure
Distribution studies in humans and animals were not found for the
oral or dermal routes of exposure.
One study suggests that benzene crosses the human placenta, with
levels in cord blood equal to or greater than those measured in maternal
blood (Dowty et al. 1976).
4.2.4 Metabolism
Many of the studies elucidating the biotransformation of benzene
used routes of exposure other than inhalation, oral, and dermal. There
is no available evidence to suggest that the route of administration has
any substantial effect on the subsequent metabolism of benzene, either
-------
40 Section A
in humans or in animals. For these reasons, as well as for clarity of
the discussion, this section will not be divided into route-specific
sections.
Data regarding human metabolism of benzene have been limited to
studies that identify unmetabolized benzene in the breath and phenolic
metabolites in the urine of humans exposed by inhalation and are
discussed in the following section on excretion. Qualitatively, the
metabolism and elimination of benzene appear to be similar in humans and
laboratory animals, but no directly comparable studies are available.
Early metabolic studies with experimental animals focused on the
identification and quantitation of metabolites, while more recent
investigations have emphasized the mechanism of the initial benzene
oxidation and have characterized the reactive species responsible for
benzene-induced toxicity. The liver is the major site of benzene
metabolism; consequently much of the research has focused on this organ.
Benzene metabolism has been studied in vitro using liver homogenates,
cell supernatant fractions containing microsomes, and preparations of
microsomes. Most of the available evidence suggests that benzene
toxicity is produced by one or more metabolites rather than by benzene
itself; however, bioactivation of benzene is complex.
The metabolism of benzene initially involves its oxidation to form
hydroxylated benzenes, with phenol as the major metabolite. The enzymes
catalyzing the hydroxylation of benzene are mixed-function oxidases
which are mostly found in the liver, but also occur in bone marrow, the
target organ of benzene toxicity (C. A. Snyder 1987). Possible routes of
biotransformation are shown in Fig. 4.1.
C. A. Snyder (1987) proposes that the formation of the major
hydroxylated benzenes involves its oxidation via two concurrent
pathways, one by direct hydroxylation and the other by indirect
hydroxylation via an epoxide (benzene oxide) intermediate. The direct
oxidation of benzene is thought to be mediated by one or more free
radicals, superoxide anion, or hydrogen peroxide. In addition, an enone
(cyclohexadione) may be involved in both the direct and the indirect
hydroxylation of benzene (Hinson et al. 1985).
Further metabolic products are formed by the introduction of a
second hydroxyl group to form hydroquinone and/or catechol or a third
hydroxyl group to form 1,2,4-trihydroxybenzene or by conjugation
reactions to produce glucuronides and sulfate esters before urinary
excretion. Additionally, the hydroxylated metabolites can be oxidized to
their corresponding quinones or semiquinones (C. A. Snyder 1987). In
guinea pig microsomes, hydroquinones are products of phenol metabolism
that may be further oxidized to yield p- or o-benzoquinone (Smart and
Zannoni 1985). A minor metabolite, phenylmercapturic acid, may be formed
by enzymatic reactions of benzene oxide with glutathione (Jerina et al.
1968).
Because of the stability of the benzene ring, only a small number
of ring-opened metabolites are formed. House liver microsomes catalyze
ring opening in the presence of NADPH, producing muconaldehyde, a known
hematotoxin (Latriano et al. 1986). Small amounts of trans,trans-muconic
-------
101
MDRECT
HVDROXVLATION
OLUTATHIONE
CO2H TRANSFERASE
I
SCHaCM
I
CH3CNH
II
O
-ALANME
-OlYCME
PHENVLhCRCAPTURC ACD
101
DRECT
HVDROXYLATON
CONJUGATIONS
SULMTES ESTERS .
GLUCURONDES
ELMNATEO M URME
/ I \
DBECT • MOMECT
HVDROXVLATION
OH
/HVDROXVLATION V
t \
OH
IOI
C=C
H02C
AOD
8ULMTES.ESTERS.*
OLUCURONDES
ELMMATEO M URME
REACTIONS WITH NUCLEOPHLIC
MACROMOLECULES PROTENS DNA RNA
n
o
to
n
to
Fig. 4.1. Bioiransformation of benzene.
-------
42 Seccion 4
acid (Che corresponding diacid of muconaldehyde) were found in the urine
of rabbits and mice receiving oral doses of ^-^C-labeled benzene (Parke
and Williams 1953, Gad-el-Karim et al. 1985). The expired air of rabbits
also contained minor amounts of labeled carbon dioxide, indicating
complete benzene metabolism (Parke and Williams 1953).
• '
The liver, the repository of cytochrome enzymes thought to be
involved in the oxidation of benzene in mammalian systems, plays an
important role in the bioactivation of benzene. Sammett et al. (1979)
provided corroborative evidence for this role by showing that partial
hepatectomy of rats diminished both the rate of metabolism of benzene
and its toxicity, suggesting that a metabolite formed in the liver is
necessary for toxicity.
Benzene metabolism in bone marrow is not clearly understood.
Although bone marrow possesses a limited capacity to metabolize benzene,
it is insufficient to account for the levels of metabolites (phenol,
hydroquinone, and catechol) in this tissue. The rate of benzene
metabolism in bone marrow is lower than that in liver and is attributed
to the low level of mixed-function oxidase activity found in bone
marrow. Phenol, however, appears to be readily metabolized by bone
marrow (Irons et al. 1980a, Irons 1985).
A number of investigators have suggested that covalent binding of
benzene metabolites to cellular macromolecules is related to its
mechanism of toxicity. For example, benzene metabolites have been found
to bind to proteins in mouse liver, bone marrow, kidney, spleen, blood,
and muscle (Longacre et al. 1981a); to proteins in perfused bone marrow
preparations (Irons et al. 1980a) and in rat liver DNA (Lutz and
Schlatter 1977); and to DNA in rabbit and cat bone marrow mitochondria
(Rushmore et al. 1984). The inhibition of RNA synthesis in liver and
bone marrow mitochondria has been correlated with covalent binding of
benzene metabolites to DNA (Kalf et al. 1987.)
Benzene has been found to stimulate its own metabolism, thereby
increasing the rate of toxic metabolite formation. Pretreatment of mice
with benzene stimulated benzene metabolism by liver microsomes, while
pretreatment with phenolic metabolites did not (Dean 1978, Gonasun et
al. 1973). The rate of benzene metabolism can be altered by pretreatment
with various compounds. Benzene is metabolized largely by mixed-function
oxidases in the hepatic microsomes. Therefore, chemicals which stimulate
the activity of this enzyme system also increase the rate of benzene
metabolism. Phenobarbital pretreatment has been shown to increase the
rate of benzene metabolism by 40% in rats and 70% in mice. SKF-52SA
inhibited benzene metabolism in the rat, while toluene inhibited benzene
metabolism in both rat and mouse (R. Snyder and Kocsis 1975, Sato and
Nakajima 1979). Gonasun et al. (1973) reported that carbon monoxide,
aniline, aminopyrine, and cytochrome C metapyrene inhibit benzene
metabolism in mouse liver microsomes. Ethanol ingestion as well as
dietary factors, such as food deprivation and carbohydrate restriction,
also enhance the metabolism of benzene in rats (C.A. Snyder et al.
1981a, Sato and Nakajima 1985).
-------
Toxi.coLogi.caL Data M
4.2.5 Excretion
4.2.5.1 Inhalation
Hunan. Following inhalation exposure to benzene, humans eliminate
the compound in unchanged form in the exhaled air and in metabolized
form in urine. Estimates of the fraction of benzene excreted in the
expired air have ranged between 12 and 50% (Teisinger et al. 1952,
Srbova et al. 1950; Nomiyama and Nomiyama 1974a,b) The respiratory
elimination is described as triphasic. The initial component has a half-
life of -0.9 h, similar to the value determined in rats (Rickert ec al
1979). The second, slower phase has a half-life of 3 h, and the third
has a half-life of >15 h. No differences in respiratory elimination were
observed between men and women (Nomiyama and Nomiyama 1974a,b).
Hunter (1968) reported that the level of benzene in expired air
rapidly decreased when exposure ceased, but that benzene could be
detected up to 24 h after exposure, suggesting that it is possible to
back-extrapolate to the concentration in inspired air. However, the
amount of benzene excreted in expired air will vary not only with the
dose, but also with the extent of metabolism in the body. Consequently,
levels in the breath may not be proportional to the dose.
Urinary excretion of benzene metabolites, primarily phenol,
constitutes another important pathway for benzene elimination. Most of
the phenol is excreted in the form of sulfate esters (Teisinger et al.
1952), but significant amounts of glucuronides may be present,
especially after exposure to high concentrations of benzene (Sherwood
1972). In an inhalation study conducted by Teisinger et al. (1952),
28.8% of the absorbed benzene was excreted as phenol, 2.9% as
pyrocatechol, and 1.1% as hydroquinone. The urinary excretion was
highest within the first 24 h following exposure and was essentially
complete within 48 h, while the urinary excretion of hydroquinone was
slower, but still usually completed within 48 h.
Urinary phenol excretion has been used as an indicator of overall
benzene exposure, with urinary levels of 75 mg/L indicating an exposure
to about 10 ppm (8-h TWA) (NIOSH 1974) and 100 mg/L indicating an
exposure to 200 ppm-h (25 ppm for 8 h) (Sandmeyer 1981). Recently, Inoue
et al. (1986) measured the urinary excretion of phenol in workers
following a 7-h workshift exposure to 1 to 76.4 ppm benzene and obtained
a correlation of 0.891 between exposure level and urinary phenol
excretion.
Animal. As in humans, benzene is eliminated by expiration from the
lungs and via excretion in the urine of experimental animals. Only a
small amount is excreted in feces. Exhalation is the major route of
excretion of unmetabolized benzene (IARC 1982). A biphasic pattern of
elimination was observed in rats exposed to 500 ppm for 6 h, with half-
times for expiration of 0.7 and 13.1 h (Rickert et al. 1979). The
initial half-life of 0.7 h was similar for blood, bone marrow, and other
organs; fat, with a half-time of 1.6 h, was the only tissue that
differed markedly from blood.
The major route of excretion following a 6-h inhalation exposure of
rats and mice to various concentrations of ^-^C-benzene appeared to be
-------
44 Section 4
dependent on the Inhaled concentration (Sabourin et al. 1986). At lower
concentrations (13 to 130 ppm in rats and 11 to 130 ppm in mice), >85%
of the excreted radioactivity was identified as urinary metabolites and
<6% was in the expired air. At higher concentrations (260 or 870 ppm in
rats and 990 ppm in mice), 11 to 48% of the excreted radioactivity was
exhaled in the expired air as unmetabolized benzene, suggesting
saturation of the metabolic pathways for benzene.
4.2.5.2 Oral
Human. No studies are available.
Animal. Parke and Williams (19S3) administered radiolabeled
benzene by oral intubation to rabbits and recovered 43% of the label as
exhaled, unmetabolized benzene and 1.5% as carbon dioxide. Urinary
excretion amounted to about 35% of the dose. The isolated urinary
metabolites were mainly in the form of phenolic sulfates and glucuronides
and included phenol (23%), hydroquinone (4.8%), catechol (2.2%),
trans,trans-muconic acid (1.3%), phenylmercapturic acid (0.5%), and
1,2,4-trihydroxybenzene (0.3%). The rest of the radioactivity (5 to 10%)
remained in the tissues or was excreted in the feces. This same general
profile of urinary metabolites is also found in rats (Cornish and Ryan
1965), mice (Longacre et al. 1981a), and cats and dogs (Oehme 1969). the
chemical structures of the urinary metabolites are given in Fig. 4.2.
The effect of dose on the excretion of ^-^C-benzene administered
orally has been studied in rats and mice (Sabourin et al. 1986). At
doses of <15 mg/kg, >80% of the administered dose was excreted in the
urine of both species. As the dose was Increased from 15 to 150 mg/kg.
the amount of benzene exhaled in the breath increased to 50% of the
administered dose in rats and 71% in mice. The exhaled benzene was
largely in the form of unmetabolized benzene, again suggesting that
saturation of the metabolic pathways had occurred.
4.2.5.3 Dermal
Human. No studies are available.
Animal. No studies are available.
4.3 TOXIC ITT.
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Overview
Individual case reports of acute benzene lethalities have appeared
in the literature since the early 1900s. The benzene concentrations
encountered by the victims were not often known. However, tissue levels
of the chemical have been reported for some victims. Lethality in humans
has been tentatively attributed to asphyxiation, respiratory arrest,
central nervous system (CNS) depression, or cardiac arrhythmia.
Benzene appears to be of low acute toxicity when administered to
animals by various routes, but sudden death may occur at high
concentrations. Lethality in animals has been ascribed to ventricular
fibrillation or accelerans stimulation.
-------
Toxicological Daca
OH
PHENOL
OH
HYDROQUINONE
OH
OH
OH
CATECHOL
H02C
H
H Nc-n'C02H
\ xc-c\ *
H trans. trana-MUCONIC ACID
H
S—CH0—CH —
I
HN
COgH
PHENYLMERCAPTURIC ACID
—CH,
OH
OH
1.2.4.-TRWYDROXYBEN2ENE
OH
Fig. 4.2. Urinary metabolites of benzene.
-------
46 Section 4
4.3.1.2 Inhalation
Human (case reports). Tauber (1970) reported a case of acute
benzene toxicity in which the chemical overflowed from a tank in a light
oil loading area. Sudden death, attributed to the combination of high
air concentrations of benzene, excitement and running on the part of the
victim, and the presence of toluene in the atmosphere, occurred in a
worker exposed to the fumes. Benzene levels were 0.38 mg% in the blood,
1.38 mg% in the brain, and 0.26 mg% in the liver.
Winek and CoHorn (1971) reported three cases of accidental death
due to intentional acute exposure to benzene. One boy, who died as a
result of "sniffing" rubber cement containing benzene, had a blood level
of benzene of 0.094 mg% and a kidney level of 0.55 mg% (Winek et al.
1967). Another death occurred when a boy sniffed straight benzene. In
this case, benzene tissue levels were: 2.0 mg% in the blood, 0.06 mg% in
the urine, 1.9 mg% in the kidney, 1.6 mg% in the liver, 1.1 mg% in the
bile, 2.23 mg% in fat, 3.9 mg% in the brain, and 1.0 mg% in the stomach.
In a third victim, who was sniffing glue and accidentally shot himself
while in a euphoric state, the blood level was 6.5 mg%.
At autopsy, Winek and Collom (1971) observed inflammation of the
respiratory tract, hemorrhages of the lungs, congestion of the kidneys,
and cerebral edema, but no hematological effects, even when benzene
levels in the blood were as high as 2 mg/100 mL. The suggested causes of
death following exposure to high concentrations of benzene were
asphyxiation, respiratory arrest, CNS depression, or cardiac arrhythmia
(Winek and Collom 1971; R. Snyder and Kocsis 1975, as reported in
Andrews and Snyder 1986).
Hamilton (1922) reported on several work-related cases of lethal
acute benzene exposures, some of which occurred in spite of extensive
precautions. In two cases, rescuers died.
Based on the data of other investigators, Sandmeyer (1981)
correlated the signs and symptoms of acute benzene toxicity via
inhalation (the most common route of exposure) with concentration and
duration of exposure. Sandmeyer (1981) estimated that exposure to
benzene concentrations of 19,000 to 20,000 ppm for 5 to 10 min may be
fatal. The rapidity of death in such cases suggests that acute lethality
may be caused by benzene itself, not a metabolite.
Animal. Animal lethality data indicate that benzene is of low
acute toxicity via the respiratory route (0'Bryan and Ross 1986). An
inhalation LC50 value for rats was calculated as 13,700 ppm for a 4-h
exposure (Drew and Fouts 1974). Smyth et al. (1962) reported that 4 of 6
rats died following a 4-h exposure to 16,000 ppm benzene.
Nahum and Hoff (1934) investigated the mechanism of sudden death in
benzene toxicity. Cats and monkeys, having undergone various treatments,
were exposed to high concentrations of benzene. The intact animals
exhibited extrasystoles and ventricular tachycardia of a pre-
fibrillation type. Adrenalectomy reduced, but did not abolish, the
ventricular extrasystoles; removal of both stellate ganglia did not
reduce the frequency of ventricular rhythms. However, the ventricular
rhythms were abolished by removal of both the adrenals and the ganglia
and were restored by injections of adrenalin. Respiratory failure also
-------
Toxicological Data 47
occurred during the period when the animals were narcotized. The
Investigators concluded that benzene causes the liberation of adrenalin
and sensitizes the myocardium to its action and that death may occur
suddenly from ventricular fibrillation or accelerans stimulation or
both. Other animals died from respiratory failure.
In addition to the studies listed below, other acute lethality daca
for benzene in experimental animals have been reviewed in Sandmeyer
(1981) and IARC (1982).
4.3.1.3 Oral
Human. The lethal oral dose of benzene in humans has been
estimated at 10 mL (8.8 g) (Thienes and Haley 1972, as reported in
Sandmeyer 1981).
Lethal oral doses have produced signs and symptoms of staggering
gait, vomiting, shallow and rapid pulse, somnolence, and loss of
consciousness, followed by delirium, pneumonitis, collapse, and then
sudden CNS depression (Von Oettingen 1940, as reported in Sandmeyer
1981); more moderate doses produce dizziness, excitation, and pallor,
followed by flushing, breathlessness, headache, weakness, constriction
of the chest, and fear of impending death (Sandmeyer 1981). The victims
may experience visual disturbances and convulsions. Feelings of
excitement and euphoria may quite suddenly change to weariness, fatigue
and sleepiness, followed by coma and death (Lurie 1952, as reported in
Sandmeyer 1981). In one case, accidental ingestion of benzene may also
have induced ulceration of the gastrointestinal mucosa (Appuhn and
Goldeck 1957; Caprotti et al. 1962. both as reported in EPA 1980b).
Animal. Animal lethality data indicate that benzene is of low oral
acute toxicity (0'Bryan and Ross 1986). Oral LD50 values for rats ranged
from 0.93 to 5.96 g/kg (Cornish and Ryan 1965, as reported in IARC 1982,
Withey and Hall 1975); the values varied with age and strain of the
animals (Kimura et al. 1971, as reported in Sandmeyer 1981). In the
mouse the oral LD5Q was 4.7 g/kg (Savchenko 1967, as reported in
Sandmeyer 1981).
4.3.1.4 Dermal
No information was available regarding benzene-induced lethality in
humans or animals via dermal exposure.
4.3.2 Systemic/Target Organ Toxicity
The most significant health effects of benzene are hematotoxicity.
immunotoxicity, and neurotoxicity.
4.3.2.1 Hematotozlc ity
Overview. Humans exposed to benzene have developed marked
hypoplasia of the bone marrow with pancytopenia (a decrease in the
various cells of the circulating blood); some individuals surviving the
marrow depression have developed myelogenous leukemia.
Pancytopenia and its variations and aplastic anemia have been
detected following chronic exposure to benzene in a variety of
-------
48 Section 4
situations, primarily occupational. The case studies reviewed below
characterize the variety of hematological parameters that can be altered
in humans exposed to benzene.
In one study, pancytopenia developed in 32 workers exposed for
periods ranging from 4 months to IS years to estimated concentrations of
ISO to 650 ppm benzene. However, these and other data found in the
literature fail to establish a relationship between the extent of
exposure and effect. Only one study was found which attempted to
establish a correlation for noncarcinogenic hematotoxicity in workers
exposed to low concentrations of benzene, -20 ppm. From these data, the
investigator estimated that benzene poisoning may occur at levels of
about 10 ppm.
The hematotoxic effects observed in humans have been reproduced in
animals. Although more animal than human data are available from which
to determine low- or no-effect levels of benzene hematotoxicity, the
data show that animal responses to benzene exposure are variable and may
depend on factors such as species (differences observed in various
species may be due to inherent interspecies variability and/or
differences in exposure regimens), strain, duration of exposure, or
whether exposure is intermittent or continuous (the same concentration
of benzene is more toxic when exposure is continuous). Also, wide
variations have been observed in normal hematological parameters,
complicating statistical evaluation. However, in spite of the
variability, some consistent findings in benzene toxicity have been
noted. For example, lymphocyte levels have been depressed most severely
and in the shortest time, anemia does not occur as frequently as
lymphocytopenia, and granulocytes appear to be the most resistant of the
circulating cells in response to benzene exposure.
The experimentally induced hematological effects of benzene appear
to be the same regardless of route of administration. Leukopenias have
been reported in animals exposed subchronically via inhalation to
concentrations of 60 or 88 ppm and via oral administration of doses of
SO mg/kg. Dose responses have been demonstrated in several cases.
Numerous studies have shown that benzene-induced bone marrow
depression is the result of damage to the pluripotential stem cells
and/or the early proliferating committed cells in either the erythroid
or the myeloid lines. Pluripotent stem cell levels have been altered by
short-tern exposure to 100 ppm benzene. Other studies have demonstrated
suppression of the UBC and R£C lines.
There is general agreement among the various investigators in the
field of benzene coxicity that benzene metabolites, not benzene, are the
primary toxic agents in the induction of hemato- and immunotoxicity.
This agreement has evolved from studies in which agents known to alter
benzene metabolism (toluene, Aroclor-1254, phenobarbital, and ethanol)
have also altered benzene toxicity. Toluene, Aroclor-1254, and
phenobarbital appear to alleviate benzene toxicity, while ethanol
generally increases benzene toxicity.
The hematotoxic effects of the benzene metabolites benzene oxide,
hydroquinone, phenol, catechol, and trans,trans-mucondialdehyde have
been demonstrated experimentally.
-------
lexicological Data 49
Inhalation, human. Aksoy et al. (1972) studied 32 patients that
had been exposed to benzene concentrations estimated at 150 to 650 ppm
(based on spot measurements) for 4 months to 15 years. These individuals
exhibited severe blood dyscrasias that included pancytopenia with
hypoplastic, hyperplastic, or normoplastic bone marrow. Eight of the 32
patients died with thrombocytopenic hemorrhage and infection.
Yin et al. (1987b) conducted a study in China involving 508,818
workers exposed to benzene. Of these workers, 4.98% were exposed to
benzene alone, and 95.02% were exposed to mixtures containing mainly
benzene, toluene, and xylene. The levels of benzene detected at 95% of
the work stations ranged from 0.06 to 844 mg/m3. One and one-third
percent of the work stations had levels of >1,000 mg/m3, and 64.6% had
levels of <40 mg/m3. In the overall study, 2,676 cases of "benzene
poisoning" were found (24 aplastic anemia, 9 leukemia, and the remainder
presumably leukopenia). The prevalence rate of "benzene poisoning" was
0.94% in workers exposed to benzene alone and 0.44% in workers exposed
to mixtures. One of the major findings of the study was in the
shoemaking industry. "Benzene poisoning" was found in 28 of the 141
shoemaking factories studied (124 cases in 2,740 employees). A positive
correlation was observed for prevalence of poisoning and benzene
concentration (correlation coefficient, 0.42; P < 0.05). In one
workshop, there were four cases of aplastic anemia in 211 workers
(1.25%) exposed to benzene and chlorobutadiene (3:1) for 118.5 days to a
mean concentration of 1,035.6 mg/m3. The prevalence of benzene-induced
aplastic anemia in the shoemaking industry was about 5.8 times that in
the general population.
Findings similar to these have been reported in the literature for
other individuals or groups of individuals chronically exposed to
benzene in occupational situations. For example:
• pancytopenia has been reported in one individual with 13 years of
exposure in which bleeding was observed with a normal platelet
count; the platelets were, however, functionally and
morphologically abnormal (Favre-Gilly and Bruel 1948, as reported
in Goldstein 1977);
• 23/332 rotogravure workers exposed for 6 to 60 months to benzene
vapor concentrations of 11 to 1,069 ppm had severe hematological
abnormalities (Goldwater 1941);
• 6/217 apparently healthy workers in small shoe factories exposed to
benzene concentrations of 30 to 210 ppm for 3 months to 17 years
had pancytopenia (Aksoy et al. 1971, as reported in Goldstein
1977);
• six rotogravure printers exposed to 24 to 1,060 ppm (Erf and Rhoads
1939, as reported in Goldstein 1977) had pancytopenia. It was
suggested that bone marrow is hyperplastic early in toxicity and
hypoplastic later on;
• 1/216 workers exposed in the watch industry (Guberan and Kocher
1971, as reported in Goldstein 1977) died of aplastic anemia;
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50 Section 4
• 25/1,104 workers in a rubber factory exposed to concentrations of
up to 500 ppm (average, 100 ppm) developed severe pancytopenia; 83
others had mild hematological abnormalities (Wilson 1942, as
reported in Goldstein 1977).
Other cases are reviewed in Hamilton (1922), Aksoy et al (1976)
Goldstein (1977), and IARC (1982).
Inhalation, animal. Generally, hematotoxicity has not been
associated with acute inhalation exposure to benzene. However, the
following subacute and subchronic studies demonstrate adverse
hematological effects in animals, similar to those observed in humans.
Li et al. (1986) examined the effect of benzene and other solvent
vapors on peripheral blood alkaline phosphatase levels in female Vistar
rats. The animals were exposed to 0, 20, 50, 100, 300, 1,000, or
3,000 ppm benzene for 7 days, and enzyme activities were determined on
serum and leukocytes. Serum levels of the enzyme were unaffected by the
exposures. Leukocyte levels of alkaline phosphatase were unaffected at
20 and 50 ppm, showed a dose-dependent increase at 100 and 300 ppm
(P < 0.01), but increased no further at 1,000 or 3,000 ppm. The elevated
enzyme levels were observed following exposure to benzene, but not to
the other solvents. As the enzyme levels increased, the leukocyte levels
decreased. Both effects were alleviated by administration of toluene.
These results suggest a relationship between benzene-induced increased
enzyme levels and leukopenia.
Ward et al. (1985) demonstrated changes in the peripheral blood and
bone marrow of CD-I mice and Sprague-Oawley rats exposed subchronically
to 300 ppm benzene. Fifty male and 50 female rats per group and 150 mice
per group were exposed to 1, 10, 30, and 300 ppm benzene vapor, 6 h/day,
5 days/week, for 13 weeks and were sacrificed at various time points up
to 91 days after exposure. Hematological effects were not observed at 1,
10, or 30 ppm. At 300 ppm, however, male and female mice exhibited
significant increases (P < 0.05) in mean cell volumes and mean cell
hemoglobin values and decreases (P < 0.05) in hematocrit, hemoglobin,
RfiC count, leukocyte count, platelet count, and percentage of
lymphocytes. These changes were first observed on day 14 or day 28 and,
in the males only, persisted to the end of the study. The most common
compound-related histological findings included: myeloid hypoplasia of
the bone marrow, splenic periarteriolar lymphoid sheath depletion,
lymphoid depletion in the mesenteric lymph node, increased
extramedullary hematopoiesis in the spleen, and plasma cell infiltration
of the mandibular lymph node. All of these lesions were present at early
sacrifice time points and persisted throughout the study, increasing in
severity and incidence with time. The effects were present more often in
males than in females and were more severe in males.
In the rats, less severely affected than the mice, the major
hematological effects, statistically significant at 300 ppm (P < 0.05),
consisted of decreased leukocyte counts in males on day 14 and in
females on day 91 and decreases in percentage of lymphocytes in both
males and females on days 14 through 91. The only exposure-related
histological lesion observed was a slightly decreased femoral marrow
cellularity.
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lexicological Daca 51
Wolf et al. (1956) studied the effects of repeated inhalation
exposure to benzene on male rats. Benzene levels of 80 ppm (175
exposures for rabbits) or 88 ppm (136 exposures for rats. 193 exposures
for guinea pigs) induced leukopenia, increases in average spleen
weights, and histopathological changes in the bone marrow in the rats,
guinea pigs, and/or rabbits. Based on these results, the investigators
suggested that for humans the safe level for repeated vapor exposure to
benzene is well below 80 ppm. In addition to benzene, Wolf et al. (1956)
tested eight alkyl benzenes, including toluene, styrene, and vinyl
toluene. Of the nine, benzene appeared to be the most toxic and was the
only chemical that affected the hematopoietic system.
Other examples of characteristic hematological symptoms of benzene
poisoning and the exposures that produced them include: leukocytopenia
(100 ppm, continuous exposure for 2 days) (Gill et al. 1980);
lymphocytopenia (400 ppm. 6 h/day for 9.5 weeks) (Cronkite et al. 1982),
and in some cases granulocytopenia (4,000 ppm, 6 h/day produced "rapid"
decrease) (Gill et al. 1980) or transient granulocytosis (300 ppm,
6 h/day for 4 weeks) (C. A. Snyder et al. 1978).
Benzene - induced changes in the peripheral blood reflect injury to
the cells of the hematopoietic organs. Special assays have been
developed to detect changes in leukocytes and erythrocytes at various
stages of development; these assays have been used extensively to study
the mechanistic aspects of benzene - induced hematotoxicity.
Toft et al. (1982), using mice', demonstrated that benzene
concentrations in the range of occupational exposure levels reduced the
number of nucleated cells in marrow per tibia and the number of colony-
forming granulopoietic stem cells (CFTI-C) per tibia. Continuous exposure
to 21 ppm benzene for 4 to 10 days significantly (P < 0.05) reduced boch
parameters, and intermittent exposure (8 h/day, 5 days/week for 2 weeks)
to 21 ppm significantly (P < 0.05) reduced the CFU-C per tibia. The
results were dose dependent. Toft et al. also observed that short and
high exposures had minimal effects on the parameters studied.
Cronkite et al. (1985) demonstrated similar depression and, in
addition, recovery of the pluripotential stem cells of the bone marrow.
C57B/6 BNL mice were exposed to 10, 25, 100, 300, or 400 ppm benzene for
2 to 16 weeks. Exposure to 10 and 25 ppm for 2 weeks did not result in
adverse effects, but exposure to 100 ppm significantly reduced overall
cellularity and the number of pluripotential stem cells of the bone
marrow (P < 0.003 and P < 0.001, respectively). The peripheral blood
lymphocyte count was not affected at 10 ppm, but showed a dose-related
reduction aC the higher doses. Granulocyte levels were unaffected. Stem
cell recovery was studied in the 300-ppm exposure group. In the animals
exposed for 2 and 4 weeks the stem cell numbers had returned to control
levels by 2 weeks after exposure, those exposed for 8 weeks had
recovered by 16 weeks, and those exposed for 16 weeks had recovered
incompletely to 92% of control values by 25 weeks. Lymphocyte levels in
the peripheral blood of all exposure groups (300 ppm) eventually
recovered to normal. The animals began dying about 9 months after
exposure, mainly of thymic and nonthymic lymphomas.
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52 Section 4
Other investigators have demonstrated similar pluripotential stem
cell depletions in mice (Gill et al. 1980, Green et al. 1981b, C. A.
Snyder et al. 1981b, Cronkite et al. 1982), as well as reductions in the
granulocyte/macrophage progenitor cells (Green et al. 1981b, C. A.
Snyder et al. 1981b). The benzene metabolites benzene dihydrodiol,
hydroquinone, and phenol'did not affect bone marrow cellularity or
progenitor cell (CFU-C) numbers as severely as did benzene (Tunek et al
1981).
In studies on the erythroid cell line, Longacre et al. (1981b)
demonstrated 60 to 80% decreases in the incorporation of 59Fe into the
bone marrow precursors in mice injected subcutaneously with 6 to 20
doses of 440 or 880 mg/kg benzene. The effect was dose related. Bolcsak
and Nerland (1983) also demonstrated that benzene and, to a lesser
extent, its metabolites phenol, catechol, and hydroquinone significantly
decreased 59Fe incorporation into developing erythrocytes. Baarson et
al. (1984) and Valle-Paul and Snyder (1986) demonstrated that repeated
exposures to 10 ppm benzene reduce the progenitor red cells (CFTJ-E) in
mice.
Oral, human. No data were found for benzene-induced hematotoxicicy
in humans exposed by the oral route.
Oral, animal. Wolf et al. (1956) reported dose-related
hematological effects in female rats administered repeated oral doses of
benzene. Doses of 1, 10, 50, and 100 mg/kg/day were administered via
oral intubation for -26 weeks. Olive-oil-treated rats served as vehicle
controls. Leukopenia and erythrocytopenia were observed at the two
highest doses, slight leukopenia was observed at the 10-mg/kg dose, and
there was no effect at the 1-mg/kg dose.
Similar results were reported in a more recent oral study (NTP
1986). F344/N rats and B6C3F1 mice received doses of 0, 25, 50, 100,
200, 400, or 600 mg/kg in corn oil for 17 weeks (NTP 1986). The rats
exhibited dose-related leukopenia, lymphoid depletion in the spleen at
200 mg/kg, and increased extramedullary hematopoiesis in the spleen at
600 mg/kg (120 days of exposure). Mice in the 400- and 600-mg/kg groups
had a dose-related leukopenia.
As in subchronic studies, oral administration of benzene to
C57BL/6N mice and F344 rats at doses of 0, 50, 100, or 200 mg/kg,
5 days/week, for 103 weeks resulted in dose-related lymphocytopenia and
leukocytopenia in both species (NTP 1986). The mice, in addition, had
lymphoid depletion of the splenic follicles and thymus and hyperplasia
of the bone marrow.
Dermal, human. No data were found regarding hematotoxicity in
humans exposed dermally to benzene.
Dermal, animal. No data were found regarding hematotoxicity in
animals exposed dermally to benzene.
General discussion. Hematotoxicity is not a significant concern in
cases of acute exposure to benzene. However, in light of the serious
nononcogenic and oncogenic hematopoietic effects observed in humans
exposed subchronically and chronically to the chemical, numerous
experimental studies have focused on the bone marrow.
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Toxicological Data 53
Because of a paucity of data on the relationship between exposure
and effect in human studies and the variety of conditions under which
exposure occurs, it is difficult to determine from the literature the
lowest dose at which adverse effects can be observed in humans. However,
Chang (1972) studied 119 workers exposed to benzene concentrations of
-20 ppm and related'henratological changes to concentration and duration
of exposure. From these data he has suggested that benzene poisoning may
occur at levels as low as 10.1 ppm. American Conference of Governmental
Industrial Hygienists (ACGIH) estimates, however, are higher.
The progression and consequences of benzene-induced pancytopenias
are very similar to those of idiopathic aplastic anemia (Goldstein
1977). Three possible exceptions to this are fairly high incidences of
bone marrow hyperplasia, lymphocytopenia, and macrocytosis that have
been observed in benzene anemia, but not in idiopathic anemia.
The benzene-induced cytopenias, which can occur as a group or in
various combinations, may be related to specific adverse health effects.
For example, a decrease in circulating granulocytes diminishes the
bodily defenses against infections; this may account for the fact that
many victims of benzene toxicity have died from infections (Goldstein
1977). Thrombocytopenia, another cause of death in benzene poisoning,
induces capillary fragility, petechiae, subcutaneous bleeding
(bruising), or frank bleeding. Lymphocytopenia and eosinophilia, which
may be related to alterations in immune function, have been reported in
some cases.
Evidence is accumulating for a positive association between
pancytopenia or aplastic anemia and later development of leukemia.
Vigliani and Saita (1964) described 13 cases of "benzene leukemia," of
which 9 were hemocytoblastic (or myeloblastic), 1 was chronic myeloid, 2
were erythremia, and 1 was erythroleukemia. In all cases in which a long
and severe exposure to benzene could be established, the leukemia was
hemocytoblastic in type, frequently preceded by aplastic anemia with
leukopenia. Aksoy and Erdem (1978) followed 44 benzene-exposed patients
with pancytopenia. The workers had been exposed to high concentrations
of benzene (ISO to 650 ppm) for 4 months to 15 years. Leukemia (the type
was not described) developed in six of them within 6 years of follow-up.
Other evidence of a relationship between pancytopenia and leukemia has
been reported (Hernberg et al. 1966, Vigliani and Forni 1976, and Aksoy
1981, all as reported in C. A. Snyder 1987; DeGowin 1963; Aksoy et al.
1976). According to Aksoy (1978), aplastic anemia is detected in
subjects generally while they are still exposed to high concentrations
of benzene; leukemia may occur at the same time or shortly after
exposure has ceased; however, in a few cases, the latency period between
exposure and the onset of leukemia has been long.
The potential mechanisms for the development of pancytopenia in
humans include the destruction of bone marrow stem cells, the impairment
of the differentiation of these cells, or the destruction of more mature
hematopoietic cell precursors and circulating cells (Goldstein 1977).
Pancytopenia can also result from the combined destruction of the
peripheral blood and bone marrow elements. These mechanisms have been
explored in animal experiments.
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54 Section 4
The role of che microenvironment In the depression of the colony-
forming units of the bone marrow has also been investigated. There is
limited evidence that the stromal cells, particularly macrophages, may
be targets for benzene - induced myelosuppression (Kalf et al. 1987). This
was suggested by the results of an acute study by Frash et al. (1976),
in which the colony-forming potential of bone marrow cells was not
affected when the cells were incubated with benzene prior to injection
into a host animal, but was decreased when benzene was injected into
lethally irradiated recipients after the normal bone marrow cells were
injected. Gaido and Wierda (1984) demonstrated that benzene metabolites,
particularly hydroquinone and benzoquinone, were toxic to stromal cells
in vitro and that the stromal toxicity resulted in impaired
granulocyte/monocyte colony formation.
Several molecular mechanisms for myelotoxicity have been proposed.
These include suppression of RNA and DNA synthesis (Post et al. 1985,
Moeschlin and Speck 1967), alkylation of cellular sulfhydryl groups
(Irons 1985), disruption of the cell cycle (R. Snyder et al. 1981, Irons
et al. 1979), oxygen activation (or free radical formation) (Irons
1985), and covalent binding of benzene metabolites to cellular
macromolecules (R. Snyder et al. 1978, Gill and Ahmed 1981, Longacre et
al. 1981a).
Previous sections in this report have demonstrated that benzene and
its metabolites localize in the bone marrow and that the metabolites are
responsible for various hematotoxic effects. When several of the
metabolites of benzene were compared with the parent compound in
hematotoxicity studies, the metabolites were less toxic than benzene.
Tunek et al. (1981) suggested that perhaps the metabolites tested may
conjugate strongly in the liver and other organs and may not reach the
bone marrow in amounts sufficient to produce the expected effect. On the
other hand, one metabolite of benzene, Crans.Crans-muconaldehyde (LD5Q,
6.7 to 7.1 mg/kg). was highly toxic to mice when administered at the
dose of 2 mg/kgi intraperitoneally, for 10 to 16 days (Witz et al.
1985). The treatment resulted in a statistically significant decrease in
RBC count, hematocrit, hemoglobin, bone marrow cellularity, and hepatic
total and free sulfhydryl content. There was a dramatic increase in UBC
and spleen weights at 16 days.
It has, also been shown that agents that alter benzene metabolism
also modify benzene toxicity. Ethanol, which accelerates the
hydroxylation of benzene and transforms phenol into highly toxic
metabolites (Sato et al. 1980, Nakajima et al. 1985), has increased the
severity of benzene-induced anemia, lymphocytopenia, and reduction in
bone marrow cellularity and has produced transient increase in
normoblasts in the peripheral blood and atypical cellular morphology
(C. A. Snyder et al. 1981a, Baarson et al. 1982, Nakajima et al. 1985).
The modulating effects of ethanol are dose dependent (Sato et al. 1981).
The enhancement of the hematotoxic effects of benzene by ethanol is of
particular concern for benzene-exposed workers who consume alcohol.
4.3.2.2 Imaunotoxicity
Overview. Lymphocytes play an important role in the immune
response. Benzene - induced hematotoxicity involves the erythroid,
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lexicological Data 55
myelold, and lymphold lineages, of which Che lymphoid line appears co be
the most sensitive. Some of the manifestations of benzene-induced
immunotoxicity are reviewed in the following sections.
Alterations in serum immunoglobulins and complement levels and
indications of benzene-induced autoImmunity and allergy have been
observed in benzene-exposed workers. Animal studies support the findings
of immune dysfunction in humans and further define the various
parameters of the immune response that are altered in response to
benzene exposure. These studies show that the components responsible for
antibody production (B-cells) and those responsible for cell-mediated
immunity (T-cells) are significantly depressed by benzene concentrations
as low as 10 ppm, depending on the parameter measured. Impaired cell-
mediated immunity results in decreased resistance to infectious agents
and to transplanted tumor cells.
Inhalation, human. Altered serum immunoglobulins and complement
levels have been found in workers exposed to benzene and other solvents
(Lange et al. 1973a,b; Roth et al. 1972; Smolik et al. 1973, all as
reported in Goldstein 1977). Renova (1962, as reported in Goldstein
1977) detected antibodies against leukocytes, platelets, and red cells
in the sera of chronically exposed workers.
Symptoms of immune stimulation (allergy) have been reported in
workers chronically exposed to benzene. For example, eosinophilia, an
indication of an allergic response, has been noted by several
investigators (Aksoy et al. 1971, Hernberg et al. 1966, Bernard and
Basset 1946, Blaney 1950, Duvoir and Derobert 1942, all as reported in
Goldstein 1977). Lange et al. (1973a, as reported in Goldstein 1977)
reported a positive leukocyte autoagglutinin test associated with
decreased granulocyte levels, suggestive of allergic blood dyscrasia.
Roth et al. (1973, as reported in Goldstein 1977) emphasized the role of
reticulosis and autoimmune phenomena in the pathogenesis of bone marrow
damage.
Inhalation, animal. Rozen et al. (1984) demonstrated in a dose-
response study that short-term inhalation exposure (6 h/day for 6 days)
to benzene at near occupational exposure levels significantly depressed
the proliferative responses of bone-marrow-derived B-cells and splenic
T-cells. CS7B1 mice were exposed to benzene concentrations of 0, 10, 30.
100, or 300 ppm. The lipopolysaccharide-induced B-lymphocyte
proliferative response was depressed (P £ O.OS) at 10 ppm, and the
phytohemagglutinin (PHA)-induced T-cell response was depressed
(P £ O.OS) at 31 ppm, without causing a significant concomitant
depression in the numbers of T- or B-cells. Peripheral lymphocyte counts
were depressed at all levels, but erythrocyte counts were depressed only
at 100 and 300 ppm.
Following the exposure regimen that previously had induced thymic
lymphoma in mice, Rozen and Snyder (198S) then demonstrated that benzene
concentrations of 300 ppm 6 h/day for 115 exposures reduced the
abilities of T- and B-cells to respond to mitogenic stimuli and markedly
reduced the numbers of B-lymphocytes in the bone marrow and spleen and
the number of T-lymphocytes in the thymus and spleen (Rozen and Snyder
1985). In addition, a compensatory proliferation was observed in cells
of the bone marrow and thymus in response to the benzene exposures.
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56 Section 4
Benzene suppressed the primary antibody response to fluid tetanus
toxoid (FTT) by 74 to 89% in Swiss albino mice exposed to 400 ppm of the
chemical 6 h/day for 5, 12, or 22 exposures (Stoner et al. 1981).
Similar exposure to adsorbed tetanus toxoid (APTT) for 5, 12, or 22 days
also suppressed the primary response, by 8, 36. and 85%, respectively.
Significant suppression of the responses to both antigens was also seen
with exposures to 200 ppm benzene for 10 to 20 days, but no significant
effect was seen at 50 ppm. At benzene concentrations of 50, 200, or
400 ppm, the secondary antibody response to tetanus antitoxin was
unaffected. The investigators concluded that the threshold dose for
repression of the primary antitoxin responses is between 50 and 200 ppm
inhaled benzene.
Rosenthal and Snyder (1985) studied the effect of subacute exposure
to benzene on cell-mediated immunity by measuring host resistance to
infectious agents. Mice were exposed to benzene concentrations of 10,
30, 100, and 300 ppm for either 5 days prior to (preexposure regimen) or
5 days prior to and 7 days during (continuous exposure regimen)
infection with Lisceria monocycogenes. On days 1, 4, and 7 of infection,
splenic bacterial counts were made, and T- and B-lymphocytes were
enumerated by a direct immunofluorescence technique. These results were
compared with those of appropriate air controls.
Preexposure to the benzene concentration of 300 ppm resulted in
increased bacterial numbers (730% of controls) on day 4. Lower
concentrations of benzene had no such effect. Continuous exposure, on
the other hand, produced increased bacterial counts in the spleen on
day 4 at all but the 10-ppm concentration. Concentrations of 30, 100,
and 300 ppm increased the bacterial counts to 490, 750, and 720% of
controls, respectively. Bacterial counts were not increased on days 1
and 7 at any benzene concentration for both exposure regimens,
indicating recovery of the immune response at day 7. This indicates a
delay in the cell-mediated immune response. In addition, a
concentration-dependent depression was noted in T- and B-lymphocyte
populations (P £ 0.05 at £30 ppm). B-cells were more sensitive to
benzene than were T-cells on a percentage of control basis.
Rosenthal and Snyder (1986) tested another parameter of cell-
mediated immunity, that of tumor resistance. Male C57B6J mice were
exposed to 100 ppm benzene (6 h/day, 5 days/week, for 20 exposures) and
were then injected with cells from a virus-induced tumor. Ninety percent
of the benzene-treated mice developed lethal tumors, in comparison with
only 30% of the non-benzene-treated controls.
Other routes of exposure. No data were found to document
immunetoxicity in humans or animals exposed orally, or by dermal
application, to benzene.
The various parameters and mechanisms of benzene immunotoxicity
have been investigated in animals injected with the chemical
subcutaneously and intraperitoneally, as well as in in vitro
experiments. These Important studies support the results of inhalation
studies in demonstrating that (1) benzene depresses antibody formation
in mouse spleen cells, reflecting alterations in spleen cell function
(Vierda et al. 1981); (2) benzene produces a selective reduction in the
number of B-lymphocytes in the circulating blood of rabbits (Irons and
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lexicological Data 57 -
Moore 1980); and (3) metabolites of benzene (catechol, hydroquinone,
1.2,4-benzotriol, and benzoquinone) are cytotoxic to spleen cells,
reduce the number of progenitor cells from the spleen and bone marrow,
and/or suppress T- and B-lymphocyte mitogen responses (Wierda and Irons
1981, Wierda et al. 1980, both as reported in Vierda et al. 1981; Irons
et al. 1981; Pfeifer and Irons 1981).
General discussion. The immune system, a complex and widespread
organization of organs and cells, is responsible for allergic reactions,
tumor immunity, host-graft reactions, immunological tolerance, the
defense of the body against microbial infections, and the pathogenesis
of various occupational disorders of the lung and skin. Injury to the
immune system can have serious health consequences.
An important function of the immune system is the immunosurveillance
of carcinogenesis, in which lymphocytes are thought to play an important
role. Goldstein (1977) and Leong (1977) postulated that benzene
leukemogenesis could be a result of the impairment of this mechanism.
Rozen and Snyder (1985) observed a compensatory proliferative
response of the cells of the bone marrow and thymus of animals following
6 months exposure to benzene at a concentration that had previously
produced thymic lymphoma in mice. The investigators suggested that the
response may play a role in benzene carcinogenicity.
Suppression of cell growth and function in the lymphoid system, as
in the bone marrow, correlates with the concentrations of hydroquinone
and catechol which accumulate in lymphoid tissue following exposure to
benzene (Greenlee and Irons 1981, Greenlee et al. 1981, Irons et al.
1980b, Wierda and Irons 1982). Hydroquinone, p-benzoquinone, phenol, and
catechol also suppress microtubule assembly and progenitor cells (Kalf
et al. 1987).
The suppression of phytohemagglutinin-stimulated lymphocyte
activation by the metabolites of benzene may be mediated through the
inhibition of microtubule function; the inactivation correlates with the
ability of the metabolites to undergo sulfhydryl-dependent autooxidation
(Irons et al. 1981, Pfeifer and Irons 1981). Irons and Neptun (1980) and
Irons et al. (1981) suggested that hydroquinone or its terminal
oxidation product, p-benzoquinone, may be responsible for these effects.
4.3.2.3 Neurotoxicity
Inhalation, human. Following acute inhalation of benzene,
individuals exhibit symptoms indicative of CNS toxicity (Sandmeyer
1981). These include drowsiness, dizziness, headache, vertigo, and
delirium and perhaps loss of consciousness. Symptoms are similar in
lethal and nonlethal exposures (EPA 1980b). The neurological effects of
benzene are thought to be direct effects of benzene rather than its
metabolites (Bergman 1979, as reported in Dempster et al. 1984).
At low chronic exposure levels, workers have experienced symptoms
of CNS lesions [i.e, dizziness when cold water is placed in the ear and
impairment of hearing (Brzecki et al. 1973, as reported in Sandmeyer
1981)]. Workers exposed to benzene in combination with other chemicals
exhibited asthenoneurotic or astheno-vegetative polyneuritis, sometimes
associated with neuronal progression, even after exposure had ceased
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58 Section 4
(Drogichina et al. 1971, as reported in Sandmeyer 1981). it is possible,
however, that CNS involvement in benzene toxicity is generally masked by
other, more visible, effects (Sandmeyer 1981).
Inhalation, animal. Disturbed neuronal transport characteristics
have been noted in animals following acute inhalation of benzene (Jonek
et al. 1965, as reported in Sandmeyer 1981).
Rabbits exposed to -45,000 ppm benzene exhibited light narcosis
(relaxation) after 3.7 min of exposure; tremors, chewing, excitement,
and running movements after 5 min; loss of pupillary reflex to strong
light after 6.5 min; loss of blink reflex to tactual stimulus after
11.4 min; pupillary contraction after 12 min; involuntary blinking after
15.6 min; and death after 36.2 min (Carpenter et al. 1944).
Dempster et al. (1984) demonstrated behavioral disturbances,
characterized by increased milk-licking, in mice exposed to benzene
concentrations of 100 ppm after 1 day of exposure and to 300 ppm after
5 days of exposure. Less sensitive parameters, home-cage food intake and
hind-limb grip strength, were reduced only at 1,000 and 3,000 ppm. The
mice were exposed to concentrations of 100, 300, 1,000, and 3,000 ppm
6 h/day for the number of days necessary to reach a minimum
concentration x time product of 3,000 ppm-days. The milk-licking change
occurred at the same time as hematological changes, suggesting that the
behavioral change may be mediated by the metabolites of benzene, as are
hematological changes.
Other routes of exposure. Geist et al. (1983) demonstrated
learning deficits in Sprague-Dawley rats given oral doses of 550 mgAg
benzene. No data were found demonstrating neurological effects in humans
or animals exposed to benzene via the dermal route. However, CNS effects
have been reported in animals following intravenous injection (Braier
and Francone 1950, as reported in Sandmeyer 1981).
General discussion. The neurotoxicity of benzene has not been
studied extensively. The most obvious effects that occur following acute
exposure to very high concentrations are fairly well documented, but the
more subtle effects that might occur from chronic exposure to low
concentrations may be masked by or overlooked because of the alterations
that take place in the hematopoietic system.
4.3.2.4 Dermal toxicity
Wolf et al. (1956) reported that benzene was slightly to moderately
irritating to the skin of rabbits and caused moderate necrosis. Ten to
20 applications of the undiluted chemical to the ear (method of Adams et
al. 1941, as reported in Wolf et al. 1956) produced erythema, edema,
exfoliation, and blistering.
4.3.2.5 Ocular toxicity
Wolf et al. (1956) tested benzene for irritation in the rabbit eye.
Two drops of the undiluted material caused moderate conjunctival
Irritation and very slight, transient corneal injury. There were very
small areas of superficial necrosis in the cornea.
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lexicological Data 59
Information was not found for benzene toxicity in other major organ
systems.
4.3.3 Developmental Toxicity
4.3.3.1 Overview
Although there is little information on the developmental toxicity
of benzene in humans, benzene has been shown to be embryo/fetotoxic in
animals, as evidenced by increased incidences of resorptions, reduced
fetal weight, skeletal variations, and altered fetal hematopoiesis.
However, benzene has not been shown to be teratogenic or embryolethal in
test animals even at levels causing toxicity to the mother, as evidenced
by reduced weight gain. Humans are most often exposed to benzene by
inhalation. This route of exposure has therefore been used in
developmental animal research more than other routes, with the rat as
the most common test animal.
4.3.3.2 Inhalation
Human. Benzene crosses the human placenta and is present in the
cord blood in amounts equal to those in maternal blood (Dowty et al.
1976). In a study of subjects with known benzene poisoning in Italy,
Forni et al. (1971b) report the case of one pregnant worker exposed to
benzene during her entire pregnancy. Although she had severe
pancytopenia and increased chromosomal aberrations, she delivered a
healthy boy with no evidence of chromosomal alterations. The following
year she delivered a normal daughter. Sometimes a normal infant survives
when the mother dies at parturition of severe anemia caused by benzene
(Messerschmitt 1972) . An increased frequency of chromatid and
isochromatid breaks and SCE was found in lymphocytes from 14 children of
female workers exposed to benzene and other organic solvents during
pregnancy (Funes-Cravioto et al. 1977). No mention was made of physical
abnormalities among the offspring. Holmberg (1979) reported the
occurrence of congenital CNS defects in children of 14 mothers exposed
to organic solvents during the first trimester of pregnancy. Only one of
these women was exposed to benzene, and she gave birth to a stillborn
anencephalic fetus; however, she was also exposed to other solvents.
Epidemiological studies of pregnant women occupationally exposed to
undefined organic solvents found no effect on birth weight (Olsen
1983a), on frequency of malformations (Olsen 1983b), or on rates of
perinatal death or malformations (Axelsson et al. 1984). In a study
conducted in the Love Canal area by Heath (1983), the outcome of
pregnancy was evaluated in populations living in the proximity of waste
dumps in which benzene had been identified. No clear increased
occurrence of abortion, birth defects, or low infant birth weight was
observed in women living next to the canal. In a study by Budnick et al
(1984), no statistically significant clusters of birth defects were
found when analyzing data from Drake Superfund Site, Pennsylvania, an
area contaminated with benzene and other carcinogens.
Animal. The many studies of exposure by inhalation during
pregnancy have shown that benzene is not teratogenic, even when the
mother and offspring show signs of toxicity. Fetotoxicity is evidenced
by decreased weight and by an increase in skeletal variants such as
-------
60 Section 4
missing sternebrae and extra ribs, which are not considered to be
malformations (Kimmel and Wilson 1973). Mouse and rabbit studies are
summarized in Table 4.1; rat studies are summarized in Table 4.2.
Murray ec al. (1979) exposed mice to 500 ppm benzene for 7 h/day on
days 6 to 15 of pregnancy and observed growth retardation and increased
skeletal variants but no malformations in fetuses and no significant
effect on incidence of pregnancy, average number of live fetuses, or
resorptions per litter. Similar results were found in rabbits exposed to
the same level. Ungvary and Tatrai (1985) exposed pregnant mice to 500
or 1,000 mg/m3 (157 or 313 ppm) benzene on days 7 to 20 of gestation and
noted a significant fetal weight retardation but no malformations.
Alterations in hematopoiesis have been observed in the fetuses and
offspring-of pregnant mice exposed to benzene (Keller and Snyder 1986).
Administration of 5, 10, or 20 ppm benzene by inhalation to pregnant
Swiss Webster mice for 6 h/day on days 6 to 15 of gestation caused
marked changes in the numbers of erythroid colony-forming cells of the
progeny. Granulocytic colony-forming cells were affected by the two
higher exposure concentrations. Some of the mice exposed prenatally were
allowed to macure and were reexposed. Their hematopoietic progenitor
cell numbers were depressed compared with controls exposed for the first
time as adults. Other hematopoietic end points were affected in a
previous study (Keller et al. 1985), where pregnant mice were exposed to
only one level of benzene, 10 ppm.
The many studies using rats provide ample data for comparison of
results, but the most helpful ones are by Kuna and Kapp (1981), Coate et
al. (1984), Green et al. (1978), and Tatrai et al. (1980a). Table 4.2
summarizes results when exposure occurred essentially only during
organogenesis. The data are arranged by level of exposure and show a
dose response. In the following paragraphs the various studies will be
discussed by end point.
Maternal toxicity, as indicated by a decrease in maternal weight
gain, is clearly evident at levels of more than 100 ppm. Resorption data
from the eight rat studies are inconclusive, because of the divergent
results. Green et al. (1978) found no increase in resorptions at the
2,200-ppm exposure level. The studies at Litton Bionetics Incorporated
(Litton 1977 and 1978, as reported by Schwetz 1983) showed an increase
in resorpcions at relatively low levels of benzene exposure, but Schwetz
observed that in the 1977 study an air temperature rise in one of the
chambers might have produced maternal stress that increased resorptions.
In the 1978 study, the experimental control value of 2% resorptions was
unusually low, skewing statistical results. The rate of resorptions at
10 and 40 ppm was comparable to historical controls.
The fetotoxicity of benzene in rats is demonstrated by retarded
fetal weight and skeletal variants. Table 4.2 shows that exposure to
high levels of benzene ranging from 50 to 2,200 ppm resulted in a
significant decrease In fetal weight, with the exception of two groups
of rats in a study by Green et al. (1978). In this study, dams breathing
air containing 100 or 300 ppm benzene bore young which were similar in
weight to control pups. Statistically significant numbers of skeletal
variations (delayed ossification, missing sternebrae, and extra ribs)
-------
Toxicologies! Data 61
Table 4.1. Summary of results of some teratological studies on benzene in (be moose and rabbit0
Animals Route
New Zealand Inhalation
rabbit
New Zealand Inhalation
rabbit
CF-1 mouse Inhalation
CFLP mouse Inhalation
ICR mouse Subcutaneous
CD-I mouse Gavage
Exposure
level
500 ppm
156 ppm
313 ppm
500 ppm
156 ppm
313 ppm
2 mL/kg
4 mL/kg
0 3 mL/kg
0 5 mL/kg
1 0 mL/kg
" — = No significant difference compared
pared with controls
* Resolutions
c Fetal death
''Abortions
Maternal Fetal
weight body
gain weight
-
DECR DECR
DECR
DECR
DECR
DECR.
DECR
DECR
DECR
with controls. DECR —
Resorptions/
fetal death/
abortions
-
INCR*
—
INCR*'C
INCR* c
INCR*'C
INCR*'C
INCR*
INCR*
Skeletal
variants Malformations
Slightly
INCR
INCR
INCR
INCR
INCR
INCR
— -
decreased compared with controls, INCR ~
References
Murray et al
1979
Ungvary and
Tatrai 1985
Murry et al
1979
Ungvary and
Tatrai 1985
Matsumoto et
al 1975
Nawrot and
Staples 1979
increased com-
-------
62
Section 4
Table 4.2, Teratology studies on inhaled benzene in rats"
Strain
S-D
S-D
S-D
S-D
S-D
S-D
CFY
S-D
S-D
S-D
CFY
CFY
CFY
S-D
CFY
CFY
S-D
CFY
S-D
a _
Hours
per day
6
7
6
6
6
6
24
7
6
6
24
24
6
24
24
7
24
6
— No signi
Benzene
(ppm)
I
10
10
10
40
40
47
30
100
100
125
125
141
300
313
470
500
940
2200
ficant diffei
Maternal
weight gain
-
:
-
-
~
DECR
DECK
-
-
DECR
DECR
DECR
-
DECR
DECR
DECR
DECR
DECR
"ence consD&rei
Resorpttons
-
[NCR
-
INCR
-
-
-
-
-
-
-
INCR
-
-
INCR
-
INCR
—
! with controls:
Fetal
weight
-
^
-
-
-
DECR
DECR
-
DECR
DECR
DECR
DECR
-
DECR
DECR
DECR
DECR
DECR
DECR -
Skeletal
variants
-
-
-
-
-
INCR
-
-
INCR
INCR
INCR
INCR
INCR
INCR
INCR
INCR
INCR
decreased con
Malformation] References
- Coate et al 1984
Kuna and Kapp 1981
Litton6
Coate et al. 1984
— Litton*
Coate et al. 1984
Tatrai et al. 1980a
Kuna and Kapp 1981
— Green et al 1978
- Coate et al. 1984
Ungvary 1985
- Tatrai et al 19806
- Tatrai et al. 1980s
- Green et al. 1978
Hudak and Ungvary 1978
- Tatrai et al. I980a
Kuna and Kapp 1981
- Tatrai et al 1980a
- Green et al. 1978
wared with contrail: INCR — incrauai
compared with controls.
Luton Bionetics Incorporated (Litton 1977 and 1978, as reported in Schweu 1983).
-------
lexicological Data 63
were found in all groups exposed to concentration levels equal to
125 ppm and higher.
Similar to the studies cited in Table 4.1, those reported in
Table 4.2 failed to find malformations as a result of benzene exposure
The highest level of exposure was 2,200 ppm (Green et al. 1978). One
exencephalic rat was found in a group exposed to 500 ppm benzene at the
Hazelton Laboratories (Kuna and Kapp 1981), where 151 pups were
examined. In the same study, out of 98 pups examined for skeletal
defects, one pup had angulated ribs and two other pups had nonsequential
ossification of the forefeet. These anomalies were not statistically
significant and may have resulted from maternal nutritional stress.
Information from the control group was inadequate, because only 11 of
the 17 control dams produced offspring. Since other studies using high
levels of benzene did not result in these malformations, there does noc
appear to be significant evidence that they were caused by benzene.
In two studies not included in Table 4.2, rats were exposed to
inhaled benzene both pre- and postconceptionally (Table 4.2 was
restricted to postconceptional exposure only). Gofmekler (1968) showed
that continuous exposure of female rats to 0.3 to 20 ppm benzene for 10
to 15 days before mating and throughout pregnancy did not affect newborn
weight, but there were differences in the weights of individual organs.
There was a slight tendency toward decreased litter sizes at higher
levels of exposure. A complete absence of litters resulted from exposure
to 210 ppm for 10 to 15 days before mating and throughout pregnancy.
Pushkina et al. (1968) exposed female rats for 20 days before mating and
throughout pregnancy. No malformations resulted. Six different
concentrations of benzene ranged from 0.3 to 210 ppm, and at the higher
levels the litter size was smaller. The weight of the fetuses decreased,
and the relative weights of their organs were reduced.
4.3.3.3 Oral
Human. No information was found.
Animal. Benzene administered orally to CD-I mice at 0.3, 0.5, or
1.0 mLAg on days 6 to 15 of pregnancy caused maternal lethality and
resorptions at the 0.5- and 1.0-mLAg levels but no increase in
malformations (Nawrot and Staples 1979). Seidenberg et al. (1986) gave
pregnant mice 1300 mgAg/day (1-47 mLAg/day) benzene by gavage on
gestation days 8 to 12. A significant reduction in fetal body weight was
observed.
4.3.3.4 Dermal
Human. No information was found.
Animal. Prolonged application of benzene to the skin of rats for
4 months at 64 or 320 mgAg/day increased the mortality of the first-
generation offspring (Malysheva 1980).
4.3.3.5 Injection
Human. No information was found.
-------
64 Section 4
Animal. Guinea pigs treated with subcutaneous Injections of
0.1 gAg/day (0.11 mL/kg/day) of a 40% solution of benzene
(0.044 mL/kg/day benzene) throughout pregnancy did not show any effect
on maternal body weight, length of gestation, number of offspring,
offspring body weight, or neonatal mortality (Desollle et al. 1967, as
reported by Barlow and Sullivan 1982). The same Investigators, using
rats, injected 0.1 gAg/day (0.11 mLAg/day) benzene in a solution of
olive oil throughout pregnancy and found no effect on duration of
pregnancy, maternal body weight, average litter size, or neonatal
mortality rates (Desoille et al. 1965, as reported by Barlow and
Sullivan 1982). No mention of malformations was made in the guinea pig
and rat studies. In a study by Matsumoto et al. (1975), ICR mice were
administered benzene by the subcutaneous route at doses of 2 or 4 mL/kg
on days 8 and 9 or 12 and 13 of gestation. An increased incidence of
delayed ossification of bones was found at the high dose level when
given on gestation days 12 and 13. A decrease in white cell counts and
hemoglobin content in the mothers was consistent with expected effects
of benzene and may have contributed to the decreased weight of the
fetuses.
4.3.3.6 General discussion
Epidemiological studies implicating benzene as a developmental
toxicant in humans have many limitations. These include exposure to
multiple substances, lack of control incidences for end points, problems
in identifying exposed populations, and lack of data on exposure levels.
Thus it is extremely difficult to make a clear assessment of the effect
of benzene on the human conceptus. The preponderance of animal data is
from inhalation experiments, because this has been the principal route
of concern. More data are needed on other routes, since exposure from
waste sites will likely also involve other routes. Inhalation results
have been fairly consistent across species. It has been suggested that
benzene fetotoxicity in the rat appears to be a function of maternal
toxicity, as the Joint occurrence of a decrease in fetal weight and an
increase in skeletal variants usually occurs when there is a decrease in
maternal weight. There is no clear-cut evidence on mechanisms of this
toxicity, and there are little data on maternal food consumption during
benzene exposure and blood levels of benzene and its metabolites in the
mothers and their fetuses. There is sufficient evidence that benzene is
not teratogenic and not overtly embryotoxic at 10 ppm.
Schwetz (1983) has provided an excellent review of research on
developmental toxicity in animals, while Barlow and Sullivan (1982) have
provided Che most comprehensive information on humans.
4.3.4 Reproductive Toxicity
4.3.4.1 Overview
There is a paucity of information on the reproductive toxicity of
benzene. Some harmful gonadal effects have been noted in experimental
animals, but the levels of exposure have been higher than those to which
humans are exposed in the modern industrial environment.
-------
Toxicologlcal Data 65
4.3.4.2 Inhalation
Human. Vara and Klnnunen (1946) examined 30 women with symptoms of
benzene toxlcity Indicating exposure to levels much higher than those In
today's working environment. Twelve of these women had menstrual
disorders (profuse or scanty periods and dysmenorrhea). Ten of these 12
women were married, and two abortions and no births took place during
their employment even though no contraceptive measures had been taken,
leading the Investigators to suggest a detrimental effect on fertility
at high levels of exposure. Gynecological examinations revealed that the
scanty menstruations of five of the patients were due to hypoplasia of
the ovaries. Menstrual disturbances (heavy bleeding) were reported In
female workers exposed to 31 ppm benzene In a Polish factory (Michon
1965, as cited in Barlow and Sullivan 1982). In another group of factory
workers, occupational benzene poisoning resulted in ovarian hypofunction
(Pushklna et al. 1968). In a study of 360 female gluing operators
exposed to petroleum (a major source of benzene) and chlorinated
hydrocarbons both dermally and by inhalation, no significant difference
in fertility between exposed workers and unexposed controls was found
(Mukhametova and Vozovaya 1972, as reported In Barlow and Sullivan
1982). However, spontaneous abortion and premature birth increased.
Animal. In a subchronic inhalation study, Ward et al. (1985)
exposed male or female CD-I mice to concentrations of 1, 10, 30, or
300 ppm benzene vapor, 6 h/day, 5 days/week for 13 weeks. Hlstopatholog-
ical changes were observed In ovaries (bilateral cysts) and testes
(atrophy/degeneration, decrease in spermatozoa, moderate increase in
abnormal sperm forms) of mice exposed to 300 ppm benzene; the severity
of the lesions was greater in the males. An inhalation study was con-
ducted by Wolf et al. (1956) exposing rabbits and guinea pigs to benzene
7 to 8 h/day, 5 days/week, for up to 6 months. The guinea pigs showed a
slight increase in average testicular weight at the 88-ppm level.
Rabbits showed slight histopathological testicular changes (degeneration
of the germinal epithelium) when exposed to 80 ppm. Gofmekler (1968)
found that continuous exposure of female rats to 210 ppm benzene for 10
to 15 days before mating and 3 weeks after mating resulted in a complete
absence of litters. It is not known whether this was due to failure to
mate, infertility, or early preimplantation losses of fertilized ova.
4.3.4.3 Oral
Human. No studies are available.
Animal. No studies are available.
4.3.4.4 Dermal
Human. No reproductive data with dermal as the only route of
exposure to benzene are available. Multiroute exposure was discussed in
the section on inhalation.
Animal. Prolonged dermal application of benzene to the tails of
adult rats for 4 months at 64 or 320 mg/kg/day did not affect the
fertilizing ability of males or the conceptional capacity of females
when mated with untreated rats (Malysheva 1980). There was, however, a
decrease in the number of spermatogonia in the males.
-------
66 Section 4
4.3.4.5 Injection
Human. No studies are available.
Animal. An increased incidence of abnormal sperm heads was induced
in male mice given five daily intraperitoneal injections of benzene in
corn oil at doses ranging from 0.5 to 1.0 mLAs (Topham 1980).
4.3.4.6 General discussion
As with studies of human developmental toxicity, evidence of an
effect of benzene exposure on human reproduction is not sufficient to
demonstrate a definite association. Exposure to benzene occurs along
with exposure to many other chemicals, so no conclusion can be drawn
relative to any single agent. There are insufficient animal data to
propose NOAELs and LOAELs.
4.3.5 Genotoxic ity
4.3.5.1 Overview
Benzene (or more likely its metabolites) causes both structural and
numerical chromosome aberrations in humans, laboratory animals, and
cells in culture and SCEs and micronuclei in in vivo animal studies.
Other positive effects found following in vivo animal exposure include
sperm-head abnormalities, inhibition of DNA and RNA synthesis, DNA
binding, and interference with cell cycle progression. DNA binding and
inhibition of DNA synthesis have also been demonstrated in vitro.
Benzene has rarely been shown to cause gene mutations.
This review is not an exhaustive critique of all available
literature on the genetic toxicity of benzene but intends to present
sufficient data to support the conclusion that benzene is a genetic
hazard to humans. This section is organized by end point under human,
animal, and in vitro headings rather than by route of administration.
This approach was taken for the following reasons: much of the
supporting data for human effects come from in vitro studies for which
route of exposure is not applicable; no in vivo animal studies
considered in this review used dermal exposure, while many used either
intraperitoneal or subcutaneous injections, routes not likely to be
important for human exposure but useful in determining potential
genotoxic effects; and virtually all human epidemiology studies report
only inhalational exposures, although concurrent dermal exposure cannot
be excluded.
4.3.5.2 Human
Available evidence for benzene- induced genetic toxicity in humans
comes from epidemiological studies of persons occupationally exposed to
benzene. Exposures reported in these studies are primarily via
inhalation, although contact with the skin may also have occurred in
some cases. The difficulties with epidemiological studies are well known
and include lack of accurate exposure data, possible exposure to
multiple chemicals, and selection of appropriate control groups.
However, the association between benzene exposure and the appearance of
structural and numerical chromosomal aberrations in human lymphocytes
-------
Toxicological Data 67
has been found so consistently that benzene can undoubtedly be
considered a human clastogen. The evidence for benzene-induced
chromosomal aberrations 'in humans has been extensively reviewed (R.
Snyder et ml. 1977. Dean 1978, Forni 1979, White et ml. 1980, IARC 1982,
C. A. Snyder 1987, van Raalte and Grasso 1982, Dean 1985).
Tough and Court Brown (1965) examined blood samples from 20 men
with benzene exposures of 1 to 20 years. Benzene exposure had stopped
2 years before, at a time when 14 of the men had shown neutropenia. The
number of lymphocytes with unstable chromosomal aberrations (Cu cells)
was significantly higher in the exposed men than in on-site or off-sice
controls (1.4% for exposed vs 0.6% for both sets of controls), while the
number of cells with stable aberrations (Cs cells) was higher than in
controls but not significantly higher. Pollini et al. (1969) found 70%
aneuploid lymphocytes in five women with benzene hemopathy. This value
dropped to 40% 5 years later, when all five women still had stable and
unstable chromosome changes. Large metacentric chromosomes of group 1-3
were often missing. Forni et al. (1971a) performed chromosome studies on
lymphocytes of workers in a rotogravure plant where benzene was used as
a solvent. The workers were exposed to benzene for 1 to 22 years (until
an epidemic of benzene poisoning led to its replacement by toluene) and
then to toluene for an additional 12 to 14 years. At the time of benzene
poisoning, concentrations of 125 to 532 ppm benzene were measured in
various parts of the plant. Statistically significant increases in both
unstable and stable chromosomal aberrations were found in benzene -
exposed workers as compared with either unexposed controls or with
toluene-only-exposed controls. Another study by Forni et al. (1971b)
found similar results in a group of 25 persons (13 men and 12 women)
following recovery from benzene hemopathy. Exposure levels were unknown
but were obviously high enough to cause clinical symptoms, in some cases
quite severe. Blood samples were taken 1 to 18 years following
recovery. The percentage of both Cs cells and Cu cells was significantly
higher in the exposed group than in the control group. Only 1 of 25
control individuals had >1% Cu cells and 1 had 1% Cs cells, compared
with 18 of 25 exposed individuals with >1% Cu cells and 17 of 25 with 1%
or more Cs cells. There was a tendency for the rate of unstable
chromosome aberrations to decrease and stable aberrations to increase or
remain steady in follow-up studies; however, there was no consistent
pattern of change. Other studies have consistently found increased
chromosomal aberrations in benzene-exposed populations (Erdogan and
Aksoy 1973, Khan and Khan 1973, Ding et al. 1983. Koizumi et al. 1979,
Van den Berghe et al. 1979). Additional case studies also support the
chromosomal-damaging effect of benzene (Hartwich et al. 1969, Forni and
Moreo 1967, Forni and Moreo 1969, Sellyei and Kelemen 1971).
4.3.5.3 Animal
Benzene-induced cytogenetic effects, including chromosome and
chromatid aberrations, SCEs, and micronuclei, have been consistently
found in in vivo animal studies (see Table 4.3). Of particular interest
are the results of a study by Tice et al. (1982) in which significant
increases in SCEs in bone marrow cells were observed in mice exposed co
28 ppm benzene for 4 h.
-------
68 Section 4
Tabfc4J la tiro gtsMtoKklry stadies of
End pout/route
Test system
GcMmaudo
ChromoMa
Results
as (no data)
ml effects
References
Chromosome aberrations
Inhalation Mouse bone marrow
Oral
Intrapentoneal
Subcutaneous
Dermal
Micron uclei
Inhalation
Oral
Intrapentoneal
Subcutaneous
Dermal
SCE
IntraperitoneaJ
Oral
Dermal
Rat bone marrow
Mouse bone marrow
Chinese hamster bone marrow
Mouse bone marrow
Rat bone marrow
Rat bone marrow
Rabbit bone marrow
No data
Mouse lymphocytes
Mouse bone marrow
Rat lymphocytes
Mouse bone marrow
Mouse circulating erythracytes
Chinese hamster bone marrow
Mouse bone marrow
Mouse bone marrow
No data
Mouse bone marrow
Mouse lymphocytes
Rat lymphocytes
Pregnant mouse bone marrow
Fetal mouse liver
No data
No data
+ Zhurkov et al. 1983.
Ticect al. 1982.
Tice et al. 1980
+ Styles and Richardson 1984.
Anderson and Richardson 1981
+ Siou et al. 1981.
Meyne and Legator 1980
-I- Skmetal 1981
+ Pavlenko et al. 1979,
Meyne and Legator 1980
+ Anderson and Richardson 1981
+ Philip and Krogh Jensen 1970
+ Kissling and Speck 1972
+ Erexson et al. 1986.
+ Toft et al. 1982.
+ Erexson et al. 1986
+ Anonymous 1986,
Gad-el Kanm et al. 1986.
Fel'dt 1985.
Harper et al. 1984.
Siou et al. 1981.
Meyne and Legator 1980.
Kite et aL 1980.
Barak et al. 1983
+ Baraleet al. 1985,
Choy et al. 1985.
Siouetal. 1981
+ Anonymous 1986,
Gad-el Kanm et al. 1986.
Meyne and Legator 1980
+ Diaz etaL 1980
+ Tice et al. 1982.
Tice et al. 1980
+ Erexson et al. 1986
+ Erexson et al. 1986
+ Sharma et al. 1985
+ Sharma et aL 1985
-------
ToxicoLogical Data
69
Table O (coadaoed)
End point
Test system
Results
References
Dominant lethal
Inhalation
Oral
Intraperitoneal
Sperm head abnormality
Inhalation
Oral
Intrapentoneal
Cell cycle progression
Inhalation
Subcutaneous
Oral
Dermal
RNA synthesis inhibition
Subcutaneous
Inhalation
Oral
Dermal
DNA synthesis inhibition
Subcutaneous
Inhalation
Oral
Dermal
DNA binding
Inhalation
Subcutaneous
Oral
Dermal
Chromosomal effects (con't)
No data
Mouse germ cells
Mouse spermatogonia
Rat germ cells
Other effects
No data
No data
Mouse (spermatogonia treated)
Mouse bone marrow
Rat bone marrow
Rat lymphocytes
No data
No data
Rat liver mitochondria
Rabbit bone marrow
No data
No data
No data
Rabbit bone marrow
No data
No data
No data
Rat liver
Rat liver mitochondria
No data
No data
Fel'dt I98S.
Pavlenko et al. 1979
Lyon 1976 (as reported
in Dean 1978)
Topham 1980
Tice et al. 1982,
Tice et al. 1980
Irons et al. 1979
Irons et al. 1979
Kalf et al. 1982
Kisshng and Speck 1972
Kisshng and Speck 1972
Lutz and Schlatter 1977
Kalf et al. 1982 .
-------
70 Section 4
Dominant lethal effects have not been conclusively demonstrated in
animals following benzene administration. Pavlenko et al. (1979)
reported dominant lethal induction in mouse spermatogonia following an
intraperitoneal injection of 3,000 mg/kg benzene. Postimplantation loss
in treated mice was approximately double that of controls. Fel'dt (1985)
found no significant dominant lethal effect in random-bred male mice
following oral administration of up to 320 mg/kg benzene. Although the
dose in the latter study is an order of magnitude lower than that in the
first study, the two reports cannot be directly compared, because of a
different route of administration and unknown genetic constitution of
the mice used. An intraperitoneal injection of 440 mg/kg benzene induced
no dominant lethality in male rats (Lyon 1976, as reported in Dean
1978). Benzene (or a metabolite) was shown by Topham (1980) to reach the
germ cells when he obtained positive results in a sperm-head morphology
assay in CBCFl mice. A dose range of 0.1 to 1.0 mL/kg/day for 5 days was
used with the sperm sampled 5 weeks after the last dose. The maximum
induction of sperm-head abnormalities occurred at 0.6 mL/kg/day, while
the highest dose tested was lethal.
4.3.5.4 In vitro
The potential genetic toxicity of benzene has been examined in a
number of cellular and subcellular systems, including isolated
mitoplasts, bacteria, yeast, and mammalian cells in culture (see
Table 4.4). End points considered in these studies were DNA binding, DNA
synthesis, DNA repair, gene mutations, and effects at the chromosome
level such as chromosome aberrations, aneuploidy, SCEs, and micronuclei
formation.
4.3.5.5 General discussion
Both structural and numerical chromosome aberrations have been found
consistently in bone marrow cells of persons occupationally exposed to
benzene. The conclusion, based on human epidemiological studies, that
benzene is a human clastogen is well supported by in vivo animal studies
and in vitro cell culture and subcellular studies. Virtually all studies
that looked for effects at the chromosomal level were positive when the
ability to metabolize benzene was present. These experimental results
are consistent with the chromosomal damage seen in exposed humans. The
leukemia observed in some benzene-exposed persons may result from the
appearance of a clone of chromosomally abnormal cells in the bone
marrow. With respect to genetic effects, no safe human exposure level
can be determined from available epidemiological data. Significant
increases in SCEs were produced in bone marrow cells of mice at 28 ppm
benzene, the lowest level tested in that study. The significance of SCEs
is unknown, but their production by a chemical is generally considered
to indicate a genotoxic potential. These exposures were via inhalation
and, based on animal studies, greater effects may result following oral
than inhalational exposure to comparable levels of benzene. Data
presented in the genotoxicity section and elsewhere in this review show
that benzene metabolites are the active entities; different metabolites
are possibly responsible for different genetic effects. Differences in
metabolic capability are likely responsible for some of the variations
in response to benzene seen in different test systems.
-------
lexicological Data 71
Table 4.4. la vitro geaotoxicity studies of bcaxcM
End pout
Test system
Results"
References
Ames test
One mutations
Salmonella lyphimurium
Azaguanine resistance Salmonella typhimunum
Histidme reversion
Methionine suppressors
Stamen hair test
Sex-linked recessive
lethal
TKtest
TK. ouabain,
HGPRT loci
Bacillus subttlu
Aspergillus nidulani
Tradescanna
Drosophila melanogaster
Mouse LSI78Y cells
Total of 15 studies using
various human, mouse, and
Chinese hamster cells
Mixed •
De Flora et al 1984.
Shimizu et al 1983.
Hermann 1981.
Shahin and Fourmer 1978.
CSSTT Study 1985*
Seixas et al 1982.
Kadenetal 1979
Tanooka 1977
Crebelli et al 1986
Schairer et al. 1979
Kale and Baum 1983
Oberly et al. 1984
CSSTT study 1985
*
Chromosome
aberrations
SCE
Micronuclei
Recombinatioa
Heritable
tramlocation
Human lymphocytes
Total of 8 studies using
Chinese hamster or human
cells
Barley, onion, and broad
bean root tips
Chinese hamster ovary and V79
cells and rat RL4 cells
Human lymphocytes
Chinese hamster ovary cells
Drosophila melanogaster
Spermatocytes
Spennatogoma
Drosophila melanogaster
Mixed Gerner-Smidt and
Fnednch 1978,
Monmoto 1976,
Koizumi et al. 1974
Mixed CSSTT study I98S*
+ Zhang and Dong 1982
-/- CSSTT study 1985*
Mixed Monmoto 1983,
Gerner-Smidt and
Fnednch 1978.
Monmoto and Wolff 1980.
Monmoto et al. 1983.
Erexson et al IMS,
-/- Douglas etal. 198S
Kale and Baum 1983
Kale and Baum 1983
-------
72 Section <4
Table 4.4 (condimcd)
End point
Test system
Results
References
DNA binding
ONA breaks
Unscheduled
DNA synthesis
Differential killing
DNA synthesis
inhibition
Other effects
Rabbit bone marrow miioplasts +
Rat liver miioplasts -t-
Rat hepatocytes -
Chinese hamster V79 cells -
Chinese hamster ovary cells Mixed
Mouse L5178 Y cells
Rat hepatocytes -
HeLa cells
EschencHia coll Mixed
Bacillus subiilu Mixed
Human leukocytes +
HeLa cells Mixed
Rushmore et al 1984
Rushmore et al 1984
Sma ei al 1983.
Bradley 1985
Swenbergetal 1976
Douglas et al 1985.
Lakhamsky and
Hendncks 1985
Pellack-Walker and
Blumer 1986
Probst et al. 1981.
Williams et al. 1985.
Probst and Hill 1985.
Glauert et al 1985''
Barrett 1985
Deflora et al. 1984,
McCarrollet al. I981b
Tanooka 1977.
McCarroll el al. 198la
Dobashi 1974
Dobashi 1974.
Painter and Howard 1982
"With/without an exogenous metabolic activation system.
Progress in Mutation Research 5 1985. Ashby J, de Series FJ. Draper M. Ishidate M Jr. Mar-
golin BH. Matter BE. Shelby MD. eds Evaluation of Short-Term Tests for Carcinogens Report of
the International Program on Chemical Safety Collaborative Study on in vitro Assays. Elsevier.
Amsterdam.
'The CSSTT working group disagreed over data analysis and therefore called the results incon-
clusive.
Weak positive result
-------
lexicological Data 73
4.3.6 CareInogen icIty
4.3.6.1 Overview
IARC concluded Chat there was sufficient evidence that benzene is
carcinogenic (leukemogenie) in humans by inhalation and there was
limited evidence that benzene is carcinogenic in animals. EPA has
similarly listed benzene as a human carcinogen, Group A, using the EPA
Cancer Risk Assessment Guidelines. There is, however, still controversy
concerning dose-response relationships in humans.
The Gene-Tox Carcinogenesis Panel categorizes benzene as having
sufficient positive evidence for carcinogenicity in animal studies, and
the NTP concluded that there was clear evidence of carcinogenicity of
benzene for the strains of rats and mice tested in their 2-year
oral/gavage bioassay program.
Data are insufficient to validate carcinogenic potential via
ingestion in humans or by the dermal route in humans or animals. It is
reasonable to assume, however, that benzene could cause cancer in humans
if ingested in sufficient quantities. The risk of cancer after dermal
exposure is probably less than by other routes, since absorption through
the skin is low.
4.3.6.2 Inhalation
Human. There are many epidemiological and case studies that
correlate benzene exposure with leukemia in humans. Although some of
these studies suggest that low levels of benzene may be carcinogenic,
this is not universally accepted. "Controversy involves the actual
levels of benzene exposure, small number of statistics, and the 'one-hit
concept' implying linear response and no threshold" (Cronkite 1986). The
duration and levels of benzene exposure in such retrospective studies
are usually deficient or cannot be obtained (Andrews and Snyder 1986),
and cause-effect relationships are complicated by exposure to other
chemicals in addition to benzene (Andrews and Snyder 1986, Dean 1978).
Pertinent information for seven selected case studies correlating
benzene exposure with carcinogenesis is presented in Table 4.5. In 1976,
OSHA and NIOSH reached the conclusion that benzene was a leukemogen in
humans (EPA 1985a, NIOSH 1977a), and other EPA reviews concur (EPA
1984a, EPA 1986). The 1982 U.K. Health and Safety Executive accepts the
relationship between exposure to benzene in higher concentration ranges
and acute myelogenous leukemia (HSE 1982, as reported in Dean 1985). The
1982 IARC Monograph on cancer summarizes: "It is established that
exposure to commercial benzene or benzene containing mixtures can cause
damage to the hematopoietic system including pancytopenia. The
relationship between benzene exposure and the development of acute
myelogenous leukemia had been established in epidemiologic studies.
Reports linking exposure to benzene with other malignancies were
considered to be inadequate for evaluation. There is sufficient evidence
that benzene is carcinogenic in man" (IARC 1982).
The studies that were used for quantitative assessment by EPA
(1986) are Ott et al. (1978), Rinsky et al. (1981), and Uong et al.
(1983, as reported in (EPA 1986). Even the better studies, however, did
-------
74 Section
Table 4.5 Cue studies of workers occupadonaUy exposed to benzene
Group studied
44 Pancytopemc patients
exposed to benzene in
adhesives
42 Leukemia patients and
21 patients with other
malignancies. 47 were shoe
workers, the remainder in
other occupations using
benzene solvents
6 of 94 Hodgkin's patients
who had been exposed to
benzene adhesives
A 35-year-old man who had
used benzene 8 yean earlier
as a paint solvent
6 Leukemia patients in
different occupations all
using benzene solvents
A 67-year-old man exposed to
benzene in a rubber
hydrochlonde plant
A 51 -year-old chemical worker
exposed to benzene 1 5 yean
earlier
Exposure level/
duration
1 50-650 ppm/
4 mo- 15 years
Not given
150-2 10 ppm
1-28 yean
200-1640
mg/m3/l8
months
Levels
unknown/
1-20 yean
16 ppm/
14 year
<2 ppm/
18 mo
Condition
observed
Leukemia
Myeloid
metaplasia
Leukemia
Multiple myeloma
Myeloblastic
leukemia
Acute
erythroleukemia
Pre leukemia
Malignant
lymphoma
Paroxymal
nocturnal
hematuna
Lung cancer (all
heavy smokers)
Hodgkin's
disease
Subacute
granulocytic
leukemia
Hemocvtoblastic
leukemia
Acute
myeloblastic
leukemia
Acute
myelogenous
leukemia
Author
call'
PC
•
DC
PC
•
•
•
PC
•
•
PC
DC
DC
DC
1981
PC
References
Aksoy and Erdem
1978
Aksoy 1980
Aksoy et al.
1974b
Sellyei and
Kelemen 1971
Vigliam and
Saita 1964
Rinsky et al.
Ott et al.
1978
DC - Direct correlation.
PC - Possible correlation.
• - Author made no claim.
-------
ToxicoLogical Daca 75
not have complete exposure information. Ott et al. (1978), while finding
an excess of leukemia deaths, points out that the varied work histories
and the lack of medical histories make a retrospective assessment of the
possible relationship to benzene exposure Judgmental. EPA used the Ott
study in combination with the other studies for risk estimates, but less
emphasis was placed on it, because of a lack of a clear-cut dose-
response relationship (EPA 1986).
The initial study by Infante, later updated by Rinsky, relied on a
1946 Industrial Commission of Ohio survey of one department and on
company surveys between 1963 and 1974 to estimate exposure levels
(Infante et al. 1977). "There was a paucity of information regarding
atmospheric levels of benzene to which workers may have been exposed,
but the available data indicated that average benzene levels generally
ranged from less than 10 ppm to 100 ppm" (White et al. 1980). In the
discussion in the IARC Monograph (1982) concerning this work, it was
stated that "the methods employed in the 1940s for measuring benzene
concentration in air, while reasonably accurate, were relatively less
sensitive than those available today." In fact, in laboratory studies,
one type of detector kit used read 40% low (Hay 1964, as reported in
Rinsky et al. 1981), and a detector tube used as late as the 1960s was
found to have an accuracy of ±50% (Ash and Lynch 1971, as reported in
Rinsky et al. 1981).
In a follow-up to the Infante study (Rinsky et al. 1981),
correspondence, memoranda, and records of air-sampling measurements from
several sources taken at various times between 1947 and 1977 were cited
as documentation of exposure levels at location 1 of the study. "There
is limited data for location 2 and no data available prior to 1946 when
an exhaust system was installed. One might infer that prior to 1946 the
presses were not enclosed and therefore benzene emissions were higher.
We believe that benzene exposures at location 2 were similar to location
1. Our analysis of the available data lead us to conclude that for the
most part employees' 8 h TWA exposures (which ranged from 100 ppm in
1941 to 10 ppm in 1969) were within the recommended limits in effect at
the time. However ... on certain days the 8 h TWA was probably
exceeded" (Rinsky et al. 1981).
The IARC Working Group "accepted the central conclusion of Infante
et al. and Rinsky et al. that excessive mortality from myelogenous
leukemia had occurred among workers with occupational exposure to
benzene that was generally within accepted limits. However the possible
contribution of the occasional excursions in exposure and of the
employment of some workers in other areas of the plant must be noted;
and in the opinion of the Working Group, these factors may have made
some contribution to the observed excess in mortality from leukemia"
(IARC 1982).
Van Raalte and Grasso (1982) did an extensive critical review of a
number of studies reporting positive results, including Infante et al.
(1977) and Rinsky et al. (1981). This review takes issue with sampling
techniques, exposure determinations, mortality standards, and other
aspects of experimental design or methodology. Goldstein (1985)
emphasizes that in dealing with a low-incidence phenomenon it is
-------
76 Section 4
difficult Co utilize general industrial hygiene measurements as a means
of typifying individual exposure. Van Raalte and Grasso (1982) and
Goldstein (1985) concluded that the cause-effect relationship between
benzene and leukemia is sufficiently clear, but Van Raalte and Grasso
assert that there are few data from which dose-effect or dose-response
relationships can be established. They claim that there is no evidence
for a leukemogenic action of benzene at low concentrations, and,
although an association has been suggested for lymphatic leukemia,
Hodgkin's disease, and non-Hodgkin's lymphomas, Van Raalte and Grasso
consider this to be questionable.
On the other hand, White et al. (1980), reviewing arguments in
OSHA's case to lower occupational benzene standards from 10 to 1 ppm,
examined a study by Thorpe (1974) in which no correlation between
benzene exposure and cancer was found. They attributed the lack of
correlation to methodologic deficiencies. They further summarized that
OSHA's earlier conclusion that no threshold could be established for
benzene is supported by the consensus of the scientific community.
Conditions observed and the investigators' assessment of
correlation from a few of the better-known epidemiological studies are
summarized in Table 4.6.
Since the quantitative assessment by the EPA, Rinsky et al. (1987)
have published a risk assessment based on an update of the previous
Infante and Rinsky studies of a cohort of 1,165 rubber workers. In order
to reduce the uncertainties posed by estimates of group exposures,
individual work histories were compiled and cumulative exposures were
estimated for each employee in the cohort based on the available past
industrial hygiene measurements, which, as discussed above, were
limited. In some cases, a single measured exposure served as an index of
exposure for a number of years. (For details of these measurements, see
Rinsky et al. 1981.) Standardized mortality ratios (SMRs) were
determined for leukemia by four cumulative exposure categories.
Cumulative exposure
(ppm-years) SMR 95% Confidence interval
< 40
40-200
200-400
> 400
Total
109
322
1,186
6,637
337
12-394
36-1,165
133-4,285
1,334-19,393
154-641
The questions discussed above remain concerning the precise levels
of benzene Co which workers were exposed. Additionally, there is no
means of assessing the impact of the manner in which workers were
exposed: I.e., short-term high-level exposure, long-term low-level
exposure, exposure at a constant level with occasional high-level
exposure, or only occasional high-level exposure, all of which could
produce Che same cumulative dose. However, the trend demonstrated is a
marked, progressive increase in SMR with increasing cumulative dose. The
-------
Toxicological Data 77
Table 4.6. Epidemiological studies of worfccn exposed to
Group studied
Mortality study of rubber
Corkers exposed to benzene
between 1940 and 1949
Follow up mortality study
of rubber workers exposed
to benzene between 1 940 and
1949
Mortality study update of
rubber workers exposed to
benzene between 1 940 and 1 949
Mortality study of 594
workers employed at a
chemical company between
1940 and 1973
Mortality study of 4.602
chemical workers employed
between 1946 and 197S
Mortality study update of
594 previously studied and
362 additional chemical
employees potentially
exposed to benzene between
Exposure level/
duration
Within legal
limits of
time, i e ,
100 to 10 ppm/up
to 10 years or
more
Within legal
limits of the
time, i e ,
100 to 10 ppm/up
to 10 years
or more
Redefined
from
<40 ppm • yean
to >400 ppm years
<0 1-35 5
ppm estimated
TWA/up to 34
years
TWA of from
<1 to >50 ppm
with peaks to
>100 ppm/6 month
to 29 years
1-30 ppm/
duration
not well
documented
Condition
observed
Leukemia (all
types)
Lymphatic
hematopoietic
cancer
Myeloid
leukemia
Monocytic
leukemia
Malignant
neoplasias of
the lymphatic
and hematopoietic
tissue
Leukemia
(myelogenous)
(monocytic)
Lymphatic and
hematopoietic
neoplasms
Leukemia
Multiple
• myeloma
Leukemia
Acute
myelogenous
leukemia
Myeloblastic
leukemia
Leukemia and
Aleukemia
Lymphatic and
hemoreticular
cancer
Non-Hodgkin's
lymphopoietic
cancer
All leukemia
Acute
myelogenous
leukemia
Author
call"
DC
DC
DC
DC
DC
DC
DC
DC
DC
PC
PC
PC
DC
PC
PC
•
DC
SMR References
506 Infante et
at 1977,
260 Infante
1978
330 Rinsky et
al 1981
560
227 Rinsky et
al. 1987
337
409
* Ott et al.
• 1978
•
97-275 Wong et al.
1983. as
91-175 reported in
EPA 1986
108-165
158-214 Bondetal.
1986
444
1938 and 1970
-------
78
Section <4
Table 4.6 (continued)
Group studied
Mortality study of workers
employed at a Texas
refinery between 1952 and 1981
Mortality study of
commercial pressmen
members of Local 51 who
died between 1950 and 1981
Exposure level/
duration
<1 ppm/up to
27 years
Levels not
given — benzene
and other
solvents/
duration not
well documented
Condition
observed
Stomach cancer
Cancer of
buccal cavity
Pharynx cancer
Larynx cancer
(No leukemia)
Lymphatic
cancer
Hematopoietic
cancer
Non-Hodgkin's
lyrnphoma
Author
call" SMR References
• • Tsai et al
• • 1983
• •
• •
• • Zoloth et
al 1986
• •
• •
9 DC — Direct correlation.
PC =• Possible correlation.
• = Author made no claim
-------
Toxicological Data 79
95% confidence intervals are quite wide, particularly for the higher
doses, which is to be expected with only nine leukemia deaths. There was
no apparent pattern for these deaths with regard to latency, which
ranged from under 5 years to more than 30 years. There was also a
statistically significant excess of death from multiple myeloma.
• f
In addition, numerous other studies have evaluated the relationship
between benzene exposure and cancer but without attempting to quantify
the relationship. Alderson and Rushton (1982) found a deficit of
leukemia and no excess of myeloid leukemia in a mortality study of
35,000 workers at eight oil refineries in the United Kingdom. There was
no monitoring for benzene exposure, but the authors say the average
benzene exposure is "likely to have been greater than for the population
as a whole."
A case-control study was conducted as an extension of this
investigation (Rushton and Alderson 1981). Based on job history, each
worker was allocated to a benzene exposure level of "low," "medium," or
"high," and deaths from leukemia were analyzed. The risk for the workers
with medium or high exposure, relative to the risk for workers with low
exposure, approached significance (? - 0.05) when length of service was
taken into account. The authors state that if there were an increased
risk of leukemia associated with benzene exposure, only a very small
proportion of the refinery work force would be affected. Alderson and
Rushton (1982) point out that the eight refineries have a quite
different range of plants and processes; that the workers have been
employed for varying lengths of time and at varying job assignments; and
that epidemiological studies at oil refineries are likely to be beset
with problems of mixed exposures and small numbers of men who have
worked at specific plants.
In a follow-up to a study by McMichael et al. (1975), Vilcosky
(1984) did not find any correlation between benzene and any of the
cancers reported. He points out, however, that "exposure" should be
reinterpreted in this study as "potential exposure" and that all of the
leukemia cases in the earlier study had died before the beginning of the
Wilcosky study.
Decoufle et al. (1983) found a significant increase of leukemia
deaths in a study of chemical workers, but made no attempt to correlate
exposure levels beyond saying that it was from fugitive emissions
peculiar to the technology, quality control, and maintenance procedures.
They also observed that some employees' personal habits such as cleaning
hands, tools, and clothes in benzene and siphoning benzene for home use
contributed to their exposure. Although not reported in other studies,
this may not be a unique occurrence.
Aksoy et al. (1974a) reported a leukemia incidence during 1967 to
1973 of 13/100,000 among 28,500 Istanbul shoe workers exposed to 150 to
650 ppm benzene for 4 months to 15 years. That is significantly higher
than the estimated 6/100,000 of the general population. After the
phaseout of benzene in 1969, the number of leukemias decreased, and none
were reported in the subsequent 3 years (Aksoy 1980). IARC (1982)
comments that "the estimates are limited by the study design
characteristics and by the uncertainties about the way in which cases
were ascertained and how many of the study population were exposed and
-------
80 Section 4
how many unexposed." EPA (1986) called the "exposure information so
imprecise that they are not suitable for quantitative assessment."
Yin et al. (1987a) did a retrospective cohort study of 28,000
benzene workers in China,- all of whom had worked in various factories
for at least half a year between 1972 and 1981; however, exposure and
employment duration were not necessarily limited to those years. Thirty
cases of leukemia (23 acute, 7 chronic) with a mean latency of 11.4
years (0.8 to 49.5 years) were found in the benzene cohort, as opposed
to 4 in a matched control cohort. Twenty-five of the leukemic workers
had already died. Information on exposure levels was collected from
company records, but there is no indication of the extent of these
records with the exception of a note that three levels were based on
only one measurement. Mean benzene levels to which workers developing
leukemia were exposed ranged from 10 to 1,000 mg/m3 (-3 to 330 ppm),
with the majority falling between 50 and 500 mg/m3 (16 to 160 ppm). It
should be noted that the exposure ranges from which the means were
derived were rather wide, indicating the possibility of at least
occasional high exposures. Only four upper-level measurements were less
than 10 ppm, while half of the remaining cases were between 10 and
100 ppm, and the other half were between 100 and 2,000 ppm. The authors
observed that the cumulative mortality of leukemia was in proportion to
the duration of the exposure to benzene up to 20 years and then leveled
off.
The same group reported that between 1979 and 1981 Chinese workers
using benzene or benzene-containing mixtures were examined, and nine
cases of leukemia were found. (Presumably, some of these may have been
reported in the earlier study discussed above.) Although one worker was
exposed for only 2 years, the others were exposed for between 7 and 25
years. No estimate of exposure levels was given for the leukemia cases,
but exposure estimates for aplastic anemia cases found in the same study
were 93 to 1156 mg/m3 (-30 to 360 ppm) (Yin et al. 1987b).
In order to give the reader a slightly broader view of the
literature than is possible within the scope of this report, some
primary sources not included elsewhere in this section are cited in
Table 4.7 along with the review in which they were found. The reader
should not assume that these were the only sources cited by the reviewer
or the sole basis for the reviewer comments included. With"the exception
of Mallory eC al. (1939, as reported in IARC 1982) and Gallinelli (1966,
as reported in Goldstein 1977), the human studies are of persons exposed
or potentially occupationally exposed to varying levels of benzene for
varying lengths of time.
Animal. Recent studies have shown benzene to be carcinogenic in
animals by inhalation although there is not universal acceptance of all
results, primarily because of the difficulty of developing reliable
animal models for benzene-induced leukemia.
The Goldstein et al. (1982a) study, using lifetime inhalation
exposure, was the first to report leukemia in test animals. Although it
is not statistically significant compared with controls, the authors
point out that the granulocytic leukemia found is extremely rare in
Sprague-Dawley rats, even after treatment with known leukemogenic
agents. They suggest the importance of the work in terms of a potential
-------
lexicological Data 81
Table 4.7. Carcraogeokity review stadia of occnpatkwally exposed workers
Reviewer
Work cited
Conditions reported
Reviewer's comments
R Snyder 1984
Kalf et al
1987
Infante and
White 1983
Cole and
Merletti 1980
I ARC 1982
McMichael
etal 1975.
Monson and
Nakano 1976
Vighani 1976,
Arpet al 1983
Browning 1965
Vighant and
Form 1976
Tabershaw and
Lamm 1977,
Zenz 1978
Aksoy 1985a LeNoir 1897
Bousser et al
1947
Vianna and
Polan 1979
Torres et aL
1970
Delore and
Borgamo 1928
Lymphatic leukemia.
myelogenous
leukemia.
lymphosarcoma
Myelogenous
leukemia
Acute myeloid
leukemia.
subacute myeloid
leukemia.
chronic myeloid
leukemia,
lymphatic leukemia,
erythroleukemia
Acute leukemia,
chronic myeloid
leukemia.
chronic lymphatic
leukemia
Leukemia
Leukemia
Lymphosarcoma
Malignant
lymphoma
IgG myeloma
Lymphoblastic
leukemia
Most observers agree that the
lowest air levels of benzene
demonstrated to produce decreases
in any circulating blood
cells in humans are in the range
of 40 to 50 ppm over a penod of
lime. Until the mechanisms of
action of benzene are determined
and used in the preparation of
nsk estimates, debates over
acceptable levels of human
exposure will continue
Benzene is a carcinogen
associated with increased
incidence of myelogenous leukemia
in humans
Epidemiologic studies of workers
have been too insensitive to
determine nsk of death from
cell types of leukemia that may
have nsk ratios of leu than
5 0. Case studies suggest an
association of chronic leukemia.
including lymphatic leukemia and
benzene
There is sufficient evidence
that benzene is carcinogenic to
hematopoietic tissues in man
(leukemia)
There seems to be sufficient
data to incriminate benzene as a
potent carcinogen causing
leukemia, malignant lympnoma,
multiple myeloma, and lung
cancer. Genetic factors may
have a role in the development
of condition
It is established that human
exposure to commercial benzene
or benzene-containing products
can cause damage to the hematop-
oietic system, including
pancytopema. The relationship
between benzene exposure and the
-------
82
Section
Table 4.7 (coatfamed)
Reviewer
Work cited
Conditions reported
Reviewer's commenu
Hunter 1939
White et aL
1980
Mallory
et al. 1939
DeGowm 1963
Tareeff et al.
1963
Goguel et al.
1967
Ludwig and
Wenhermann
1962
Galavotti and
Troisi 1950,
Nissen and
Soeborg
Ohlsen 1953,
DiGuhelmo and
lannaccone
1958.
Rozman et al.
1968.
Byron et aL
1969.
Forni ftfld Moroo
1969.
Girard and
Revol
1970
Ishimani et
al. 1971
development of acute myelogenous
leukemia has been established in
epidemiological studies.
Reports linking benzene to other
malignancies were considered to
be inadequate for evaluation.
There is sufficient evidence
that benzene is carcinogenic in
man
Lymphoblastic
leukemia (non-
occupational—
12-year-old boy
who frequently
used paint remover)
Acute myeloblastic
leukemia
Myeloid leukemia
Leukemia
Myeloid leukemia,
chronic lymphoid
leukemia,
acute leukemia,
eryihroleukemia
Myeloid leukemia
Erythromyelosu
Acute leukemia,
chronic lymphoid
leukemia,
myeloid leukemia
Leukemia
-------
Table 4.7 (continued)
Tax Leo logical Data 83
Reviewer
Work cited
Conditions reported
Reviewer's comments
Goldstein 1977
Emile-Well 1932.
Oldfelt and
Knutson 1948.
Curletto and
Ciconah 1962.
Inceman and
Tangun 1969,
Kinoshita et
al I96S,
Tzanck et al
1937.
Zini and
Alessandn
1967,
Gallmelli
1966
Appuhn and
Goldeck I9S7.
Kohli et al.
1967
Acute myelogenous
leukemia
(Nonoccupational—
16-yr-old an
student)
Erythroleukemia
Occupational exposure to benzene
appears causally related to
acute myelogenous leukemia and
its acute variants The
question of whether leukemogene-
sis occurs only after high-dose
benzene exposure leading to
significant bone marrow damage
remains unanswered
-------
84 Section 4
model for the study of benzene-Induced leukemia. The same group (C. A.
Snyder et al. 1984) suggest a possible causal relationship between
benzene and the incidence of certain tumors that rarely occur
spontaneously.
Maltoni et al. (1982c,d; 1983; 1985) have reported inducing Zyrabal
gland carcinoma, for which there is no human counterpart, and other
tumors by inhalation. The EPA Gene-Tox Carcinogenesis Panel (Nesnow et
al. 1986), in an evaluation of the Haltoni et al. (1982d) and Maltoni et
al. (1983) studies, called results of the inhalation experiments
inconclusive.
A major continuing study (Cronkite et al. 1984, 1985; Cronkite
1986) provides a basis on which a reproducible model may be built. In
this study mice were exposed to 300 ppm benzene by inhalation 6 h/day,
5 days/week for 16 weeks. This exposure regimen was selected because the
authors thought it most closely paralleled likely human exposure. Human
epidemiological studies in the literature reported that occupational!/
exposed persons were exposed for about 15% of their life span; 16 weeks
represents -15% of the life span for mice. Although precise occupational
exposures were not known, most studies indicated that workers had been
exposed to up to 250 to 300 ppm during at least part of a working day;
thus 300 ppm was chosen. The C57B1/6 and CBA/Ca mouse strains were
chosen for these studies because of their respective susceptibilities to
ionizing radiation-induced thymic lymphoma and acute myeloblastic
leukemia (AML). The strains are also recognized for their low
spontaneous rates of AML, the disease most frequently associated with
benzene exposure in humans.
Cronkite et al. (1984) reported a highly significant increase in
leukemia in C57B1/6 mice after exposure according to the above regimen.
In a continuation of that study (Cronkite et al. 1985), a definite
pattern for lymphoma appearance and mortality was observed. A first wave
of lymphoma commenced at about 150 days after exposure. The mice began
to die at 330 days, and mortality increased through 390 days, at which
time it leveled off. A second wave of lymphoma and solid tumors began
420 days after exposure, and mortality did not increase again until 570
days after exposure. This is a "significantly different pattern for the
appearance of lymphoma and solid tumors than that after lifetime
exposure (i.e. "lifetime exposure" as reported by C. A. Snyder et al.
1980). This suggests that continuous exposure either suppresses the
incidence of lymphoma or shortens the life span of the mice so that
lymphoma cannot be observed."
In 1986, Cronkite reported that 100 or 300 ppm benzene is
carcinogenic (leukemogenic) in both male and female CBA/Ca mice.
However, no experimental details for the 100-ppm effect are given in the
report.
Inhalation is the most common route of exposure to benzene for
humans, and the successful induction of cancer in animals by this route
is an important step in understanding the most basic questions
concerning benzene and human health. Some of these are the mechanisms of
cancer development, the role of genetic factors in the development of
cancer, and, most important from a regulatory standpoint, dose-response
relationships.
-------
ToxLcologLcal Data 85
Rather than describing all experiments in the text, Tables 4.8 and
4.9 summarize examples of the growing body of animal results, the
oncogenic end points observed, and the investigators' assessment of
correlation. Table 4.8 presents a summary of animal inhalation
experiments that have investigated the potential carcinogenicity of
benzene. Some author comments are given in the footnotes to this table.
Table 4.9 presents essentially the same data but allows a more detailed
examination of tumor type and animal species, while also focusing on the
lowest effective exposure concentrations.
4.3.6.3 Oral
Human. There are no studies available.
Animal. In recent years, there have been several oral/gavage
studies with positive results. There is some discussion of the relevance
of gavage studies vs other routes by which human exposure is more likely
to occur, especially inhalation and dermal (NTF 1986).
Investigation of benzene-induced neoplasia in laboratory rodents
has increased (Dean 1985). According to the EPA, recent research has not
shown that benzene is a noncarcinogen, but that the correct model
incorporating exposure route, animal strain, and species has not been
tested (EPA 1986a). Haltoni and Scarnato, exposing rats to benzene by
ingestion, were the first to demonstrate that benzene is an animal
carcinogen (Maltoni and Scarnato 1977, as reported in Maltoni 1983;
Maltoni and Scarnato 1979 as reported in Maltoni 1983).
Maltoni et al. (1982b, 1983, 1985) have reported inducing Zymbal
gland carcinoma, for which there is no human counterpart, by
oral/gavage. There seems to be general agreement for a causal role of
benzene in the formation of these tumors (see IARC 1982, R. Snyder 1984,
Dean 1985). Maltoni et al. (1982b, 1983) also report the induction of
other tumors. The EPA Gene-Tox Carcinogenesis Panel (Nesnow et al.
1986), in an evaluation of the Maltoni et al. (1982d) and Maltoni et al.
(1983) studies, concurred on their findings for the induction of Zymbal
gland and oral carcinoma by oral/gavage.
NTP has now completed a 2-year oral/gavage study of rats and mice
showing positive results (NTP 1986). For details of that study, see
Tables 4.10 and 4.11.
Rather than describing all experiments in the text> Tables 4.10 and
4.11 summarize examples of the growing body of animal results, the
oncogenic end points observed, and the investigators' assessment of
correlation. Table 4.10 presents a summary of animal oral/gavage
experiments which have investigated the potential carcinogenicity of
benzene. Some author comments are given in the footnotes to this table.
Table 4.11 presents essentially the same data but allows a more detailed
examination of tumor type and animal species, while also focusing on the
lowest effective exposure concentrations.
-------
86
Section
Table 4.8. Sommmry of inimaJ Inhalmdo. c«rctoog«^eJty expertoerti
Species"
CS7BL/6J mice
AKR/J mice
CD-I mice
SDrat
SDrat
SDrat
C57BL (6 mice)
SD raw
CS7BL [6J mice
(female))
CBa/CA mice (male)
CBA/CA mice (male)
Exposure or
observation tune
488 days '
505 days
Life
86 weeks
116 weeks
118 weeks'
64 weeks
863 days
580 days
800 days
900 days
Effect
Lymphocytic lympboma (thymic
involvement)
Myeloma
Leukemia
Malignant lymphoma
Myelogenous leukemia (acute) [I]f
Myelogenoiu leukemia (chronic) [I]
Zymbal gland carcinoma
Hepatoma
Breeders
Zymbal gland caranoir • I ]
Hepatoma [I]
Mammary carcinoma [1
Offspring-
Zymbal gland carcinoma [I]
Nasal carcinoma [I]
Hepatoma [I]
Leukemia (I)
Mammary carcinoma [I]
Thymic lymphoma [I]
Lymphoma. unspecified [I]
Zymbal gland carcinoma
Liver tumor
Chronic granulocytic leukemia
Mammary carcinoma
Lymphoraa
Solid tumor
Leukemia
Hepatoma
Author
call*
DC
DC
•
•
NC
PC"
PC
DC?
DCf
DC*
PC
•
DC
DC
PC
•
•
DC1
DC
PC
PC
DC
PC
DC
DC
DC
PC
References
C A Snyder
et al. 1980
C A Snyder
etal 1980
Goldstein et al
I982a
Maltoni et al
1982d
Maltoni et al.
1982b
Maltoni et al.
1983
Maltoni et al.
1983
Crookite et al.
1984
C A. Snyder
etal 1984
Cronkite et al.
1985
Cronkite 1986
Cronkite 1986
"SD - Sprague-Dawley.
*DC - direct correlation, NC - no correlation, PC - possible correlation, and • - no author call.
"Gene-Tox Carcinogenens Panel call (Nesoow et al. 1986)- [ + ] - positive, [I] - inconclusive.
rfThe importance of toe present study is in terms of a potential model for the studv of beniene-induced
leukemia. Although the authors claim this is the fust case of myelogenous leukemia reported in laboratory
animals, the incidence of myleoproliferative disease is not significantly higher than controls. There has. how-
ever, been no observation of spontaneous myeloproliferative disease in SD rats or CD-I mice.
'Continuous exposure to 200-300 ppra benzene for 4-7 h daily causes onset of Zymbal gland carcinoma.
One carcinoma (female) out of 158 male and 149 female controls.
•^These results provide the first evidence that benzene causes hepatomas in experimental animals, further
proof that benzene is a mulbpotential carcinogen.
'Exposure started at 12 days gestation and continued for 118 weeks. Offspring were thus exposed initially
as embryos.
*The results confirm that benzene causes the onset of zymbal gland carcinomas in SO rats, even when
given by inhalation. Incidence parallels length of treatment. Nasal carcinoma observed. Appears to cause
hepatomas and other related dysplastic and hyperplastic lesions.
'The 88 experimental controls were leukemia free. Death rates due to leukemia-lymphoma for 118 ben-
zene exposed and 354 recent historical control mice were compared by a Cox model of survival analysis. Ben-
zene is a significant variable (P < 0.0001) in predicted lymphoma-leukemia death rale.
-------
Toxicological Data 87
TaMe 4.9. Carcinogenic-related end points observed ID uiinab exposed to benzene by inhalation"
End points observed
AKR/J C57BL/6J CD-I CBA/Ca
SD rat mouse mouse mouse mouse
References
Lymphocytic lymphoma
Myelogenous leukemia
acute
Myelogenous leukemia
chronic
100/life
300/life
300/hfe
300/hfe
C A Snyder et al 1980
Goldstein et al 1982a
Goldstein et al I982a
Zymbal gland carcinoma
Hepatoma
Mammary carcinoma
Nasal carcinoma
Thymic lymphoma
Lymphoma unspecified
Liver tumor
Granulocytic leukemia
Solid tumor
Leukemia
100/life
200-300/104
100/hfe
200-300/104
300/16
300/16
100/hfe
100/hfe
300/16
C A Snyder et al. 1984
300/16 Maltom et al. 1982b (rat).
Cronkite 1986 (mouse)
C. A Snyder et al. 1984
Maltom 1983
Cronkite et al. 1984
Cronkite et al 1984
C A Snyder et al 1984
C A Snyder et al 1984
Cronkite et al 1985
300/16 Cronkite 1986
"Doses are expressed in ppm/h given 4-7 h/day. 5 days/week over a number of weeks or lifetime (e g, 300/99 =
300 ppm given for 99 weeks): exposures shown are the lowest for which author claims possible causal relationship
-------
88
Section
Table 4.10. Summary of animal oral/gavage carcinogenicity experiments
Species
strain"
SD rat
SD rat
SDrat
Wistar rat
Swiss mice
F344/N rat
Observation
time* End points observed
84 weeks Carcinoma of oral cavity
Zymbal gland carcinoma
115-157 Glioma
weeks
92 weeks Zymbal gland carcinoma [ + Y
Carcinoma of oral cavity [ + ]
Carcinoma of nasal cavity
Angiosarcoma
Leukemia
Mammary tumor
As above plus:
Hepatoma
Others
100 weeks Zymbal gland carcinoma
Carcinoma of oral cavity
Thymoma
Other hemolymphoreticular neoplasms
100 weeks Zymbal gland carcinoma
Adenocarcinoma pulmonary tumor
Hemolymphoreticular neoplasia
2 years Carcinoma of oral cavity [ + ]
Zymbal gland carcinoma [ + ]
Skin carcinoma (M) [ + ]
Author
callf
DC*
DC
NC'
DC*
DC
DC
PC
DC
DC
DC
PC
DC*
DC
*
DC
DC
DC
DC
DC1
DC
DC
References
Maltoni et al
19826
Maltoni et al.
1982a
Maltoni et al.
Maltoni et al
Maltoni et al.
NTP 1986
^
1983
1985
1985
-------
Toxicological Data 89
Table 4.10 (continued)
Species
strain"
B6C3F, mice
Observation
time* End points observed
2 years Zymbal gland carcinoma [ + ]
Malignant lymphoma [ + ]
Alveolar/bronchiolar carcinoma [ + ]
Alveolar/bronchiolar adenoma
Hardenan gland adenoma (M) [ + ]
Preputial gland carcinoma (M) [ + ]
Ovarian granulosa cell tumor (F)
Mammary gland carcinoma (F) [ + ]
Mammary gland carcmosarcoma (F)[ + ]
Author
call'
DC
DC
DC
DC
DC
DC
DC
DC
DC
References
NTP 1986
"SD = Sprague-Dawley rat.
* Actual exposure period may have been less.
CDC = Direct correlation.
NC = No correlation.
PC = Possible correlation.
* = No author call.
'These results provide the first evidence that benzene causes carcinoma of the oral
cavity in experimental animals, further proof that benzene is a multipotential
carcinogen.
TJnder our experimental conditions, benzene did not seem to produce brain tumors. One
glioma (male) out of 30 male and 30 female controls.
7Gene-Tox Carcmogenesis Panel call (Nesnow et al. 1986): [ + ] = Positive,
[I] = Inconclusive.
*Data confirm that benzene causes Zymbal gland carcinoma at two dose levels with dose
response. It induces carcinoma of the oral cavity, very unusual in our colony of
rats: also, liver angiosarcoma very rare in SD rats. Benzene increases incidence of
hemolymphoreticular neoplasms ("leukemias") and mammary carcinoma.
Benzene by ingestion or inhalation is a multipotential carcinogen in two strains of
rats and in mice and precedes a variety of tumors. Incidence of Zymbal gland
carcinoma and carcinoma of the oral and nasal cavities is affected by length of
inhalation treatment and age of animals.
'Under the conditions of these 2-year gavage studies, there was clear evidence of
carcmogenicity of benzene for male and female F334/N rats and male and female B6C3F,
mice.
-------
90 Section
Table 4.11. Carcinogenicity-related end points observed in animals exposed
to benzene by garage"
SD rat* Wistar* F344/N* Swiss' B6C3F,'
rat rat mouse mouse
Duration in weeks
End points observed 52 100 103 78 103
Zymbal gland carcinoma SO 500 50 500 50
Oral carcinoma 250 500 50
Nasal carcinoma 250
Leukemia 50
Mammary tumor 50 500
Hepatoma 250
Hemolymphoreticular 500 500
neoplasia
Skin carcinoma 200
Pulmonary adenocarcinoma 500
Malignant lymphoma 25
Alveolar/bronchial 50
carcinoma
Alveolar/bronchial 25
adenoma
Hardenan gland 25
adenoma
Preputial gland 50
carcinoma
Ovarian granulosa 100
cell tumor
Mammary gland 50
carcinoma
Mammary gland 100
carcinosarcoma
Hcpatocellular adenoma 25
Hepatocellular carcinoma 50
"Doses (mg/kg) are the lowest 5-days/week exposures at which author claims
causal relationship.
*Maltoni 1983.
'Maltoni et al. 1985.
'NTP 1986.
-------
lexicological Data 9L
4.3.6.4 Dermal
Human. There are no studies available.
Animal. There is no evidence that benzene has induced skin tumors,
although not all possible sites were examined in all experiments (IARC
1982). At one time, benzene was used as a solvent vehicle in the study
of carcinogenic compounds. As such it was applied topically as a control
without effect (Burdette and Strong 1941, Bock et al. 1959, Van Duuren
et al. 1969). Interestingly enough, Baldwin et al. (1961) argue against
the carcinogenicity of a compound being tested because "a similar tumor
incidence was observed in the benzene control" (there was no nonbenzene
control). These experiments are not considered adequate to determine
carcinogenic potential.
Bull et al. (1986) commented that it has been very difficult to
induce tumors in experimental animals with benzene and that the rate of
false-negative responses to chemicals with recognized carcinogenic
activity is quite high when tested on mouse skin.
4.3.6.5 General discussion
IARC concluded that there was sufficient evidence that benzene is
carcinogenic in humans and that there was limited evidence that benzene
is carcinogenic in animals (IARC 1982). The EPA Gene-Tox Carcinogenesis
Panel (Nesnow et al. 1986) calls benzene a sufficient positive in animal
studies, and NTP concluded that there was clear evidence of
carcinogenicity of benzene for the strains of rats and mice tested in
their 2-year oral/gavage study (NTP 1986). EPA (1988b) has verified the
weight-of-evidence classification for carcinogenicity as EPA category A,
based on a sufficient level of human evidence as supported by a
sufficient level of animal evidence. There are still questions regarding
both the mechanism of benzene carcinogenesis (Dean 1985) and the most
appropriate models for developing human risk estimates.
Based primarily on the Crump and Allen analysis of epidemiological
studies (Crump and Allen 1984) showing an excess of leukemia cases
(Rinsky et al. 1981, Ott et al. 1978, Wong 1983), OSHA has lowered the
benzene level to 1 ppm (OSHA 1987). This analysis uses the linear,
nonthreshold model generally accepted among regulatory bodies in the
United States for extrapolation of risks. In the OSHA hearings, Crump
explained, "Although many dose response forms could be posited, it was
felt that the number of leukemias is too few (there are only 16
leukemias in the Rinsky et al., Ott et al., and Wong cohorts combined)
to permit discrimination among alternative dose response models. A
linear model provides an acceptable fit to all data sets examined . . .
and the risk is not apt to be much larger than that predicted by a
linear model" (OSHA 1987).
Contributing factors influencing cancer development are not clearly
understood. Cancer may result from a multistage process occurring over a
long period of time, and presumably initial and progressive stages of
carcinogenesis may be modified by both genetic and environmental factors
(Strong 1977). Goldstein (1977) questions whether benzene may be an
-------
92 Section 4
Inducer or cocarcinogen rather Chan a direct carcinogen, and Cronkite
(1986) suggests that there is probably some repair of genetic damage
that leads to neoplastic change.
Only a small proportion of exposed individuals actually develop
leukemia; therefore it could be interpreted that there is a sensitive
subpopulation, possibly with some metabolic idiosyncrasy that allows the
formation of reactive metabolites at a specific cellular target (Dean
1985). A familial connection in benzene-related leukemia was established
by Aksoy (1985a,b). Blattner et al. (1976) describe a family involving a
father and four of five siblings with chronic lymphocytic leukemia. They
conclude that an inherited defect in a specific class of cells appears
to underlie susceptibility to leukemia in this family. Although the
authors do not mention benzene exposure, Goldstein (1977), in a review
of this work, points out that all had been employed in the dry-cleaning
business since the 1940s, a period during which benzene was widely used.
He suggests that the omission of this occupational exposure to benzene
may be evidence of a "generally lesser degree of physician recognition
of the association of benzene with leukemia."
Many mechanisms have been suggested for benzene carcinogenicity.
Leong (1977) has suggested that, through alterations in lymphocyte
populations, benzene and its metabolites may modify "immune
surveillance" and allow the development of unusual cellular species that
may lead to the development of leukemia and other neoplasms in humans.
Experimental data in animals and studies of human cases of benzene
intoxication indicate a link between nononcogenic suppression of
cellular growth and the development of leukemia. Many cases of benzene-
induced leukemia appear to have been preceded by aplastic anemia (Toft
et al. 1982). The compensatory response (regenerative hyperplasia)
observed in the bone marrow, thymus, and spleen of exposed animals may
play a role in the carcinogenic response (Rozen and Snyder 1985, C. A.
Snyder 1987). Harigaya et al. (1981) suggest that benzene may act as a
promoter, rather than an initiator, by forcing proliferation of the
hematopoietic pluripotential stem cell to maintain essential
hematopoiesis and thus hasten the appearance of preleukemic and
leukemogenic clones from stem cells that have been exposed to
leukemogenic initiaCing agents prior to benzene exposure.
One of the favored mechanisms for benzene toxicity or1-
carcinogenicity is related to the covalent binding of benzene
metabolites to cellular macromolecules. In mice administered
radiolabeled benzene for relatively short durations, metabolites have
been found covalently bound to liver, bone marrow, kidney, spleen,
blood, and fat (R. Snyder et al. 1978, Gill and Ahmed 1981, Longacre et
al. 1981a). The label was bound to the nucleic acids of the
hematopoietic cells and to nucleic acids and other macromolecules of the
mitochondria (Gill and Ahmed 1981), and, as the levels of covalently
bound and water-soluble metabolites increased, so did benzene toxicity
(Longacre et al. 1981a).
Lutz and Schlatter (1977) observed covalent binding to DNA in the
livers of rats exposed to benzene vapor. Phenol, hydroquinone, catechol,
benzoquinone, and 1,2,4-trihydroxybenzene form adducts in bone marrow
mitochondria, resulting in the inhibition of the synthesis of
-------
Toxicologies! Data 93
mitochondrial proteins that are necessary for mitochondria! function
(Kalf et al. 1982, as reported in Andrews and Snyder 1986).
The ultimate mechanism for benzene-induced hematotoxicity is not
known at this time; it could be one of the mechanisms discussed above
but most likely involves a combination of factors. Identification of the
mechanism would be -facilitated by clear identification of the specific
target cell and intracellular target of benzene and its metabolites
(Andrews and Snyder 1986).
For additional information on the carcinogenicity of benzene.
summaries and reviews of some of the animal studies can be found in I ARC
1982, Dean 1985, Maltoni 1983, Lee et al. 1983, Van Raalte and Grasso
1982, and NTP 1986. Some summaries and reviews of the human data can be
found in Goldstein 1977, Lee et al. 1983, R. Snyder 1984, Aksoy 1985a,
Aksoy 198Sb, and Kalf et al. 1987.
-------
95
5. MANUFACTURE. IMPORT, USE, AND DISPOSAL
5.1 OVERVIEW
Annual U.S. production of benzene is in excess of 1 billion
gallons, accounting for over 30% of the total produced worldwide.
Benzene is obtained almost entirely from petroleum sources. It is used
primarily as a chemical intermediate in the manufacture of various
plastics, synthetic rubbers and fibers, and resins. Such materials are
used in a wide variety of consumer goods, including plastic containers,
radios, toys, sporting goods, furniture, appliances, automobiles, tires,
adhesives, and textiles. Other uses for benzene and/or its derivatives
include dyes, drugs, pesticides and other agricultural chemicals,
lubricants, solvents, and cleaning products. Benzene also occurs in
gasoline at concentrations averaging less than 1%, but which can be as
high as 5%. On a volume basis, probably most of* the benzene produced
remains in petroleum fuels such as gasoline.
5.2 PRODUCTION
More than 90% of the benzene produced in the United States is
derived from petroleum sources. Benzene is obtained from refinery
streams (catalytic reformates), pyrolysis gasoline, and toluene
hydrodealkylation. During catalytic reforming, naphthenes and paraffins
in naphtha are converted to aromatic hydrocarbons, and the benzene is
recovered by solvent extraction (e.g., with sulpholane or tetraethylene
glycol). Pyrolysis gasoline, which is a by-product generated when
ethylene and propylene are produced by the steam cracking of lower
paraffins or heavier hydrocarbons, is a mixture of saturated
hydrocarbons, monoolefins, diolefins, styrenes, and aromatics, including
a high percentage of benzene (Hughes and Abshire 1983). In the toluene
hydrodealkylation process, toluene or toluene/xylene mixtures are
reacted with hydrogen at temperatures up to 730°C and demethylated to
produce benzene and methane. In 1981, catalytic reformates accounted for
about 50% of the total U.S. benzene production, pyrolysis gasoline 18%,
and toluene hydrodealkylation 24% (Hughes and Abshire 1983). Only about
half the benzene available through catalytic reforming is extracted; the
rest remains as a component of gasoline (IARC 1982, EPA 1985a). The
average concentration of benzene in gasoline is <1% (EPA 1985a), but it
can be as high as 4 to 5% (Holmberg and Lundberg 1985).
Benzene can also be derived from coal in the light oil produced
during coke manufacture. This source accounted for about 7% of U.S.
production in 1981 (Hughes and Abshire 1983).
Estimates of U.S. production of benzene in 1985, the most recent
year for which data are available, range from 1.275 billion gallons
(C&EN 1987b) to 1.363 billion gallons (CEH 1987). A U.S. benzene
-------
96 Section 5
production level of about 1.5 billion gallons has been predicted for
1987 (C&EN 1987a).
5.3 IMPORT
Annual imports of-benzene into the United States over past years
have generally ranged from 100 to 200 million gallons. Imports in 1987
were estimated to total 175 million gallons (C&EN 1987a). Exports were
thought to be less than 10 million gallons.
5.4 USE
Benzene recovered from petroleum and coal sources is used primarily
as an intermediate in the manufacture of other chemicals and end
products. The major uses of benzene are in the production of
ethylbenzene, cumene, and cyclohexane. Ethylbenzene (57% of benzene
production volume) is an intermediate in the synthesis of styrene, which
is used to make plastics and elastomers. Cumene (20%) is converted to
phenol, phenol derivatives, and acetone, which are used in the
manufacture of phenolic resins, epoxy resins, nylon fibers, and acrylic
resins. Cyclohexane (12%) is used to make nylon fibers and resins. Other
industrial chemicals manufactured from benzene include
nitrobenzene/aniline (5%)., linear alkylbenzene sulfonates (3%),
chlorobenzene (2%), anthraquinone, benzene hexachloride, benzene
sulfonic acid, biphenyl, hydroquinone, resorcinol, and maleic anhydride
(CEH 1986).
In the past, benzene was widely used as a solvent, but this use is
now decreasing (IARC 1982). Less than 2% of the amount produced is used
as a solvent in such products as trade and industrial paints, rubber
cements, adhesives, paint removers, artificial leather, and rubber
goods. Benzene has also been used in the shoe manufacturing industry,
the rotogravure printing industry, and chemical laboratories (OSHA 1978,
Mara and Lee 1978, both as reported in EPA 1985a). In the past, consumer
exposure to benzene occurred through the use of paint strippers,
carburetor cleaners, denatured alcohol, and rubber cement used in tire
patch kits and in arts and crafts supplies (Young et al. 1978).
Recently, Wallace et al. (1987) reported that benzene emissions could be
detected from such products as carpet glue, textured carpet, liquid
detergent, and furniture wax. For many solvent uses, benzene has been
replaced by other organic solvents; however, it may still occur as a
trace impurity in these products.
5.5 DISPOSAL
Waste by-products from benzene production processes include acid
and alkali sludges, liquid-solid slurries, and solids (Saxton and
Narkus-Kramer 1975, Gilbert et al. 1982). Although benzene is included
in the listing of Resource Conservation and Recovery Act (RCRA)
hazardous wastes (F001-F005, spent solvents; 51FR6537), it is not yet
subject to the treatment standards required for such wastes, and,
consequently, it may be disposed of legally in landfills. In the past,
landfilling has been a major method of disposing of benzene-containing
industrial wastes. Estimates of benzene levels disposed of in solid
wastes from the petroleum industry are given in Table 5.1.
-------
Manufacture, Import, Use. and Disposal 97
Table 5.1. Disposal of petroleum industry wastes containing benzene
Disposal
method
Landfilling
Landspreading
Lagoonmg
Incineration
Total
Fraction
disposed
51.1%
8.4%
397%
0.8%
Solid wastes
(kkg)
5.88 X 10*
0.97 X 108
4.57 X 10*
0.09 X 108
Benzene
(kkg)
116
19
91
2
•710
Source: Adapted from Gilbert et al. 1982. based on Jacobs
(1978) by JRB(1980b).
-------
98 Section 5
The suggested method of disposing of liquid benzene wastes is
incineration (ITII 1975, Sittig 1981). Small spills can be handled by
absorbing the benzene on paper, evaporating in a glass or metal dish in
a hood, and then burning the paper (ITII 1975).
Benzene-containing wastevater can be processed in standard
wastewater treatment systems using covered hydrocarbon/water separators
(BLackwood et al. 1979).
-------
99
6. ENVIRONMENTAL FATE
6.1 OVERVIEW
Benzene is released Co Che environment by both natural and man-made
sources, although Che anthropogenic emissions are undoubtedly Che most
significant. Annual benzene emissions from man-made sources are in che
vicinity of 236,000 metric tons. Chemical degradation reactions,
primarily che reaction wich che hydroxy radical, limit the atmospheric
residence time of benzene Co only a few days--and possibly only a few
hours--if che concentration of hydroxy radicals is sufficiently high.
Biodegradacion, principally aerobic, is Che mosC importanC environmental
face mechanism for waCer- and soil-associated benzene and, although
probably somewhat slower Chan atmospheric chemical reactions, under the
right condicions can be quiCe efficient.
6.2 RELEASES TO THE ENVIRONMENT
As che data in Sect. 7.2 indicate, benzene is being released into
the environment. However, since benzene is released both from natural
sources [e.g., crude oil seeps (Brief et al. 1980), forest fires, and
plant volatiles (Graedel 1978)] and man-made sources, careful
consideration of monitoring data is necessary. Available data suggest
that che benzene levels recorded in rural areas may be che result of
biological sources, while in urban areas the predominant sources are
probably man-made. If Chis is true, Chen seasonal variacions in benzene
release Co rural environmencs would be expecced because of che more
active biological accivicy in peak growing seasons.
The most significant source for release of benzene Co che
environment is undoubcedly from che combusCion of gasoline. An
indicaCion of Che magnitude of release can be obtained Chrough
consideration of the firsc entry in Table 6.1. It is likely that a
significant amount of the estimated 40 to 80 thousand metric tons are
released from combustion, but the exact fraction cannot be calculated
from Table 6.1. Table 6.2 presents an estimate of the annual emission of
benzene to water, and Table 6.3 provides a more detailed look at the
potential sources of benzene released to water. Other sources of
environmental release, although minor compared to Chose lisced in
Tables 6.1 and 6.2, include effluents from septic tanks (Viraraghavan
and Hashem 1986), structural fires (Lowry et al. 1985), off-gassing from
particleboard (Glass et al. 1986), and exhaled air of smokers (Wester et
al. 1986) as well as from cigarette smoke itself (Lauwerys 1979, as
reported in IARC 1982).
-------
100 Section 6
Table 6.1. Annual emissions of benzene to air
from various sources in the United States
Source Emissions (thousand metric tons)
Component of gasoline" 40.0-80.0
Production of other chemicals 44 4-56.0
Indirect production of benzene* 23.0-79.0
Production of benzene from petroleum 1.8-7.3
Solvents and miscellaneous sources 1.5
Imports of benzene 0.013
"Production, storage, transport, vending, and combustion.
*Coke ovens, oil spills, nonferrous metals manufacturing, ore mining,
wood processing, coal mining, and textile industry.
Source: Adapted from JRB Associates, Inc. I980a, as reported in
IARC 1982.
Table 6.2. Annual emissions of benzene to water in the United States
Source Emissions (metric tons)
Indirect production of benzene" 200-11,000
Solvent and miscellaneous uses 1450
Production of chemicals other than benzene 1000
Production of benzene from petroleum 630
Imports of benzene 13
"Coke ovens, oil spills, nonferrous metal manufacture, ore min-
ing, wood processing, coal mining, and textile manufacture.
Source: Adapted from JRB Associates, Inc. 1980a, as reported
in IARC 1982.
-------
Environmental Face 101
T»We 6.3. Benzene concentrations in wastewalers
Concentration (ppb)
Type of wastewater
Occurrence
High
Medium Low
Timber products
Steam electric
Leather tanning
Iron and steel manufacturing
Petroleum refining
Nonferrous metals
Paint and ink
Printing and publishing
Ore mining
Coal mining
Organic* and plastics
Inorganic chemicals
Textile mills
Plastics and synthetics
Pulp and paper
Rubber processing
Auto and other laundries
Pesticides manufacturing
Photographic industries
Pharmaceuticals
Explosives
Battery manufacturing
Plastics manufactunng
Foundries
Porcelain/enameling
Aluminum
Electronics
Oil and gas extraction
Organic chemicals
Mechanical products
Transportation equipment
Synfuels
Public-owned treatment works
Rum industry
17
21
8
6
43
35
122
22
2
30
58
60
5
17
45.
14
8
17
5
II
17
2
1
2
5
2
17
16
27
4
2
2
24S
6
150025
78819
2274 46
17600
7649 25
29169
403848
83100
20281
757106
303421
5367 79
29044
53765
2645 33
664158
41527
78585
4986
381601
5086 90
56431
142.80
12893
807
25399
281943
9012.57
95752
19515
1482.20
2660
500312
16.83
6448
2847
503
1487
3774
29 17
3592
2505
10191
2184
9494
1953
14.15
1793
2506
9730
964
3785
1626
3002
36230
448 15
14280
6945
374
13072
8843
9126
12.47
625
79631
1795
2973
879
1549
2 12
1 76
524
209
042
1 71
1 37
102
106
1 68
097
503
148
089
263
1 80
190
8 18
169
18 IS
33199
14280
997
273
744
282
1195
078
424
11043
930
0.72
390
"Number of samples containing benzene
Source: Unpublished data from EPA survey; see Shackelford and Chne
1983 for discussion of methodology
-------
L02 Section 6
6.3 ENVIRONMENTAL FATE
A tremendous volume of literature exists concerning the
environmental fate of benzene. This section will cite only a sufficient
number of these references to illustrate certain points; the reader is
directed to the following for more detailed information: CHEMFATE (1987,
an on-line database available through Syracuse Research Corporation);
Versar, Inc. (1979); and Korte and Klein (1982).
6.3.1 Transport
The volatility and solubility of benzene are properties with the
greatest influence on environmental transport of benzene. On the basis
of solubility data (1,000 mg/L at 25°C) benzene can be said to have a
fairly high solubility in water. It is considered to be a high
volatility chemical with a vapor pressure of 95 mm Hg at 2S°C (Mackay
and Leinonen 1975).
For benzene released to the air some washout in rainwater is
anticipated. Once benzene in rainwater is deposited in soil or water,
volatilization is expected to return a portion back to the atmosphere,
starting the cycle again. It is conceivable that under the proper
environmental conditions, e.g., no rain and strong winds, benzene could
be transported several miles; however, because of its reactivity with
the hydroxy radical, global transport of benzene is not likely.
When released to water, volatilization will result in a substantial
loss to the atmosphere. This potential loss is evident from the Henry's
law constant of 5.5 x 10*3 atm-m^/mol calculated by Mackay and Leinonen
(1975) [Smith et al. (1980) consider chemicals to have high volatility
if this constant is greater than 4.6 x 10'3 atm-m3/mol]. Hackay and
Leinonen (1975) estimated a half-life for benzene of 4.81 h for a
1-m-deep body of water at 25°C. Similarly, Branson (1978) estimated a
half-life of 4.8 h under the same conditions.
No information was found assessing the potential for benzene
transport to sediments. However, this is not viewed as a significant
transport process because 'the volatility of benzene would favor release
to the air, especially in waters where there is frequent exchange
between surface and bulk water. Branson (1978) notes that the chemicals
that will most likely be associated with sediments are those with low
vapor pressure and low water solubility, characteristics that do not
apply to benzene.
Benzene released to soil can be transported to the air through
volatilization, to surface water through runoff, and to groundwater as a
result of leaching. For the first two situations to occur, the release
would have Co be at or near the soil surface. If the released benzene is
buried in the earth, then the most likely transport mechanism will be
leaching to groundwater. A useful parameter for investigating the
leachability of a chemical is the soil sorption coefficient (KOc)•
According to Kenaga (1980), compounds with a KOC of <100 are considered
to be moderately to highly mobile. Thus, benzene with a KOC of 60 to 83
(Kenega 1980, Karickhoff 1981) would be considered mobile. Other than
the KOC, other parameters that must be considered to determine if
benzene will reach groundwater include the soil type (e.g., sandy vs
-------
Environmental Face 103
clay), Che amount of rainfall, the depth of the groundwater, and the
extent of degradation.
6.3.2 Transformation and Degradation
Degradation of benzene occurs through both chemical and biological
mechanisms; chemical degradation of benzene is the most important
process for atmospheric benzene and biodegradation most significant for
water- and soil-associated benzene.
6.3.2.1 Chemical degradation
There is little question that the most significant chemical
degradation process for benzene is its reaction with the atmospheric
hydroxy radical. This can easily be seen by calculating the half-lives
for the oxidation of benzene using the following method:
fOH - r-
t 4 - 0.693r (Lyman 1982) .
For OH radicals a half-life for benzene of 5.6 days can be
calculated using a value of 1.3 x 10'12 cm3/molecule•s for kQH (Gaffney
and Levine 1979) and a value of 1.1 x 106 molecules/cm3 for the
concentration of OH radicals (Lyman 1982). When an OH radical value of
1 x 10& molecules/cm3, corresponding to what might be present in a
polluted atmosphere, is used (Lyman 1982), the half-life is shortened to
1.48 h. The same method can be used for other active species such as 03
and 0(3P), but, in contrast, a half-life of 327 years for rural
atmospheres and 104 years for urban atmospheres is calculated for the
reaction of benzene with 03 using a rate constant for 03 of 7 x 10'23
cm3/molecules-s (Pate et al. 1976) and atmospheric concentrations for 03
of 9.6 x 1011 molecules/cm3 (rural) and 3 x 1012 molecules/cm3 (urban)
(Lyman 1982). Similarly, a half-life of 10.9 years for the oxidation of
benzene by 0(3P) radicals can be calculated using 7.2 x 10^
molecules/cm^ as the atmospheric concentration of 0(3P) radicals (NRC
1980b, as reported in EPA 1983) and a value for k 3 . of 0.28 x 10'13
cm3/molecule•s (Gaffney and Levine 1979). l '
Additional atmospheric reactions include those with nitrogen oxides
and sulfur dioxide, but, similar to reactions with 03 and 0(3P)
radicals, these reactions are secondary in importance to that of benzene
with OH radicals (Korte and Klein 1982). The reaction of benzene and
nitrogen oxides has been well investigated (e.g., Kopczynski 1964, Levy
1973, Nojima et al. 1975, Korte and Klein 1982), primarily to determine
the role of benzene in photochemical smog formation. The conclusion is
that benzene probably does not play a significant role in photochemical
smog formation. However, as noted by Nojima et al. (1975), some of the
products of the reaction of benzene with nitrogen oxide (laboratory
investigations) (e.g., nitrobenzene, o- and p-nitrophenol, and 2,4- and
2,6-dinitrophenol) may have potential adverse effects to human health.
Not much information is available concerning the chemical
degradation of benzene in water. However, what data are available
suggest that chemical degradation does not play an important role in the
-------
104 Section 6
fate of waterborne benzene. Using a rate constant for the reaction of
benzene with OH [(kQH of 0.31 x 1010 L/mol-s (Anbar and Neta 1967)], an
OH radical concentration in water of 1 x 10'17 mol/L (CHEMFATE 1987),
and the equation presented earlier in this section, a half-life of 0.71
year is calculated--much slower than the same reaction in air.
The direct photolysis of benzene in the atmosphere is not likely
since the upper atmosphere effectively filters out wavelengths of light
<290 run, and, according to Bryce-Smith and Gilbert (1976, as reported in
EPA 1983), benzene does not absorb wavelengths of light >260 run.
6.3.2.2 Biodegradation
The degradation of benzene by microorganisms has been well
researched, and the conclusion reached is that benzene is biodegradable
(e.g., see Haider et al. 1981, Hopper 1978, Setzkorn and Huddleston
1965, Tabak et al. 1981, Gibson 1977, Higgens et al. 1980, Smith and
Rosazza 1974, Korte and Klein 1982, Unger and Claff 1985).
The above-mentioned studies document the aerobic degradation of
benzene, and, although far less information is available, benzene
apparently is biodegraded under anaerobic conditions although probably
somewhat slower than aerobically. One study that illustrates this is the
research of Wilson et al. (1986). These investigators found that under
anaerobic conditions in the laboratory, benzene was not significantly
degraded during the first 20 weeks of incubation, but, by 40 weeks of
incubation, benzene concentrations were reduced by 72%. At 120 weeks of
incubation over 99% degradation had taken place. However, Batterman
[1986, as reported in Chea. Abscr. 104(24):212909U], in investigating
the in situ anoxic biological treatment of a hydrocarbon-contaminated
aquifer, reported the complete removal of benzene after only 6 months.
Gibson (1980) presents a proposed pathway for the anaerobic
biodegradation of aromatic compounds.
As discussed by Gibson (1980) and Hopper (1978), microbial
metabolism of benzene proceeds through the formation of cis-dihydrodiols
and, with further oxidation, to catechols which are the substrates for
ring fission. Thus, before going to catechol, benzene biodegrades to
l,2-dihydroxy-1.2-dihydrobenzene (Gibson 1980).
One important point must be made. The results of laboratory
experiments which characterize most of the above, especially those using
large numbers of organisms known to degrade benzene, must be carefully
applied to field situations. An example of this is seen in the studies
of Haider et al. (1981). Nocardia species and Pseudomonas species, after
cultivation on benzene, effectively degraded benzene after 7 days (45 to
90%); however, when 100 g soil with a mixed bacteria population was
mixed with 2 mg benzene, only 47% of the added radioactivity was
recovered as C02 after 10 weeks. Haider et al. concluded that specific
organisms which degrade benzene were present in the soil in only small
numbers.
-------
L05
7. POTENTIAL FOR HUMAN EXPOSURE
7.L OVERVIEW
A large segment of the U.S. population is exposed to benzene. This
exposure occurs primarily as a result of benzene emitted to the air from
man-made sources but also through drinking contaminated water, eating
certain foods, and smoking cigarettes. Benzene has been found in at
least 337 of 1,177 NPL hazardous waste sites. Although a large volume of
benzene is released to the environment (see Sect. 6), environmental
levels are low due to efficient environmental removal processes. The
magnitude of exposure is greatest for those individuals occupationally
exposed to benzene; however, a far greater number of individuals are
exposed as a result of benzene released from gasoline filling stations,
from smoking tobacco products, and from auto exhaust.
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
Benzene is ubiquitous in the environment. It has been identified in
soils, the aqueous environment (freshwater and saltwater), finished
drinking water, groundwater, the air of both rural and urban
environments, indoor air, tobacco smoke, and foods. The following
subsections provide relevant examples of the presence of benzene in each
of these compartments.
7.2.1 Air
As might be expected from the use of benzene as a solvent and as a
component of gasoline, the presence of benzene in air has been
extensively documented. Table 7.1 lists a selected number of these
reported instances.
These examples were, selected because they were among the more
recent reports of benzene levels. An exception is the report by Holzer
et al. (1977), which was chosen because it illustrates the difference in
levels of benzene for a rural area compared to an urban environment
within the sane geographical area. In the more recent references for
urban air, average values were generally <5 ppb. In contrast, Holzer et
al. (1977) reported an average value of 25 ppb for the air of
Tuscaloosa, Alabama, but it is not known if the current level would be
similar. The highest value in Table 7.1 is 64.6 ppb measured in the air
over Pittsburgh, Pennsylvania, during the spring of 1981. The reader is
directed to IARC (1982) and to EPA (1985a) for measurements made in the
vicinity of point sources or associated with automobile use; most, if
not all, of these are pre-1980, and their relevance for current emission
levels is not known. The highest value, 9,900 ppb, was measured near a
gasoline bulk-loading facility and the second highest, 9,400 ppb, near a
similar activity, the loading and discharging of gasoline from
-------
106
Section 7
Table 7.1. Benzene levels in air samples
Location
Concentration
• (ppb)
Comments
References
Ambient air
San Francisco. California
0.8 to 5 2
(26 ± 1 3)a
Stmson Beach. California 0 38 ± 0.39"
New Jersey, north-
eastern area
Houston. Texas
St. Louis, Missouri
Denver
Riverside. California
Staten Island
Pittsburgh
Chicago
73 km northwest of
Denver
Tuscaloosa, Alabama
Talladega
National Forest
3.9
1.4
1.3
0.84 to 37.7
(5.78 ± 5.88)*
Oil to 5.82
(1.41 ± 1.19)*
0.11 to 23.91
(4.39 ± 3.94)*
0 52 to 10.98
(3.95 ± 1.91)*
0.082 to 19.034
(4.204 ± 4.287)*
0.392 to 64.619
(5.003 ± 9.818)*
0.588 to 8.771
(2.561 ± 1.779)*
0.02 to 0.85
16 to 60
(25)'
0.2 to 1.3
Results from six
different urban
locations
21 samples;
nonurban area
Industrial area,
241 samples;
Residential
area, 49 samples;
Residential
area, 40 samples;
1978 sampling
period
Spring 1980
Spring 1980
Summer 1980
Summer 1980
Spring 1981
Spring 1981
Spring 1981
Rural area;
sampling between May
1981 and December
1982
Urban area;
sampling in February
1977
Rural area;
sampling in February
1977
Wester et al. 1986
Bozelli and
Kcbbckus 1982
Singh et al. 1982
Singh et al. 1982
Roberts et al. 1985
Holzeretal. 1977
-------
Potential for Human Exposure
107
Table 7.1 (continued)
Location
Concentration
(ppb)
Comments
Reference
Elizabeth and
Bayonne, New Jersey
Elizabeth and
Bayonne. New Jersey
Ambient air (continued)
2.7 (0.37)'
28.25 maximum
2.9 (0.25)d
13.66 maximum
Night, 81-86
samples
Day. 86-90
samples; Fall 1981,
conversions from
Mg/m3 made
Indoor air
9.6 ± 1 55,
158.3 maximum
8.38 ± 0.43.
83.82 maximum
Night, 346 to
348 samples
Day, 339 to 341
samples;
Fall 1981 sampling
period; /ig/m3
converted to ppb
Wallace et al. 1985
Wallace et al. 1985
"Average ± standard deviation.
* Arithmetic average ± standard deviation.
'Average.
''Weighted arithmetic mean (standard error).
-------
108 Section 7
road tankers. Most of the atmospheric benzene levels documented In the
IARC and EPA documents are, however, much less (e.g., 9- to 19-ppb
average concentrations recorded near a cumene manufacturing plant in
Philadelphia and an average of 0.9 ppb measured near the American
Cyanamid Company in Linden, New Jersey). Table 7.1 also lists values for
benzene in the air of residences in the Elizabeth and Bayonne, New
Jersey, areas (see Wallace et al. 1985). The interesting aspect of this
study was the observation that the benzene levels in the indoor air were
greater than those recorded in the air outside the residences. In a
follow-up report, Wallace and Pellizzari (1986) present a comparison of
benzene levels in indoor air from homes occupied by smokers vs homes
without smokers. In the fall and winter, homes with smokers (N - 345)
had average benzene concentrations of 52 ppb compared to 30 ppb in homes
without smokers (N - 164). In spring and summer, the levels were
comparable (about 15 ppb) probably due to houses being more open. This
points to the possible significance of passive smoking as a source of
benzene exposure.
7.2.2 Water
Representative examples of benzene concentrations that have been
measured in rainwater, surface water, sea water, drinking water, and
groundwater are shown in Table 7.2. Measurable levels range from
0.005 ppb in the Gulf of Mexico to 330 ppb in contaminated well water of
New York, New Jersey, and Connecticut.- Not shown in Table 7.2 is an
atypically high concentration of benzene of 24,000 ppb which was found
in subsurface water samples taken near extensive gas and oil deposits
(Ochsner et al. 1979, as reported in IARC 1982).
7.2.3 Soil
The only measured values of benzene found for soil was in a study
by Fentiman et al. (1979), who recorded levels ranging from <2 to 191 ppb
in the vicinity of five industrial facilities using or producing benzene.
7.2.4 Other
Benzene has been identified in several types of foods [e.g.,
Jamaican rum (120 ppb), irradiated beef (19 ppb), and heat-treated
canned beef (2 ppb)] (NCI 1977, as reported in EPA 1985a). EPA (1985a),
after reviewing a number of sources, provides the following
nonquantitative list of benzene-containing foods: haddock fillet, dry
red beans, blue cheese, cheddar cheese, cayenne pepper, pineapple,
roasted filberts, potatoes (cooked peels), cooked chicken, hothouse
tomatoes, strawberries, black currants, roasted peanuts, soybean milk,
and codfish.
Lauwerys (1979, as reported in IARC 1982) found that cigarette
smoke contained 0.047 to 0.064 ppb of benzene. Similarly, Wester et al.
(1986) observed that the breath of smokers (residents of the San
Francisco area) contained higher levels of benzene (6.8 ± 3 ppb) than
the breath of nonsmokers (2.5 ± 0.8 ppb). More dramatic differences in
the breath of smokers compared with that of nonsmokers was seen by
Wallace and Pellizzari (1986), who report average benzene breath levels
of 51 ppb for smokers (N - 198) and 8 ppb for nonsmokers (V - 322).
-------
Potential for Human Exposure
109
Table 7.2. Benzene levels in water samples
Source type Location
Rainwater United Kingdom.
Surface water United States
Concentration
(ppb) Comments
872
NQJ River and lake water
1 to 7 Heavily industrialized
river basins. 40 of 240
sites positive, sampling
from August I97S through
September 1976
References
Colenutt and
Thorburn 1980
Shackelford and
Keith 1976
Ewmg et al 1977.
as reported in
CHEMFATE 1987
Sea water
Lake Erie
United States
Lake Michigan
Lake Zurich,
Switzerland
United Kingdom
Gulf of Mexico
Drinking water United States
Ontario
Oto I
I to 13
(4 avg )
I to 7
0028
6 5 to 8 9
0005 toOOlS
0005 to 0175
NQ
0 I to 0 3
< 0 2 (avg )
SO
04
One of two sites
positive, sampling during
I97S and 1976
13 sampling locations
upstream and downstream
near industrial outfall
Five of nine sites
positive, sampling during
I97S and 1976
Surface water
Lake water
Unpolluted waters.
sampling during 1977
Polluted waters.
sampling dunng 1977
24 documented occurrences
7 of 113 sites positive
Presumably an average
of 700 1975 samples
Absorption/desorption of
benzene from anthracite
coal screenings used as
Tilter medium
Konasewich et al
1978. as reported
in CHEMFATE 1987
and HSDB 1987
Fentiman et al
1979
Fentiman et al
1979
Grob and Grab 1974
Colenutt and
Thorburn 1980
Sauer 1981
Sauer 1981
Shackelford and
Keith 1976
EPA I980b
Brass et al. 1977
Kraybill 1977
Smilheeial 1978
Groundwater
Groundwater
New York, New Jersey.
Connecticut
United States
United States
30-330
> 100
NQ
NQ to 100
Contaminated
well water
Well water from
Jacksonville. Florida
8 5% occurrence in a
federal survey
Found in leachate from some
residential wells adjacent
to a landfill; deep drinking
well had highest concentration
Burmaster 1982. as
reported in
CHEMFATE 1987
EPA I980b
Dyksen and Hess
1982
Stuart et al.
1985
*NQ - not quantified.
-------
110 Section 7
7.3 OCCUPATIONAL EXPOSURES
Without question, individuals employed in industries which use or
make benzene are at the greatest risk of encountering potential adverse
health effects from benzene exposure. It has been estimated that
2,000,000 to 3,000,000 persons in the work force are potentially exposed
to benzene (NIOSH 1974, NTP 1985). In a 1985 Federal Register notice
(OSHA 1985), OSHA presents a table (see Table 7.3) illustrating some of
the types of industries and associated levels of benzene exposure and
the number of individuals exposed. The number of estimated workers
exposed is less than that given by NIOSH but may be partially explained
in that not all workers and associated job categories are represented. A
significant number of workers (17,336) are potentially exposed to 8-h
TWA concentrations of benzene ranging from 5.1 to 10.0 ppm. Using
10 ppm, a daily exposure level on a milligram per kilogram basis can be
calculated. Assuming a 70-kg adult and a 30% systemic absorption rate,
and using 10 m3 as the daily intake of air, a daily intake of 1.4 mgAg
is determined. Dermal absorption was not considered in the above
calculation. Although various studies, such as those of Franz (1984) and
Susten et al. (1985), indicate that dermal absorption of liquid benzene
can occur (see Sect 4.2.2.3 for a detailed discussion of dermal
absorption), no data were found for the dermal absorption of benzene
vapor; inhalation is considered to be the most significant route of
exposure to the chemical.
7.4 POPULATIONS AT HIGH RISK
Other than individuals who are occupationally exposed, discussed in
the preceding section, special risk populations include those living
near certain chemical manufacturing sites, cigarette smokers, and
individuals living adjacent to landfills. For persons living near
landfills, the extent and media-associated exposure will depend on
whether their drinking water comes from groundwater and whether the
discarded benzene is buried sufficiently deep to eliminate the
possibility of volatilization to the air. For these three special risk
populations, some estimates of daily intake can be generated. From the
data presented in Sect. 7.2.2., it is not unreasonable to assume that an
individual could be exposed to 100 ppb in drinking water (well water).
Thus, for the average daily water consumption of 2 L, an individual
would consume 200 Mg/day benzene or, for a 70-kg adult, 2.86 /ig/kg/day.
With respect to cigarette smoking, EPA (1985a), using the data of
Newsome et al. (1965, as reported in EPA 1985a), which showed that a
40-mL draw of cigarette smoke contained 6.1 /ig of benzene, and assuming
15 draws per cigarette, 20 cigarettes smoked per day, and a daily air
intake of 20 m3, calculated that the equivalent annual average
atmospheric exposure would be 92 pg/m3 (28 ppb). On a weight/weight
basis, a 70-kg individual who smokes 20 cigarettes a day would take in
7.8 /ig/kg/day (assuming a systemic benzene absorption rate of 30%).
Mara and Lee (1978, as reported in EPA 1985a) have estimated that
as many as 200,000 people may be exposed to annual benzene average
concentrations of 4.1 to 10.0 ppb and another 80,000 to annual average
concentrations of >10 ppb as a result of living in the vicinity of
-------
Potential for Human Exposure 111
Table 7.3. Number of employees exposed to beueae (by exposure levels
sad by industry divisions)"
8-hour TWA benzene concentrations (ppm)
Industry sector
Petrochemical producers
Petroleum refineries
Coke and coal chemical
Tire manufacturers
Bulk terminals
Bulk plants
Transportation via tank truck
Total of all sectors
000-010
5.460
36.510
—
34.645
14.556
26.845
32.558
150.574
011-050
4.064
14.751
3.550
24.375
8,260
15.234
10.996
81.230
051-10
1.224
2,600
422
4,095
1,335
2,461*
2.523
14.660
1 1-50
1.212
2.148
436
1,820
932
1.7I8C
1.380
9.646
5 1-100
159
283
71
0
1,988
14,787
48
17.336
100 +
122
226
18
0
25
46C
95
533
Total*
12.242
56.517
4,499
65.000
27,095
61.093
47.600
274,047
"This table summarizes the worker groups for which OSHA has good exposure data. However, due to the
ubiquitous nature of benzene (e.g., it is naturally occurring constituent of crude oil. natural gas. and coal),
OSHA was not able to obtain exposure data for some worker groups exposed to benzene such as od and gas
well drillers.
Figures do not total in some cases due to rounding.
rNumber in original table was in error, number presently in table obtained as a result of personal com-
munication with OSHA)
Source Adapted from USOSHA 1985
-------
112 Section 7
chemical manufacturing plants. Exposure levels of 4.1 to 10.0 ppb would
yield a body burden of 1.13 to 2.76 ^g/kg/day for a 70-kg man (assuming
a 30% systemic absorption factor).
-------
113
8. ANALYTICAL METHODS
The analytical methods commonly used to identify and measure
benzene levels in various environmental and biological media are given
in Tables 8.1, 8.2, and 8.3. Recommended methods are briefly reviewed in
the following sections.
8.1 ENVIRONMENTAL MEDIA
8.1.1 Air
8.1.1.1 Sample collection and preparation
Air samples for benzene analysis are usually preconcentrated by
passing the sample through an adsorbent or trap. Commonly used
adsorbents are Tenax resin, silica gel, activated carbon, and
carbonaceous polymeric compounds. Benzene can also be preconcentrated by
cryogenic trapping (Table 8.1).
Benzene, as a volatile organic, presents difficulties in collection
and handling methods. These problems are discussed in the following
additional references: Withey and Martin (1974), Baslet (1974), Angerer
et al. (1973).
8.1.1.2 Methods
Gas chromatography (GC) coupled with flame ionization detection
(FID), photoionization detection (PID), or mass spectrometry (MS) is the
most commonly used method for analyzing for benzene in air (Table 8.1).
Of these methods, GC/PID and GC/FID provide a greater degree of
sensitivity than GC/MS, but the latter procedure is more reliable in
identifying benzene in samples containing multiple components having
similar GC elution characteristics. Various spectrophotometric methods
have also been used for determining benzene in air samples. These are
generally not as sensitive as the GC methods. EPA has sponsored the
development of an atomic line molecular spectrometer (ALMS) to monitor
levels of benzene and other organics in ambient air, particularly near
waste disposal and industrial production sites (Hadeishi et al. 1985).
This method has a detection limit of 250 ppb (by volume) at 184.9 nm.
For determining atmospheric levels of benzene in the workplace,
several different analytical methods are acceptable to OSHA (OSHA 1985),
however, the recommended procedure involves the collection of the sample
vapors on charcoal adsorption tubes followed by GC/MS analysis (NIOSH
Method S-311). Other acceptable methods include portable direct reading
instruments, real-time continuous monitoring systems, and passive
dosimeters (OSHA 1985). The latter methods generally have a sensitivity
in the part-per-million range.
-------
114 Section 8
Sample
matrix
A -bient and/or
oc.upational
atmospheres
Sample
preparation
Tenax trap. He
desorption
Adsorbent trap.
thermal desorption
Silica gel trap, water
desorption, headspace
analysis
NA
Tenax trap, thermal
desorption, cryogenic trap
Charcoal trap, CSj
desorption
Tenax GC trap.
thermal desorption.
cryogenic focusing
Cryogenic trap
with liquid 02 or Ar,
thermal desorption
Cryogenic trap.
thermal desorption
Charcoal trap.
CSj desorption
Direct injection
Cryogenic trao.
thermal desorction
Cryogenic or Tenax GC
trap, thermal desorption
Cryogenic trap.
thermal desorption
NA
Silica gel trap
Direct analysis
Direct analysis
NA
NA
Silica gel trap
Analytical
method"
GC
GC/MS
GC/MS
GC/FID
GC/FID
GC/FID
GC/FID/MS
GC/FID
GC/FID
GC/FID
GC/PID
5C/PID
GC/PID
GC/PID
Photo.
Spectra
UV Spectra.
UV Spectra.
Spectra.
IR Spectra
Indicator tube:
UNICO tube
AUER tube
DRAGER tube
Limit of
detection
>0 1 ppb
NA
0 1 ppb
<2 5 ppm
0 03 ppb
009 ppb
0003 ppb
<0.06 ppb
NA
<2.5 ppm
0.25 ppb
0.5 ppb
Spot
Ippt
210 ppm
<3S ppm
10 ppm
250 ppb
25 ppb
0 15 ppm
1 5 ppm
10 ppm
5 ppm
5 ppm
Accuracy
NA
NA
NA
+08%
(at 25 ppm)
+ 44%
NA
±60%'
±86%'
(at 1.4 ppb)
±8%rf
+08%
(at 25 ppm)
±51%'
NA
±3.6%rf
NA
NA
NA
NA
NA
NA
NA
±15%
NA
NA
NA
References
Fentunan et al. 1979
Jonsson and Berg 1980*
Gruenke et al. 1986
NIOSH 1977
Martin et al. 1980
Baxter et al. 1980'
Roberts et al. 1984
Singh et al. 1985
Holden et al. 1985
NIOSH 1974, I977b
Clark et al. 1984
Kowalski et aL 1985
Reineke and Baechmann 1985
Nutmagul and Cronn 1985
Du Pont'
Maffett et aL 1956C
Berkley et al. 1984/
Hadeishi et al. 1985
Hager 1973'
Henan 1973*
Koljkowsky 1969'
Matbesoo Scientific*
Auer*
Drager*
-------
Analytical Methods 115
TaMe8.1 (continued)
Sample
matrix
Near spill sites
Landfills/waste sites
Industrial emissions
Sample
preparation
Direct analysis
Carbon trap, carbon
disulfide desorption
Tenax GC trap.
thermal desorption
NA
Analytical
method'
Elect rochem
GC/FID
GC/FID/ECD/MS
GC/FID
Limit of
detection
NA
NA
001 ppb
0 I ppm
Accuracy
NA
NA
NA
NA
References
Stetter et al 1986
Colenutt and Davies 1980C
Harkovetal 1985
Knoll etal 1978
"<-.(- /M<; =» oac rhrnmatnoranhv /mass SOeclrometrv
GC/FID - gas chromatography/flame lomzation detection
GC/PID - gas chromatography/photoionization detection
Photo ™ photometry
Spectro. - spectrometry
UV Spectro — ultraviolet atomic line molecular spectroscopy
IR Spectro - infrared spectroscopy
*NA •» data not available.
cAs reported in I ARC 1982.
''Relative standard deviation.
'As reported in Verschueren 1983.
•^As reported in Hadeishi et al 1985.
-------
116 Section 8
Table 8.2. Analytical methods for neaswiog benzene k?eb in water and soil
Sample
matrix
Surface water
and/or
effluents
Sample
preparation
N2 purge, Tenax GC trap."
thermal desorption
He purge, polymer trap,
thermal desorption
Inert gas purge, adsorbent
Analytical
method0
GC
GC/MS
GC/MS
Limit of
detection
01 ppb
0 1 ppb
1 ppt
-0 03 ppb
NA
(at 1 ppb)
-1- 11%
(at O.I Mg/L)
NA
NA
NA
NA
NA
NA
-48%
(at 0 1 Mg/L)
NA
NA
Hammers and Bosnian 1986
Bradley and Frenzel 1970
Brass et al. 1977
Stuart et al 1984
Schultze and Kjeldsen 1985
Sawhney and Kozloske 1984
Fentiman et al 1979
Hammers and Bosnian 1986
Ferrano et al 1985
Harland et al 1985
JGC — gas chromatography.
GC/MS ~ gas chromatography/mass spectrometry
GC/FID • gas chromatography/flame wmzation detection
GC/PID — gas chromatography/photoiomzation detection
LRS — Laser-Raman spectroacopy.
*NA - data not available.
cAs reported in IARC 1981
Relative standard deviation.
'Representative measurement and not detection limit.
-------
Analytical Methods 117
Table 8J. Analytical methods for measuring benzene levels in biological samples and food
Sample
matrix
Blood
Unne
Breath
Tissues
Human milk
Foods
Fruits and
vegetables
Shellfish
"GC-
chromatoKrai
Sample
preparation
Headspace analysis
Headspace collection
cryogenic trap, thermal
desorption
N2 purge, Tenax GC-"
silica gel trap
He purge, Tenax GC trap
Dissolve in pentane
Mix with sodium
citrate solution
NA
Adsorbent gels
Cryogenic trap.
Tenax GC trap.
thermal desorption
Tenax GC trap.
Headspace analysis
Treat with chlorobenzene.
ethanol, and water
He purge. Tenax GC trap.
thermal desorption
NA
Mix with water and
methanol, puree.
azeotropic distillation
Tissue homogenized.
Nj purge, Tenax GC-sdica
gel trap, thermal desorption
gas chromatograpby. GC/MS -
jay/flame lomzation detection.
Analytical
method"
GC/MS
GC
GC/MS
GC/FID
GC/FID
GC/FID
GLC
GC
GC
GC/MS
GC/MS
GC/MS
GC/MS
GC/MS
GC/MS
GC/FID
GC/MS
Limits of
detection
2 ng/mL
I6ppb
OS ppb
NA
08-48 pg/L
20 Mg/L
1 pg/mL.
(phenol)
0 14 ppm
<1 ppb
r-Jppt
35ppt
01 ppb
NA
NA
<10 ppt/
NA
NA
Accuracy
NA*
NA
S<*CVC
(at 2 ppb)
-2%d
NA
NA
NA
NA
NA
NA
±10-30%
NA
NA
NA
NA
-16%
(at 1 Mg/g)
NA
References
Gruenke et al 1986
Wallace 1986
Antome et al 1986
Michael et al 1980
Ghimenti et al. 1978'
Pinigma and Mal'tseva 1978'
LauwenjS 1979. as reported
in van Sittert and deJong 198S
Sherwood and Carter 1970. as
reported in I ARC 1974
Conkleetal 1975
Umanaetal 1985
Wallace 1986
Gruenke et al 1986
Nagataetal 1978'
Michael et al. 1980
NCI 1977
Kozioski I98S
Ferranoet al. 198S
gas chromatography/mass spectrometry, GC/FID — gas
°NA - data not available.
CCV - coefficient of variation
rf2 Mg chlorobenzene spike.
'As reported in IARC 1982.
/Estimated from tabulated data given.
'As reported in Verschueren 1983.
-------
118 Section 8
8.1.2 Water
8.1.2.1 Sample collection and preparation
Benzene is usually isolated from aqueous media by the purge and
trap method. An inert gas such as nitrogen is used to purge the sample.
The benzene is then trapped on an adsorbent substance, such as Tenax GC
or activated charcoal, and then thermally desorbed (Table 8.2). Liquid-
liquid extraction procedures using solvents in which benzene is more
readily soluble have also been used. The solvent is removed by selective
evaporation. Additional information regarding sample collection and
preparation can be found in a manual recently published by the Office of
Drinking Water, EPA, Volatile Organic Chemicals: Methods and Monitoring
Document (EPA 1987b).
8.1.2.2 Methods
GC alone, or coupled with FID, FID, or MS, is commonly used to
analyze for benzene in aqueous media (Table 8.2). Sensitivity of these
methods is generally <1 ppb. For the analysis of drinking water, EPA
recommends purge and trap GC (EPA Method 503.1), purge and trap GC/MS
(EPA Method 524.1), purge and trap capillary column GC/MS (EPA Method
524.2), and purge and trap GC with photoionization and electrolytic
conductors in series (EPA Method 502.2) (EPA 1987b). For the analysis of
wastewaters, EPA recommends GC (EPA Method 602) or GC/MS (EPA Method
624).
8.1.3 Soil
8.1.3.1 Sample collection and preparation
Benzene can be isolated from soil samples by the purge and trap
method, continuous liquid extraction, or Soxhlet extraction.
8.1.3.2 Methods
Soil samples have been analyzed for benzene using GC and GC/FID
(Table 8.2). A detection limit as low as 1 ppt has been reported for one
method (Hammers and Bosnian 1986).
8.1.4 Food
8.1.4.1 Sample collection and preparation
Sample collection and preparation for the analysis of benzene in
foods includes the purge and trap method, headspace gas analysis, and
azeotropic distillation of samples pureed with water and methanol
(Table 8.3).
8.1.4.2 Methods
Chromatographic procedures, particularly GC/FID and GC/MS, have
been used to analyze for benzene in foodstuffs (Table 8.3). Little
quantitative data are available, but limits of detection can be <10 ppb.
-------
Analytical Methods 119
8.2 BIONEDICAL SAMPLES
Analytical methods have been developed to measure benzene levels in
exhaled breath, in blood, and in various body tissues. Urinary analysis
for phenol, a benzene metabolite, has also been used as a measure of
benzene exposure.
8.2.1 Fluids/Ezudates
8.2.1.1 Sample preparation
Benzene can be extracted from blood samples by several methods
(Table 8.3) including: (1) the purge and trap method using an inert gas
such as nitrogen or helium and an adsorbent such as Tenax GC (Antoine et
al. 1986), (2) cryogenic trapping of headspace gas (Wallace et al.
1986), (3) dissolving in pentane (Ghimenti et al. 1978), (4) mixing with
a sodium citrate solution (Pinigina and Mal'tseva 1978, as reported in
IARC 1982), or (5) mixing with toluene (Snyder CA et al. 1975; Jirka and
Bourne 1982).
Collection and preparation of breath samples for benzene analysis
usually involves concentrating the sample with adsorbents such as Tenax
GC followed by thermal desorption. Cryogenic traps have also been used.
For phenol determinations, urine samples are subjected to acid
hydrolysis and extraction. NIOSH (1984) recommends hydrolyzing the
sample with either concentrated hydrochloric acid or 70% perchloric acid
and extraction with diethyl ether. Roush and Ott (1977) utilized a
modification of this method in which the hydrolyzed urine was saturated
with sodium chloride before extraction with isopropyl ether. The
addition of sodium chloride increased the extraction efficiency of the
ether.
8.2.1.2 Methods
GC coupled with FID or MS is used to analyze for the presence of
benzene in blood (Table 8.3). Limits of detection are <1 ppb. It should
be noted that current technology limits the interpretation and the
validity of values for blood levels of benzene generated in various
monitoring programs and their laboratories.
GC and GC/MS are also used to measure benzene levels in exhaled
breath. Limits of detection are in the part-per-trillion* range.
An indirect method for evaluating benzene exposure involves
measuring urinary levels of the benzene metabolite phenol with gas
liquid chromatography (GLC) or colorimetry. NIOSH (1984) recommends the
use of gas chromatography in combination with a flame ionization
detector. The estimated limit of detection for this method is 0.5 Mg/»L
urine.
One of the main problems involved in measuring urinary phenol
levels to monitor benzene exposure is the variance in individual base
line phenol levels. Roush and Ott (1977) detected levels of phenol
exceeding 75 mg/L in the urine of individuals who had no known exposure
or whose TWA benzene exposure was less than 5 ppm (75 mg/L was proposed
by NIOSH, in 1974, to be an indication of unacceptable benzene
-------
120 Section 8
exposure). As mentioned previously, urinary phenol excretions can be
increased by exogenous nonbenzene sources such as dietary protein (Folin
and Denis 1914); medicines that contain phenylsalicylate (Pepto-Bismol®
and Chloraseptic* lozenges) (Kociba et al. 1976); asprin (Fishbeck et
al. 1975); and calamine lotion and phenol-camphor-liquid petrolatum
preparations (Ruedemann and Deichmann 1953). See Sect. 2.2.2 for further
discussion of biological monitoring of benzene exposure.
8.2.2 Tissues
8.2.2.1 Sample preparation
Benzene has been extracted from various tissue samples by
dissolving in a mixture of chlorobenzene, ethanol, and water at 60°C
(Nagata et al. 1978, as reported in IARC 1982).
8.2.2.2 Methods
GC coupled with MS has been used to analyze for the presence of
benzene in body tissues (Table 8.3). Little information is available
concerning sensitivity and accuracy of the method.
-------
121
9. REGULATORY AND ADVISORY STATUS
Regulatory standards and advisory guidelines for benzene are
summarized in Table 9.1 and briefly reviewed in the following sections.
9.1 INTERNATIONAL
The World Health Organization has recommended a drinking water
guideline for benzene of 0.01 mg/L, a level corresponding to an excess
lifetime cancer risk of 10'5 (WHO 1984).
9.2 NATIONAL
9.2.1 Regulations
9.2.1.1 Media-specific
Air. In 1971, OSHA promulgated an occupational exposure standard
for benzene which included a 10-ppm permissible exposure limit (PEL) for
an 8-h TWA concentration, a 25-ppm ceiling limit, and a 50-ppm maximum
(10-min) ceiling limit (OSHA 1971). In 1987, this standard was revised
to 1 ppm for an 8-h TWA concentration and 5 ppm for a short-term
exposure limit (STEL) (OSHA 1987). In the same ruling, OSHA also set 0 5
ppm as the action level for benzene (OSHA 1987).
Water. In 1985, the EPA Office of Drinking Water proposed setting
the Maximum Contaminant Level (MCL) for benzene in drinking water at
0.005 mg/L (EPA 1985d). This standard was promulgated in 1987 (EPA
1987a).
Food. No information was found indicating whether benzene levels
in foodstuffs are limited by the U.S. Food and Drug Administration
(FDA). Under the Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA), benzene is exempt from food tolerance restrictions provided it
is used in accordance with good agricultural practice and only applied
to growing crops (EPA 1985e).
9.2.1.2 Hazard ranking
Benzene is a priority toxic pollutant, and it has been classified
by EPA as a hazardous substance (Clean Water Act), a hazardous air
pollutant (Section 112 of the Clean Air Act), and a hazardous waste
constituent (RCRA).
Based on weight-of-evidence of carcinogenicity and carcinogenic
potency, EPA has assigned benzene a "medium" hazard ranking (EPA 1986)
However, a hazard ranking is only for a specific exposure scenario
(e.g., accidental spills) and is not applicable to chronic low-level
exposures.
-------
122 Section 9
Table 9.1. Regulations and advisory guidance for benzene
Concentration
Medium
mg/L
ppm
Risk
level
Exposure
condition
Application
References
Water
001
InteraatioMl advisory goidanet
Drinking water
10 5 Lifetime
National reflation
WHO 1984
Air
Water
1
5
0005
8-h TWA"
STEL*
MCI/
Occupational
Occupational
Dnnkiag water
OSHA 1987
OSHA 1987
EPA I987a
National advisory guidance
Air
Water
Water
01
05
10
10
0
0
0000066
000066
000068
00066
00068
0.068
0.334
12.5
0001
10-hTWA
Action level
15-mia CLrf
8-h TWA
Lifetime
MCLG*
10~* Lifetime
10 Lifetime
10 6 Lifetime
I0~{ Lifetime
10 5 Lifetime
10 4 Lifetime
10-day HA7
7-day SNARL'
Scale refBtatioM
Lifetime
Otter
Occupational
Occupational
Occupational
Occupational
Ambient water
Drinking water
Ambient water
Ambient water
Drinking water
Ambient water
Drinking water
Drinking water
Drinking water
Drinking water
Drinking water
Groundwater
Listed at a
hazardous substance
NIOSH 1986
OSHA 1987
NIOSH 1986
ACGIH 1986
EPA 1980a,b
EPA I984c
EPA !980b
EPA 1980b
EPA I985a
EPA 1980b
EPA I985a
EPA I985a
EPA 1985a
NRC 1980a
FPC/API 1986
(Flonda)
Hazardline 1986
(California)
'Time-weighted average.
Soon-term exposure limh.
c Maximum contaminant leveL
Celling value.
'Maximum contaminant level goal
' Health advisory.
'Suggested no-adverse-response level
-------
Regulatory and Advisory Status 123
9.2.L.3 Emission and effluent regulations
Because benzene is- considered a toxic waste, federal hazardous
waste management procedures must be complied with for any industrial
process involving the generation, transport, treatment, storage, and
disposal of the chemical. According to the Comprehensive Environmental
Response, Compensation and Liability Act (CERCLA) of 1980, notification
must be made to the National Response Center when benzene releases into
waterways reach or exceed 1,000 Ib. EPA has proposed that this minimal
reportable quantity (RQ) be decreased to 10 Ib. Benzene is also listed
as a toxic chemical subject to annual reporting of environmental
releases under Section 313 of the Emergency Planning and Community Right
to Know Act of 1986.
Although benzene has been designated as a RCRA hazardous waste and
is included in the F001-F005 listing of spent solvents (51FR6537), it is
not subject to the recently promulgated treatment standards for such
wastes (51FR40572). It is expected that treatment standards for benzene
will be promulgated by August 8, 1988.
Priority pollutant effluent limitations [new source performance
standards (NSPS) with best available technology (BAT)] set the maximum
daily discharge rate for benzene at 0.057 mg/L per day, with a monthly
average not exceeding 0.021 mg/L (EPA 1985b).
Federal regulations limit daily disposal of benzene in effluents
from coke-production facilities to either 0.0000215, 0.0000250. or
0.0000355 kg/kkg, depending on the type of coke plant. For new coke
plants, daily discharges are limited to either 0.0000319 or 0.0000355
kg/kkg, depending on the type of plant (CFR Title 40, Parts 420.13 and
420.14)
Benzene is regulated under the Clean Water Act Effluent Guidelines
as stated in 40 CFR Parts 400-475. For each point source category,
benzene is either regulated as part of a group of chemicals controlled
as Total Toxic Organics (TTO), has a regulatory limitation provided for
by the particular 40 CFR Part Number (RL), or has a zero discharge
limitation for the particular 40 CFR Part Number (ZDL). The point source
categories with their effluent limitation designation and specific 40
CFR part numbers, as summarized by the EPA (1988a), are as follows:
electroplating (TTO, part 413); organic chemicals (RL, part 414); iron
and steel manufacturing (RL, part 420); steam electric (RL, part 423);
asbestos (ZDL, part 427); timber products processing (ZDL, part 429);
metal finishing (TTO, part 433); paving and roofing (ZDL, part 443);
paint formulating (ZDL, part 446); ink formulating (ZDL, part 447); gum
and wood (ZDL, part 454); carbon black (ZDL, part 458); metal molding
and casting (TTO, part 464); and copper forming (TTO, part 468). The
effluent guidelines are examined in detail in 40 CFR under the
appropriate part number.
EPA proposed National Emission Standards for Hazardous Air
Pollutants (NESHAPS) for five potential benzene emission sources--maleic
anhydride plants, ethylbenzene/styrene plants, benzene storage vessels,
benzene fugitive emission sources, and coke by-product plants. The
proposed NESHAPS for the first three categories were withdrawn by EPA in
1984 (49FR23558). In 1981, the EPA proposed a national standard for
-------
124 Section 9
fugitive emissions of benzene which would prohibit detectable emissions
from processing equipment that contains materials with benzene
concentrations of 10% or more by weight (EPA 1981, as reported in IARC
1982). NESHAPS was promulgated in 1984 and is set at 10 g/day, not to
exceed an ambient air level of 0.01 /ig/m3. Final action on the proposed
NESHAPS for coke by-product recovery plants is expected in 1987.
9.2.1.4 Consumer products regulations
In 1978 the U.S. Consumer Product Safety Commission (CPSC) proposed
banning all commercial products (excluding gasoline and laboratory
reagents) containing 0.1% or more benzene (by volume). However, in 1981
the CPSC withdrew its proposal after determining that the current levels
of benzene did not pose a significant risk to consumers (CPSC 1981).
9.2.2 Advisory Guidance
9.2.2.1 Media-specific
Air. NIOSH has recommended that the occupational exposure standard
for benzene be revised to a 10-h TWA of 0.1 ppm (0.32 mg/m3) with a
15-min ceiling value of 1 ppm (3.2 mg/m3) (NIOSH 1986).
The threshold limit value (TLV) for benzene recognized by the ACGIH
is 10 ppm for an 8-h TWA (ACGIH 1986). A notice has also been given by
ACGIH that the current 25-ppm STEL for benzene will be deleted from its
list of recommended exposure standards.
Water. EPA's Office of Water Regulations and Standards is
responsible for establishing water quality criteria for water
pollutants. Water quality criteria are qualitative or quantitative
estimates of the concentration of a substance which, when not exceeded,
will ensure a water quality sufficient to protect a specified end use.
Such criteria are nonenforceable recommendations which do not take into
consideration economic or technical feasibility.
For known or suspect carcinogens such as benzene, EPA has taken the
position that, because carcinogenicity is considered to be a
nonthreshold toxic effect, water quality criteria for such substances
should be set at zero for the maximum protection of human health (EPA
1980a, 1980b). However, because zero levels may not be attainable, EPA
has followed a procedure of estimating the concentrations of a substance
in ambient waters which would correspond to incremental increases in
lifetime cancer risks of 10-5, 10'6, and 10'7. For benzene the
corresponding levels were estimated to be 6.6, 0.66, and 0.066 Mg/L,
respectively (EPA 1980b).
Because of benzene's known carcinogenicity, EPA's Office of
Drinking Water has set the maximum contaminant level goal (MCLG) for
benzene in drinking water at zero (EPA 1984c; EPA 1985c). The MCLG is a.
nonenforceable guideline. The Office of Drinking Water has also
estimated the benzene concentrations in drinking water that would
correspond to carcinogenic risks of 10'4, 10'5, and 10'6. These values
are 68, 6.8, and 0.68 MgA. respectively (EPA 1985a).
-------
Regulatory and Advisory Scacus L25
EPA also issues nonenforceable health advisories (HAs) for drinking
water contaminants based on noncarcinogenic health effects. HAs identify
maximum safe drinking water concentrations for specified exposure
periods. The 10-day HA for benzene was reported as 354 jig/L (EPA I985f)
In 1980, the National Research Council (NRC) derived a suggested
no-adverse-response level (SNARL) for benzene in drinking water. Using
the data of Wolf et al. (1956) for the occurrence of leukopenia and
erythrocytopenia in rats exposed to benzene, NRC calculated a 7-day
SNARL of 12.6 mg/L (NRC 1980a).
Food. No information was found concerning advisory guidelines for
limiting benzene levels in foodstuffs.
9.2.3 Data Analysis
9.2.3.1 Care inogenic potency
Benzene has been classified by EPA in Group A - Human carcinogen
(EPA 1986, EPA 1988b). This category is for agents for which there is
sufficient evidence to support a causal association between exposure and
cancer in humans and, in the case of benzene, a sufficient and
supporting level of animal evidence. According to IARC (1982), there is
"sufficient evidence" that benzene is carcinogenic to man and "limited
evidence" that benzene is carcinogenic in experimental animals
(Group A).
The EPA has developed quantitative unit cancer risk estimates for a
number of known or suspect carcinogens. The methodology for developing
these estimates is given in Anderson (1983). For benzene, EPA (1986)
derived a cancer risk estimate from data obtained in epidemiologic
studies on workers exposed to benzene vapors (Rinsky et al. 1981, Wong
et al. 1983, Ott et al. 1978). Using an average derived from the
application of several mathematical models, a combined risk estimate of
2.6 x 10*2 was calculated for an exposure to 1 ppm benzene [equivalent
to 0.029 (mg/kg/day)"^ for a lifetime exposure]. For this estimated
potency value, the air concentration associated with an excess risk of
10*5 was derived as 10*5 divided by 2.6 x 10'2 or 3.846 x 10'4 ppm. An
evaluation of Rinsky (1987) data and its impact on cancer potency has
not been developed by EPA as yet.
9.3 STATE
(Regulations and advisory guidance from the states were still being
compiled at the time of printing.)
9.3.1 Regulations
California currently lists benzene as a hazardous substance subject
to the minimum standards for management of hazardous and extremely
hazardous wastes (Hazardline 1987).
9.3.1.1 Media-specific
Air. No information was found.
-------
126 Section 9
Water. In Florida, Che maximum permitted benzene concentration in
drinking water and the most common class of groundwaters is 1
(1 ppb) (FPC 1986).
Food. No information was found.
• *
9.3.2 Advisory Guidance
No information was found.
-------
127
10. REFERENCES
AAI. 1980. Alliance of American Insurers. Handbook of organic industrial
solvents. 5th ed.
ACGIH (American Conference of Governmental Industrial Hygienists). 1986.
TLVs. Threshold Limit Values for Chemical Substances in the Work
Environment Adopted by ACGIH, with Intended Changes for 1986-1987, and
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169
11. GLOSSARY
Acute Exposure--Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Bioconcentration Factor (BCP)--The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Carcinogen--A chemical capable of inducing cancer.
Ceiling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure--Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotozicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
Frank Effect Level (PEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
EPA Health Advisory--An estimate of acceptable drinking water levels for
a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH)--The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-impairing symptoms or irreversible
health effects.
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170 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the lexicological Profiles.
Imnunologic Toxicity--The occurrence of adverse effects on the immune
system that may result.from exposure to environmental agents such as
chemicals.
In vitro--Isolated from the living organism and artificially maintained,
as in a test tube.
In vivo--Occurring within the living organism.
Key Study—An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentration(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(SO) (LCso)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(50) (LDSO)--The dose of a chemical which has been calculated
to cause death in 50% of a defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL)--The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
Lowest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
Malformations--Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level—An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen--A substance that causes mutations. A mutation Is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
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Glossary 171
Neurotoxlcity--The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL)--That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
No-Observed-Effect Level (NOEL)--That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL)--An allowable exposure level in
workplace air averaged over an 8-h shift.
q *--The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The q.* can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for
food, and /Jg/nr* for air).
Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ)--The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are: (1) 1 Ib
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Toxicity--The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL)--The maximum concentration to which
workers can be exposed for up to IS min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
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172 Section 11
Target Organ Toxlclty--This term covers a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
Teratogen--A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV)--A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA)--An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UP)--A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population,
(2) the uncertainty in extrapolating animal data to the case of humans,
(3) the uncertainty in extrapolating from data obtained in a study that
is of less than lifetime exposure, and (4) the uncertainty in using
LOAEL data rather than NOAEL data. Usually each of these factors is set
equal to 10.
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173
APPENDIX: PEER REVIEW
A peer review panel was assembled for benzene. The panel consisted
of the following members: Dr. E. P. Cronkite, Brookhaven National
Laboratory (retired); Dr. Carroll A. Snyder, New York University Medical
Center; and Dr. Robert Snyder. State University of New Jersey, Rutgers
Campus. These experts collectively have knowledge of benzene's physical
and chemical properties, toxicokinetics, key health end points,
mechanisms of action, human and animal exposure, and quantification of
risk to humans. All reviewers were selected in conformity with the
conditions for peer review specified in the Superfund Amendments and
Reauthorization Act of 1986, Section 110.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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