TECHNICAL REPORT DATA
ffteat rtmd liuaucnons on Me reverse txfort compithns)
1. REPORT NO.
FPA/60Q/a-8Q/Q86
4. TITLE AND SUBTITLE
Updated Health Effects Assessment for Benzene
3. RECIPIENT'S ACCESSION NO
PB90-U2381/AS
k. REPORT DATE
t. PERFORMING ORGANIZATION CODE
7. AUTMOR(S)
I. PERFORMING ORGANIZATION REPORT NO.
PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268 _____^_
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
IS SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 32991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an.exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient .evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Croup
8. DISTRIBUTION STATEMENT
Public
IB. SECURITY CLASS
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EPA/600/8-89/086
August, 1989
HEALTH EFFECTS ASSESSHENT
FOR BENZENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI. OH 45268
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DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with benzene.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxlcologlc and environ-
mental data were located through on-Hne literature searches of the TOXLINE,
CANCERLINE and the CHEMFATE/DATALOG data bases. The basic literature
searched supporting this document Is current up to March, 1987. Secondary
sources of Information have also been relied upon 1n the preparation of this
report and represent large-scale health assessment efforts that entail
extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1979. Carcinogen Assessment Group's Final Report on
Population Risk to Ambient Benzene Exposures. Prepared by the
Office of Health and Environmental Assessment, Carcinogen Assess-
ment Group, Washington, DC, for the Office of A1r Quality Planning
and Standards, Research Triangle Park, NC. EPA-450/5-80-004. NTIS
PB82-227372.
U.S. EPA. 1980a. Ambient Mater Quality Criteria Document for
Benzene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH, for the Office of Water Regulations and Standards,
Washington, DC. EPA 440/5-80-018. NTIS PB 81-117293.
U.S. EPA. 1983a. Reportable Quantity for Benzene. Prepared by
the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH, for the Office of
Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1983b. Review of Toxlcologlc Data 1n Support of Evalua-
tion for Carcinogenic Potential of Benzene. Prepared by the Office
of Health and Environmental Assessment, Carcinogen Assessment
Group, Washington, DC for the Office of Solid Waste and Emergency
Response, Washington, DC.
U.S. EPA. 1985a. Drinking Water Criteria Document for Benzene.
Prepared by the Office of Drinking Water, Washington, DC. Final
Draft (on Public Comment). NTIS PB86-118122.
U.S. EPA. 1985b. Interim Quantitative Cancer Unit Risk Estimates
Due to Inhalation of Benzene. Prepared by the Office of Health and
Environmental Assessment, Carcinogen Assessment Group, Washington,
DC, for the Office of A1r Quality Planning and Standards, Research
Triangle Park, NC. Internal Report.
111
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The Intent 1n these assessments 1s to suggest acceptable exposure levels
for noncarclnogens and risk cancers/potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope, which tended to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure 1s assumed. Animal data used for RfD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$i) and oral (RfD$Q)
exposures.
The RfD (formerly AIC) 1s similar In concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfDn,) or Inhalation (RfDj) exposure with the Implicit assumption that
exposure by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained In U.S.
EPA (1984).
For compounds for which there Is sufficient evidence of carclnogenlclty,
RfD$ and RfD values are not derived. For a discussion of rUk assessment
methodology for carcinogens refer to U.S. (1980b). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-j*s have been computed, 1f
appropriate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context, the
reader Is referred to the preface of this document. The preface outlines
limitations applicable to all documents of this series as well as the appro-
priate Interpretation and use of quantitative estimates presented.
Considerable human data are available Unking Inhalation exposure to
benzene with leukemia. A carcinogenic slope for Inhaled benzene of
2.9xlO~2 (mg/kg/day)"1 may be estimated using data from several
ep1dem1olog1cal Investigations. Animal data concerning the cardnogenldty
of Inhaled benzene are corroborative.
Data regarding cancer Incidence 1n humans following oral exposure to
benzene were not located. Animal studies clearly associate oral exposure to
benzene with Increased Incidences of several types of cancer. A carcino-
genic slope of 2.9xlO~2 (mg/kg/day)"1 was estimated for oral exposure to
benzene. This value was obtained by route extrapolation using the
Inhalation occupational data.
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE 1
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 3
2.1. ORAL 3
2.2. INHALATION 3
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 5
3.1. SUBCHRONIC 5
3.1.1. Oral 5
3.1.2. Inhalation 5
3.2. CHRONIC 7
3.2.1. Oral 7
3.2.2. Inhalation 8
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 10
3.3.1. Oral ; 10
3.3.2. Inhalation 10
3.4. TOXICANT INTERACTIONS 12
4. CARCINOGENICITY 13
4.1. HUMAN DATA 13
4.1.1. Oral 13
4.1.2. Inhalation 13
4.2. BIOASSAYS 17
4.2.1. Oral 17
4.2.2. Inhalation 22
4.3. OTHER RELEVANT DATA 24
4.4. WEIGHT OF EVIDENCE 25
5. REGULATORY STANDARDS AND CRITERIA 27
vl
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TABLE OF CONTENTS (cont.)
Page
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
6.2. REFERENCE DOSE (RfD)
6.3. CARCINOGENIC POTENCY (q-|* or UNIT RISK SLOPE). . . .
6.3.1. Oral
6.3.2. Inhalation
REFERENCES
DIX Summarv Table for Benzene
. . 30
. . 30
. . 30
. . 30
. . 30
. . 31
. . 33
. . 56
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LIST OF TABLES
No. TUIe Page
4-1 Incidences of Leukemia and Zymbal Gland and Mammary
Gland Carcinomas 1n Sprague-Dawley Rats Given Benzene
by Gavage 18
4-2 Incidences of Neoplastlc Lesions 1n F344/N Rats Adminis-
tered by Gavage 19
4-3 Incidences of Neoplastlc Lesions 1n B6C3F1 Mice Adminis-
tered Benzene by Gavage 20
4-4 Incidences of Hematopoletlc Tumors In Mice Exposed to
Benzene Vapors by Inhalation 23
5-1 National Occupational Exposure Limits for Benzene 28
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
bw Body weight
CAS Chemical Abstract Service
CS Composite score
NOEL No-observed-effect level
ppm Parts per million
RfO Reference dose
RfOj Inhalation reference dose
RfOg Oral reference dose
RfD$ Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfD$o Subchronlc oral reference dose
SMR Standardized mortality ratio
STEL Short-term exposure limit
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The physical and chemical properties and environmental fate of benzene
(CAS No. 71-43-2) are given below:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Octanol/water partition
coefficient:
B1oconcentrat1on factor:
Soil sorptlon coefficient (Koc)
Half-lives 1n Air:
Mater:
Surface soil:
monocycllc aromatic hydrocarbon
78.12
95.2 mm Hg at 25°C
(Callahan et al., 1979)
1750 mg/l at 25°C
(Banerjee et al., 1980)
135 (recommended value)
(Hansch and Leo, 1985)
132 (Banerjee et al., 1980)
12.6 (Mackay, 1982)
-26.7 (Vowles and Mantoura, 1987)
-6 days (Atkinson, 1985)
3-23 days (Lay et al., 1985;
Wakeham et al., 1983)
0.3-1.6 days (Jury et al., 1984)
In water, the dominant fate determining processes for benzene are
predicted to be volatilization and blodegradatlon. In an aquatic modeling
study, U was estimated that 32% of benzene 1n water 1s lost by blodegrada-
tlon, 66% loss occurs by volatilization and 2% remains In water (Mackay et
al., 1985). The overall half-life (from all loss processes) of benzene In a
marine ecosystem during winter, spring and summer and 1n a pond during fall
was found to be 13, 23, 3.1 and 5 days, respectively (Lay et al., 1985;
Wakeham et al., 1983).
0037H
-1-
08/31/89
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In surface layers of soil, the dominant removal process Is expected to
be volatilization. The volatilization half-lives for benzene 1n soil (1 and
10 cm deep) were estimated to be 0.3 and 1.6 days, respectively (Jury et
al., 1984). Considering Its reasonably high water solubility and reasonably
low soil-water distribution coefficient (Vowles and Mantoura, 1987), benzene
1s expected to leach from subsurface soil. Conlgllo et al. (1980) reported,
however, only an 8.5% frequency of occurrence of benzene 1n groundwater
samples throughout the United States, compared with a 70% frequency for
chloroform. Therefore, both volatilization and blodegradatlon may account
for the primary loss of benzene from soil before It has the chance to leach
appreciably from soil to groundwater. The overall half-life of benzene 1n
groundwater was estimated to be 0.3-1.0 years (Zoeteman et al., 1981).
The dominant removal mechanism of atmospheric benzene 1s Us reaction
with photochemically generated hydroxyl radicals. The atmospheric half-life
reported above 1s based on a reaction rate constant of 1.28xlO~12
cm3/molecule-sec at 25°C (Atkinson, 1985) and an average hydroxyl radical
concentration of 106 molecules/cm3. A half-life of 6 days In air
suggests that benzene would be transported long distances In air from Us
sources of emission.
0037H -2- 08/31/89
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Sabourln et al. (1987) Investigated the gastrointestinal absorption of
benzene In F344/N and Sprague-Dawley rats and B6C3F1 mice. All test animals
were 13-week-old males and were given single gavage (0.5-300 mg/kg) or
IntraperHoneal (0.5-150 mg/kg) doses of 14C-benzene 1n corn oil. Cumula-
tive excretion of radioactivity was measured 1n expired air, urine and feces
for 48 hours after treatment. Using a formula for determining gastrointes-
tinal absorption that Incorporates excretion data following oral and Intra-
perltoneal treatment, gastrointestinal absorption was measured at >97% at
all dose levels 1n both strains of rats and B6C3F1 mice.
2.2. INHALATION
Sabourln et al. (1987) exposed young adult male F344/N rats and B6C3F1
mice by nose only to 14C-benzene 1n air at 26-2600 vg/l (26-2600
mg/m3) for 6 hours. Respiratory volume was measured and the Inhaled
dosage of radlolabeled benzene was estimated. The proportion of Inhaled
14C-benzene retained was estimated as the amount of radioactivity retained
1n the carcass at the end of the exposure period or as the amount of radio-
activity excreted over a 56-hour postexposure period. Retention values
decreased from 33 to 15% 1n rats and from 50 to 10% In mice as the exposure
concentration was Increased from 26 to 2600 yg/l.
Data regarding the Inhalation absorption of benzene by humans suggest an
absorption factor of -50%. Nomlyama and Nomlyama (1974) exposed three men
and three women to benzene at 52-62 ppm (166-198 mg/m3) for 4 hours and
estimated respiratory retention. Respiratory uptake (the difference between
the concentration of benzene In Inhaled and exhaled air expressed as a
percent of the concentration 1n Inhaled air) was measured at 46.9% with
little difference between men and women.
0037H -3- 04/12/88
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Srbova et al. (1950) exposed volunteers to 47-110 ppm (150-351 mg/ma)
benzene for up to 3 hours and estimated mean respiratory absorption (uptake)
at 53.8%, using a method of estimation similar to that described by Nomlyama
and Nomlyama (1974).
Hunter and Blair (1972) exposed human volunteers to 63-405 mg/m3
benzene for various lengths of time and measured the concentrations of
benzene 1n Inhaled and exhaled air. Benzene retention, estimated from
graphs of Inhaled and exhaled concentrations, was -44%. In an earlier
experiment (Hunter, 1968), benzene retention was estimated at 55-60% using
concentrations of 100-120 mg/ma.
0037H -4- 04/12/88
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
/
3.1. SUBCHRONIC
3.1.1. Oral. Wolf et al. (1956) dosed groups of 10 female Wlstar rats
(~2.75 months old) with benzene at 1, 10, 50 or 100 mg/kg by gavage 5 days/
week for 187 days to study effects on the hematopoletlc system. The control
group, consisting of 20 matched animals, received only the vehicle, which
was an olive oil solution emulsified with 5-10% aqueous solution of acacia.
No effect on the hematopoletlc system was seen at the 1 mg/kg level, very
slight leukopenla was observed at the 10 mg/kg level, and leukopenla and
erythrocytopenla were noted at both the 50 and 100 mg/kg levels.
Pertinent data regarding the effects of subchronlc oral exposure of
humans to benzene were not located 1n the available literature.
3.1.2. Inhalation. In a series of experiments, Delchmann et al. (1963)
exposed groups of -40 male and female Sprague-Dawley rats to benzene vapors
at levels of 15-831 ppm (48-2655 mg/m3) for 5-13 weeks. Rats exposed to
>61 ppm (195 mg/ma), 5 hours/day, ~5 days/week over a period of 38-46 days
developed significant leukopenla after 1-4 weeks of exposure. Rats exposed
to benzene vapors at 47 ppm (150 mg/m3), 7 hours/day for 180 days over a
period of 245 days had slight or moderate leukopenla, which began at 7-8
weeks of exposure and persisted to the end of the study. Likewise, leuko-
penla was observed among rats exposed to 44 ppm (141 mg/m3) benzene, 7
hours/day, 5 days/week for 8 weeks. Leukopenla was not observed 1n groups
of rats exposed to benzene levels <31 ppm (99 mg/m3), 7 hours/day, ~5
days/week for periods of 88-126 days. There were no overt signs of toxlc-
1ty, effects on body weight gain, anemia or gross pathologic changes at any
exposure level (15-831 ppm benzene). Rats exposed to either 61 or 831 ppm
of benzene vapors were examined for bone marrow changes, but there were no
0037H -5- 04/12/88
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differences when compared with control animals. No differences between
treated and control rats were observed during extensive hlstopathologlcal
examination of control rats and those exposed to 15, 31 or 47 ppm benzene.
Wolf et al. (1956) exposed groups of 10-25 male and female Wlstar rats,
5-10 male guinea pigs and 1-2 male rabbits to benzene vapors at levels of
>88 ppm (>281 mg/m3, for rats and guinea pigs) and >80 ppm (>256 mg/m3,
for rabbits), respectively, 7 hours/day, 5 days/week for 204-269 days.
Leukopenla was seen In all three species at these exposure levels. In
addition, rats exposed to >88 ppm benzene had Increased spleen weights;
guinea pigs exposed to >88 ppm had growth depression. Increased spleen and
testes weights and unspecified hlstopathologlc changes 1n the bone marrow;
and rabbits exposed to >80 ppm had unspecified hlstopathologlc changes 1n
the kidneys and testes. In the same study, rats exposed to benzene vapors
at 2200 ppm (7030 mg/m3) had depressed growth and unspecified hlstopatho-
loglc changes In the spleen and bone marrow, 1n addition to the effects also
seen at the lower exposure levels.
No hematologlc effects were seen 1n rats, guinea pigs or dogs exposed to
benzene vapors at a level of 17.6 ppm (56.2 mg/m3) continuously for up to
127 days (Jenkins et al., 1970).
Green et al. (1981) exposed a group of 11 or 12 male CD-I mice to
benzene vapors at a level of 302 ppm (965 mg/m3), 6 hours/day, 5 days/week
for 26 weeks. Treatment-related effects Included -50% mortality by the end
of the study, as well as marked lymphocytopenla, anemia and reduction of
bone marrow and spleen cellularlty and spleen weight.
In a more recent study (Ward et al., 1985), groups of 150 CD-I mice/sex
and 50 Sprague-Dawley rats/sex were exposed to benzene at 1, 10, 30 or 300
ppm (3, 32, 96 or 958 mg/m3), 6 hours/day, 5 days/week for <13 weeks.
0037H -6- 04/13/88
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Blood counts and clinical chemistry tests were performed on animals from all
groups, complete hlstopathologlcal examinations were performed on controls
and 300 ppm group animals, and limited hlstopathologlcal examinations were
performed on 10 and 30 ppm group animals. At 300 ppm, rats had leukopenla
and decreased bone marrow cellularlty, and mice had leukopenla, anemia,
testlcular atrophy, decreased spermatogenesls, ovarian cysts and thymlc
atrophy. No significant effects were observed In either species at 10 or
30 ppm.
Pertinent data regarding the effects of subchronlc Inhalation exposure
of humans to benzene were not located In the available literature.
3.2. CHRONIC
3.2.1. Oral. NTP (1986) administered benzene In corn oil by gavage to
groups of 50 male and 50 female F344/N rats and equal numbers of B6C3F1
mice, 5 days/week for 103 weeks. Dosage levels were 0, 50, 100 and 200
mg/kg/day for male rats and 0, 25, 50 and 100 mg/kg/day for female rats and
mice of both sexes. Significantly reduced survival was observed near the
end of the study In high-dose male and middle- and high-dose female rats.
All treated groups of male rats exhibited a statistically significant and
dose-dependent lymphocytopenla throughout most of the study. A similar but
less consistent trend was noted 1n female rats. Lymphold depletion was
observed 1n the spleens of all treated groups of rats; a dose-related
lymphold depletion was observed 1n the splenic follicles (both sexes of
rats) and thymus (male rats). Hyperplasla of the adrenal occurred In
low-dose rats of both sexes, hyperplasla of the Zymbal gland occurred In
low-dose male and middle-dose female rats, and hyperkeratosls and acanthosls
occurred 1n the forestomachs of high-dose male rats.
0037H -7- 04/12/88
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Male and female mice 1n the high-dose group had significantly reduced
survival near termination of the study. Lymphocytopenla was evident 1n
middle- and high-dose male mice for most of the study, but results In female
mice were equivocal. Hyperplasla of the bone marrow occurred 1n all treated
groups of mice and adrenal hyperplasla occurred 1n at least one sex at each
exposure level. Hyperplasla and hyperkeratosls of the forestomach, hyper-
plasla of pulmonary alveolar epithelium, Zymbal gland, harder Ian gland and
preputlal gland, and epithelial hyperplasla and senile atrophy of the ovary
were Increased 1n Incidence 1n some treated groups. These effects were
attributed to treatment with benzene.
3.2.2. Inhalation. Snyder et al. (1980) examined the heinatotoxlc and
carcinogenic effects of benzene to mice by exposing groups of 50 male AKR/J
mice to filtered air or air containing 100 ppm (319 mg/m21) benzene, 6
hours/day, 5 days/week for life (up to 505 days). There was no significant
difference 1n median survival or rate of weight gain between treated and
control mice. From the first week of exposure through the end of the
experiment, marked Increase 1n lymphocytopenla and slight, but statistically
significant, anemia were reported for treated mice. Bone marrow hypoplasla
was observed In 10/50 treated mice and 1n 1/50 controls. Similar but more
severe effects on these parameters were reported In AKR mice 1n an earlier
study conducted at a higher exposure level of 300 ppm benzene 1n the same
laboratory (Snyder et al., 1978).
Snyder et al. (1980) also exposed groups of 40 male C57B1/6J mice to
filtered air or air containing 300 ppm (958 mg/ma) benzene, 6 hours/day, 5
days/week for life (up to 488 days). A decreased survival rate was reported
for treated mice, with a median survival of 41 weeks for the treated group
and 75 weeks for the control group. Body weight gain of treated mice was
0037H -8- 04/12/88
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depressed relative to controls. From the first week of exposure through the
end of the experiment, marked lymphocytopenla and anemia were observed In
treated mice relative to controls. Bone marrow hyperplasla was observed In
13/40 benzene-exposed mice and 1n none of the corresponding control mice.
In an earlier experiment by Snyder et al. (1978), Sprague-Dawley rats,
tested similarly at 300 ppm (958 mg/m3) benzene, exhibited a trend toward
anemia and had a milder lymphocytopenla than had either AKR mice (Snyder et
al., 1978) or C57B1 mice (Snyder et al., 1980) at the same exposure level.
There are numerous reports of the effects of chronic Inhalation exposure
to benzene 1n humans. Chronic exposure of humans to benzene vapor causes
pancytopenla, which Is a reduction of blood erythrocytes, leukocytes and
thrombocytes (platelets) (U.S. EPA, 1980a; IARC, 1982; ACGIH, 1980; NIOSH,
1974). In early (mild) cases of chronic benzene poisoning, a decrease 1n
only one type of blood element may occur (anemia, leukopenla or thrombocyto-
penla), and the disease appears to be reversible on cessation of exposure.
Severe pancytopenla (aplastlc anemia) as a result of exposure to benzene 1s
often associated with a marked reduction In bone marrow cellularlty (U.S.
EPA, 1980a; IARC, 1982). The best evidence for the causal relationship
between benzene exposure and pancytopenla Is derived from occupational
studies 1n which the appearance of pancytopenla In workers occurred after
the use of benzene was Instituted, and ceased after benzene was replaced
with another solvent (U.S. EPA, 1980a). According to NIOSH (1974), occupa-
tional exposures to benzene at 300-700 ppm (958-2236 mg/m3) have been
linked consistently with blood dyscraslas (Greenburg, 1926; Savllahtl, 1956;
Vlgllanl and Salta, 1964). The lower limit of exposure that will result 1n
hematologlc effects 1n humans 1s not well defined, but 1s thought to be <100
0037H -9- 08/31/89
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ppm {Hardy and Elklns, 1948; Pagnotto et al., 1961; Pagnotto, 1972). There
1s some evidence for Impairment of the Immune system In humans chronically
exposed to benzene (Lange et al., 1973; Smollk et al., 1973).
An additional consequence of chronic benzene exposure 1s the Induction
of acute myelogenous leukemia In humans (Section 4.1.) (U.S. EPA, 1980a;
IARC, 1982). According to IARC (1982), there Is sufficient evidence that
benzene 1s carcinogenic to humans.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pregnant mice were given gavage doses of benzene at levels
of 0.3, 0.5 or 1.0 ml/kg/day (790, 1320 or 2640 mg/kg/day) on days 6-15 of
gestation (Nawrot and Staples, 1979). Increased mortality among the dams
and Increased resorptlon of embryos occurred at >0.5 ml/kg/day. At the 1
mg/kg/day dose level (given on days 6-15 or days 12-15 of gestation), there
was no statistically significant change 1n the Incidence of malformations.
3.3.2. Inhalation. In most Inhalation teratogenlclty experiments,
benzene was not teratogenlc and was fetotoxlc only at level;; of exposure
that were also maternotoxlc (U.S. EPA, 1980a; IARC, 1982). In one study,
however, evidence of fetotoxUHy was observed 1n mice 1n the absence of
maternotox1c1ty (Hurray et al., 1979), and In another study, suggestive
evidence of teratogenlc potential was observed In rats at maternotoxlc
exposure levels (Kuna and Kapp, 1981).
Hurray et al. (1979) exposed CF-1 mice and New Zealand rabbits to
benzene vapors at a concentration of 500 ppm (1597 mg/m3). Groups of 35
and 37 mice were exposed to room air or 500 ppm benzene, respectively, for 7
hours/day, on days 6-15 of gestation. Groups of 20 rabbits were exposed to
room air or 500 ppm benzene for 7 hours/day, on days 6-18 of gestation.
0037H -10- 04/12/88
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Changes 1n body weight and overt signs of tox1c1ty were not observed In
exposed animals of either species, nor were differences 1n numbers of
resorptlons or viable fetuses observed. Mean fetal body weight was signifi-
cantly lower (p<0.05) 1n Utters from benzene-exposed mice, but not 1n
Utters from benzene-exposed rabbits. Utters of benzene-exposed mice had
statistically significant Increases In several minor skeletal variants
considered to be Indicative of delayed development, but not 1n major mal-
formations. Treatment-related effects were not seen 1n Utters of benzene-
exposed rabbits.
Kuna and Kapp (1981) exposed pregnant Sprague-Dawley rats to benzene by
Inhalation on days 6-15 of gestation. Hated females were exposed to 0 ppm
(17 females), 10 ppm (32 mg/m3, 18 females), 50 ppm (160 mg/m3, 20
females) or 500 ppm (1597 mg/m3, 19 females) for 7 hours/day. No overt
signs of toxlclty were seen In any of the pregnant dams except for reduced
weight gains on days 5 through 15 of gestation 1n the 50 and 500 ppm groups.
No differences were seen In maternal erythrocyte, leukocyte or differential
leukocyte counts, or 1n Implantation efficiencies or number of resorptlons.
Mean crown rump length was significantly reduced (p<0.05) 1n Utters of dams
exposed to 500 ppm, and mean fetal body weights were reduced (p<0.05) 1n
both the 50 and 500 ppm groups. Delayed ossification occurred at 50 and 500
ppm, and four fetuses (from four Utters) of the 500 ppm group had skeletal
variants or anomalies; one fetus had exencephaly, one had angulated Mbs and
two had out-of-sequence ossification of the forefeet. In addition, Utters
from the high-dose group contained three fetuses with dilated lateral and
third brain ventricles. Historical Incidences of exencephaly, angulated
ribs, out-of-sequence ossification of the forefeet, and dilated lateral and
third brain ventricles were very low 1n control rats; these specific
abnormalities had not previously occurred together 1n a single experiment.
0037H -11- 04/12/88
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In the 50 ppm group, delayed ossification of the rib cage and extremities
was seen. No anomalies were noted 1n the lowest dose or control Utters.
Keller and Snyder (1986) Investigated the effects of maternal exposure
to benzene on the development of the hematopoletlc system 1n fetuses and
offspring of Swiss-Webster mice. Mated mice were exposed to 0, 5, 10 or 20
ppm (0, 16, 32 or 64 mg/m3), 6 hours/day on days 6-15 of gestation. A
dose-related Increase 1n fetal differentiated erythrold colony-forming cells
(CFU-E) was observed at 5 and 10 ppm; a decrease 1n CFU-E was noted at 20
ppm. Some significant changes 1n CFU-E and GM-CFU-C were observed 1n 2-day-
old neonates and 6-week-old adults following in utero exposure, but no
pattern of response was discerned and the biological significance of the
results 1s unclear.
3.4. TOXICANT INTERACTIONS
Benzene metabolism, and therefore benzene toxldty, may be altered by
simultaneous exposure to some other solvents (e.g., xylene, toluene). These
other aromatic solvents are oxidized by many of the same hepatic enzyme
systems that metabolize benzene (Ikeda et al., 1972). Since benzene metabo-
lites rather than the parent compound are suspected of Inducing bone marrow
toxldty. Inhibition of benzene metabolism (hydroxylatlon) by toluene may
Increase the toxlclty of benzene (Andrews et al., 1977; U.S. EPA, 1980a).
This synerglsm might possibly explain the failure to Induce leukemia In
animals with exposure to benzene alone (NAS, 1976).
0037H -12- 04/12/88
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the cardnogenldty of benzene by
oral exposure to humans were not located In the available literature.
4.1.2. Inhalation. IARC (1982) has summarized many case studies that
suggest a causal relationship between exposure to benzene by Inhalation and
leukemia 1n humans (Delore and Borgomano, 1928; Bowdltch and Elklns, 1939;
Hunter, 1939; Mallory et al., 1939; OeGowIn, 1963; Tareeff et al., 1963;
V1gl1an1 and Salta, 1964; Goguel et al., 1967; Aksoy et al., 1971, 1972;
Aksoy, 1980; Ludwlg and Werthemann, 1962; Galavottl and Tro1s1, 1950; Nlssen
and Soeborg Ohlsen, 1953; D1 Gugllelmo and lannaccone, 1958; Rozman et al.,
1968; Bryon et al., 1969; Fornl and Horeo, 1969; Glrard and Revol, 1970;
Goldstein, 1977). Because these studies are secondary to several epide-
miology studies for assessing human cancer risk associated with Inhalation
exposure to benzene, these case studies will not be discussed further.
These data are more completely reviewed by IARC (1982) and Goldstein (1977).
A number of epidemiology studies have associated occupational exposure
to benzene (either alone or 1n conjunction with other organic solvents) with
an Increased Incidence of leukemia (Aksoy, 1977, 1980; Aksoy et al., 1971,
1972. 1974; Infante et al., 1977a,b; Ott et al., 1978; Ishlmaru et al.,
1971; V1gl1an1, 1976; Flshbeck et al., 1978; Thorpe, 1974; McMlchael et al.,
1975; Monson and Nakano, 1976; Tyroler et al., 1976; Brandt et al., 1978;
Flodln et al., 1981; Harden et al., 1981; Greene et al., 1979; Rushton and
Alderson, 1980, 1981; Tabershaw and Lamm, 1977; Rlnsky et al., 1981, 1987;
Wong et al., 1983). Only studies Important 1n risk assessment are discussed
1n this section. The other epidemiology studies are reviewed In IARC (1982)
and U.S. EPA (1978a, 1980a).
0037H -13- 08/16/89
-------
Aksoy/(1977) examined the effect of benzene exposure on the Incidence of
leukemia or "preleukemla" among a group of 28.500 workers employed In the
shoe Industry of Turkey. The mean duration of employment and mean age of
this cohort were 9.7 years (range, 1-15 years) and 34.2 years, respec-
tively. Benzene exposure was reported to have occurred In small, poorly
ventilated work areas, with peak exposures of 210-650 ppm (671-2078
mg/m3). Of the 28,500 subjects studied, 34 cases of leukemia or pre-
leukemla were Identified. This corresponds to an annual leukemia Incidence
of -13/100,000 workers, which yields a relative risk of ~2 when compared
with the annual estimate of 6/100,000 for the general population. In a
later follow-up study, eight additional cases of leukemia were reported, and
there was suggestive evidence of an Increase 1n other malignant diseases
(Aksoy, 1980).
Infante et al. (1977a,b) examined the leukemogenlc effects of benzene
exposure on a cohort of 748 white males exposed to the solvent during the
manufacture of a rubber product from 1940-1949. Vital statistics were
obtained for 75% of the cohort through mid-1975. When compared with either
of two separate control populations, the general American population and
workers 1n another Industry not using benzene, a statistically significant
(p<0.002) excess of leukemia was found. Infante et al. (1977a) reported a
5-fold excessive risk of all leukemia and a 10-fold excessive risk of myelo-
cytlc and monocytlc (probably myelomonocytlc) leukemlas combined. The lag
period for chronic myelocytlc leukemia (one case) was 2 years from Initial
benzene exposure, while the lag period for acute myelocytlc and monocytlc
leukemia (six cases) was 10-21 years. The work environment was reported to
be free of contamination by solvents other than benzene. The air concentra-
tions of benzene were generally below the recommended limits In effect
0037H -14- 08/31/89
-------
during the period of the study (I.e., 100 ppm 1n 1941, 50 ppm In 1947, 35
ppm 1n 1948, 25 ppm 1n 1957 and 10 ppm 1n 1969).
Rlnsky et al. (1981) published a follow-up report to the Infante et al.
(1977a,b) studies using the same cohort but with vital status data obtained
for 98% of the workers compared with 75% In the Infante et al. (1977a,b)
reports. Among 748 workers exposed to benzene for >1 day between 1940 and
1950, seven workers died of leukemia. Based on U.S. death rates standard-
ized for age, sex and calender time period, 1.25 leukemia deaths were
expected, resulting 1n a statistically significant SHR of 560 (p<0.001).
The mean duration of exposure to benzene was brief; and 437 (58%) of the
workers were exposed for <1 year. In workers exposed for >5 years, deaths
from leukemia resulted In an SMR of 2100. Had four additional known cases
been Included (they were excluded for technical reasons), the SMR would have
been 3780. The Investigators estimated past exposure and concluded that,
although generally TWA exposures fell within permissible limits 1n effect at
the time of exposure, benzene concentration occasionally rose to several
hundred ppm 1n some areas of the plant.
Rlnsky et al. (1987) have published an update of risk assessment of a
cohort of 1165 rubber workers, as reported by Infante et al. (1977a,b) and
Rlnsky et al. (1981). 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. Standardized mortality
ratios were determined for leukemia by four cumulative exposure categories
(I.e., <40, 40-200, 200-400 and >400 ppm • years) and a marked,
progressive Increase In standardized mortality ratios was observed with
0037H -15- 08/31/89
-------
Increasing cumulative dose. There was no apparent pattern for nine leukemia
deaths with regard to latency, which ranged from under 5 years to more than
30 years.
Ott et al. (1978) used a retrospective cohort analysis to examine the
mortality of 594 Individuals occupatlonally exposed to benzene In chemical
manufacture during 1940-1973. Three deaths attributable to leukemia (two
acute myelogenous leukemia and one myeloblastlc leukemia) were reported
among the 594 workers compared with 0.8 case of expected leukemia deaths
(excluding lymphocytlc or monocytlc cell types), based on Incidence data
from the third National Cancer Survey (SMR=375). The difference between
observed and expected Incidence had marginal statistical significance
(p<0.05). The TWA benzene concentration to which the three subjects who
died of leukemia were exposed was estimated to be <10 ppm (32 mg/m3).
Wong et al. (1983) examined the mortality data of 7676 workers employed
for >6 months In the period January 1, 1946 to December 31, 1975 1n seven
chemical plants In which exposure to benzene occurred. A total of 4602
workers were exposed to benzene. The exposed group was divided Into two
categories; those exposed continuously (exposed at least 3 days/week) vs.
those exposed Intermittently. Air concentrations and TWA exposures to
benzene were estimated. The remaining 3074 workers constituted an Internal
control group. VHal statistics were compiled through December 31, 1977;
1036 of the 7676 workers had died and death certificates were obtained for
1013 (97.8%). SMRs were calculated for several causes of death using data
from the United States population for comparison. SMRs were slightly but
not statistically significantly >100 for lymphatic and hematopoletlc cancer,
and within the general category of hematopoletlc cancer, specifically for
leukemia, non-Hodgk1ns lymphoma and non-Hodgk1ns lymphopoietic cancer when
0037H -16- 08/16/89
-------
compared with the general population. However, the relative risk of death
from lymphatic and hematopoletlc cancer was significantly Increased with a
dose-response relationship between excess cancer risk and cumulative dose
when compared with data from Internal controls. The Investigators noted
that deaths from hematopoletlc cancers were unusually low 1n the control
cohort.
Only a small proportion of exposed Individuals actually develop leukemia
and It has been suggested that there Is a sensitive subpopulatlon, possibly
with some metabolic Idiosyncrasy that allows the formation of reactive
metabolites at a specific cellular target. Blattner et al. (1976) described
a family Involving a father and four of five siblings with chronic
lymphocyctlc leukemia. They all had been employed 1n the dry cleaning
business since the-1940s, a period during which benzene was widely used.
4.2. BIOASSAYS
4.2.1. Oral. Maltonl and Scarnato (1979) observed Increases 1n Zymbal
gland and mammary gland carcinomas 1n female Sprague-Dawley rats and
leukemia In male rats administered benzene by gavage. Three groups of 30 or
35 animals of each sex were treated 4-5 times/week for 52 weeks at dose
levels of either 50 or 250 mg/kg bw. The control group, consisting of 30
male and 30 female rats, received olive oil only. The tumor Incidences for
this study are summarized 1n Table 4-1.
More recent evidence for the cardnogenlclty of benzene to orally-
exposed animals was provided by the 2-year NTP (1986) gavage study using
rats and mice. Details of the protocol and tumor Incidences are presented
In Tables 4-2 (rats) and 4-3 (mice). In rats, benzene administration was
associated with Zymbal gland carcinomas and squamous cell paplllomas and
0037H -17- 08/31/89
-------
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carcinomas of the oral cavity and of the skin. In mice, benzene administra-
tion was associated with malignant lymphoma, particularly In males, and
tumors of the Zymbal gland, lung, harderlan gland, preputlal gland, ovary,
mammary gland and possibly the liver.
4.2.2. Inhalation. A statistically significant Increase 1n hematopoletic
neoplasms was reported for male C57B1/6J mice (n=40) exposed by Inhalation
to 300 ppm (958 mg/m3) benzene, 6 hours/day, 5 days/week for 488 days
(Snyder et a!., 1980). These tumor Incidences are summarized In Table 4-4.
In the same study, there was no Increase 1n tumors In 50 male AKR/J mice
exposed to 100 ppm (319 mg/m3) benzene under the same exposure schedule
(see Table 4-4). Snyder et al. (1980) also failed to find a statistically
significant Increased Incidence of tumors 1n male Charles River CD-I mice
(number not specified) exposed to 100 or 300 ppm of benzene under the same
exposure schedule previously described; however, myelogenous (myelold)
leukemia was observed 1n two CD-I mice exposed to 300 ppm of benzene.
Leukemia was observed 1n 1/40 male Sprague-Dawley rats exposed to benzene
vapors at a level of 100 ppm, 6 hours/day, 5 days/week for life (Snyder et
al., 1980). Because leukemia Is seldom observed In CD-I mice and Sprague-
Dawley rats, the authors concluded that benzene exposure may have been
responsible for these cancers.
A major continuing study (CronkHe et al. 1984, 1985; Cronklte, 1986)
provides a basis on which a reproducible model can be built. In this study
C57B1/6 BNL and CBA/Ca mice were exposed to 0, 10, 25, 100, 300 or 400 ppm
(0, 32, 80, 319, 958 and 1276 mg/m3), 6 hours/day, 5 days/week for 16
weeks followed by lifetime observation. This exposure regimen was selected
because the authors thought H most closely paralleled likely human
exposure. Human ep1dem1olog1cal studies 1n the literature reported that
0037H -22- 08/16/89
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occupatlonally-exposed persons were exposed for -15% of their Hfespan and
16 weeks represent ~15?C of the Hfespan for mice. The C57B1/6 and CBA/Ca
mouse strains were chosen for this study because of their low spontaneous
rates of acute myeloblastlc leukemia, the disease most frequently associated
with benzene exposure In humans.
Preliminary results associate benzene with leukemia In both strains of
mice at concentrations >25 ppm. An elevated Incidence of leukemia was
associated with CBA/Ca mice exposed by the same schedule to >100 ppm (319
mg/m3). No dose-related effect Information 1s available for evaluation at
this point.
4.3. OTHER RELEVANT DATA
Benzene has been tested extensively for genotoxlc properties. Benzene
was not mutagenlc 1n several bacterial and yeast systems. Including Salmo-
nella typhlmurlum both 1n the presence and absence of an exogenous metabolic
activating system (Lyon, 1976; Dean, 1978; Shahln and Fournler, 1978;
Lebowltz et al., 1979; Kaden et a!., 1979), Saccharomyces cerevlslae
(Cotruvo et al., 1977) and Escher1ch1a coll (Rosenkranz and Lelfer, 1980).
A preliminary study suggests that benzene oxide, a postulated Intermediate
metabolite of benzene, might be mutagenlc In S. typhlmurlum (IARC, 1982).
Benzene was also negative In the sex-linked recessive lethal mutation assay
with Drosophlla melanoqaster (Nylander et al., 1978) and the mouse lymphoma
forward mutation assay (Lebowltz et al., 1979). Equivocal results have been
obtained 1n assays for clastogenlc effects of benzene on mammalian chromo-
somes in vitro, but accumulated data seem to suggest that benzene metabo-
lites may be responsible In those cases with positive results (IARC, 1982;
Koizumi et al., 1974; Horlmoto, 1976; Gerner-Smldt and FMedrlch, 1978; Diaz
et al., 1979; Horlmoto and Wolff, 1980). Several Investigators have
reported positive results 1n mouse mlcronucleus assays following treatment
0037H -24- 08/16/89
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x
wfth benzene (Lyon, 1976; D1az et al., 1980; HHe et al., 1980; Meyne and
Legator, 1980). Benzene-Induced chromosomal aberrations 1n bone marrow
cells from rabbHs (K1ssl1ng and Speck, 1971), mice (Meyne and Legator,
1978, 1980) and rats (Dean, 1969; Philip and Krogh Jensen, 1970; Lyapkalo,
1973; Lyon, 1976; Dobrokhotov and Enlkeev, 1977; Anderson and Richardson,
1979) have also been reported.
Numerous Investigators have examined the effect of benzene on the
chromosomes of bone marrow cells and peripheral lymphocytes from both
symptomatic and asymptomatic workers with either a current or a past history
of exposure to benzene. Many of these Investigators found significant
Increases- In chromosomal aberrations In both symptomatic and asymptomatic
groups, some of which persisted for years after cessation of exposure (IARC,
1982; Poll1n1 and Colombl, 1964a,b; Poll1n1 et al., 1964, 1969; Polllnl and
B1scald1, 1976, 1977; Fornl et al., 1971a,b; Fornl and Moreo, 1967, 1969;
Hartwlch et al., 1969; Sellyel and Kelemen, 1971; Erdogan and Aksoy, 1973;
Hudak and Gombosl, 1977; Van den Berghe et al., 1979; Tough and Court Brown,
1965; Tough et al., 1970; Funes-Cravloto et al., 1977; Plcclano, 1979;
Hartwlch and Schwanltz, 1972; Khan and Khan, 1973; Fredga et al., 1979;
Sarto et al., 1984)).
4.4. WEIGHT OF EVIDENCE
The case reports reviewed by IARC (1982) and Goldstein (1977) relating
cardnogenlclty In humans with exposure to benzene, coupled with the
epldemlologlcal studies by Infante et al. (1977a,b), Rlnsky et al. (1981,
1987) and Ott et al. (1978) provide sufficient direct human evidence for the
cardnogenlclty of benzene.
0037H -25- 08/16/89
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Animal bloassays, which demonstrate Increased Incidence of many tumor
types In orally-exposed rats and mice (Maltonl and Scarnato, 1979; NTP,
1986) and suggest Increased Incidence of hematopoletlc tumors 1n mice
exposed by Inhalation (Snyder et al., 1980; Cronklte et al., 1984, 1985;
CronkHe, 1986), may be considered corroborative data that are supportive of
a carcinogenic role for benzene. Applying the criteria for weight of
evidence adopted by the U.S. EPA (1986a), benzene Is appropriately desig-
nated a Group A human carcinogen.
0037H -26- 08/17/89
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5. REGULATORY STANDARDS AND CRITERIA
Regulations and recommended guidelines reported by 15 countries for
limiting occupational exposure to benzene are summarized 1n Table 5-1. The
current ACGIH (1986) THA-TLV for benzene Is 10 ppm (30 mg/m3).
The U.S. EPA (1980a) has estimated ambient water concentrations of
0.066, 0.66 and 6.6 vQ/l associated with excess cancer risks of 10"7,
10~6 and 10~5, respectively. These estimates are based on an earlier
CAG analysis (U.S. EPA, 1978b), which used the epidemiology studies
performed by Infante et al. (1977a,b), Aksoy (1977) and Ott et al. (1978).
0037H -27- 08/16/89
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TABLE 5-1
National Occupational Exposure UrnUs for Benzene3
Country
Australia
Belgium
Czechoslovakia
Finland
Hungary
Italy
Japan
The Netherlands
Poland
Romania
Sweden
Switzerland
United States
OSHA
ACGIH
NIOSH
Year
1978
1978
1976
1975
1974
1978
1978
1978
1976
1975
1978
1978
1980
1987
1983
1980
Concentration
(mg/ma) (ppm)
30
30
50
80
32
20
30
80
30
30
50
15
30
6.5
NR
NR
NR
3.2
1.5
30
75
3.2
10
10
NR
NR
10
NR
10
25
10
NR
NR
5
10
2
10
25
50
1
5
10
25
1
Interpretation
TWAb
TWAb
TWA
celling (10 minutes)
TWAb
TWAC
TWAb
celling
TWAb
ceH1ngb
max1mumb
TWAb
maximum (15 minutes)
TWAb
TWA
celling
peakd
TWA
STEL
TWA
STEL
celling (60 minutes)
Status
guideline
regulation
regulation
regulation
regulation
regulation
guideline
guideline
guideline
regulation
regulation
guideline
guideline
regulation
regulation
regulation
regulation
regulation
regulation
guideline
guideline
guideline
0037H
-28-
08/16/89
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TABLE 5-1 (cent.)
Concentration
Country
USSR
Yugoslavia
Year
1980
1971
(mg/m3)
5
50
(ppm)
NR
15
Interpretation
celling5
ceH1ngb
Status
regulation
regulation
aSources: ACGIH, 1983; ILO, 1980; NIOSH, 1980; OSHA, 1980; IARC, 1982
bSk1n Irritant notation added
cMay be exceeded 5 times/shift as long as average does not exceed value
dPeak limit above celling — 10 minutes
NR * Not recorded
0037H
-29-
08/16/89
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD.)
d
Benzene 1s a known carcinogen for which data are sufficient for estimat-
ing carcinogenic potency. Therefore, It Is Inappropriate to calculate an
oral or Inhalation RfDg for benzene.
6.2. REFERENCE DOSE (RfD)
Benzene 1s a known carcinogen for which data are sufficient for estimat-
ing carcinogenic potency. Therefore, 1t 1s Inappropriate to calculate an
oral or Inhalation RfD for benzene.
6.3. CARCINOGENIC POTENCY (q.,* or UNIT RISK SLOPE)
6.3.1, Oral. Oral cancer data Include a 52-week gavage study using rats
by Haltonl and Scarnato (1979) and a 103-week gavage study using rats and
mice sponsored by the NTP (1986). Benzene was clearly carcinogenic In rats
and In mice 1n these studies. Benzene Is an EPA Group A carcinogen, which
means that human data are sufficient to support a causal association between
exposure and cancer. Therefore, 1t 1s more appropriate to base estimation
of carcinogenic potency on human rather than animal data.
U.S. EPA (1978b) derived a slope factor of 0.024074 (ppm)'1 for
Inhalation exposure to benzene based on the epidemiology studies by Aksoy
(1977), Infante et al. (1977a,b) and Ott et al. (1978). In estimating
excess cancer risk associated with benzene In ambient water, U.S. EPA
(1980a) chose the Inhalation unit risk slope developed by CAG (U.S. EPA,
1978b) over an estimate of carcinogenic potency derived from the first
positive oral rat study (Maltonl and Scarnato, 1979). The reasoning for
this decision 1s that 1t Is more appropriate to base risk assessment on
human rather than animal data, even 1f route-to-route extrapolation Is
Involved, when sufficient human data are available.
0037H -30- 08/31/89
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In a later CAG assessment (U.S. EPA, 19855), an Inhalation unit risk
slope of 2.60xlO"2 (ppm)"1 was developed from the ep1dem1olog1cal data
of Rlnsky et al. (1981), Wong et al. (1983) and Ott et al. (1978). This
estimate was considered as "single best Judgment unit risk estimate" by CAG
(U.S. EPA, 1986b). U.S. EPA (1986b) stated that this slope factor was
equivalent to 2.8xlO~r (mg/kg/day)"1. A slope factor for oral exposure
was calculated to be 5.6xlO~2 (mg/kg/day)"1, by dividing the Inhalation
unit risk slope with absorption factor for Inhalation (0.5).
In a recent CRAVE meeting (March 1, 1988), the oral slope factor for
benzene has been verified to be 2.9xlO~2 (mg/kg/day)"1 based on the
occupational data that served as the basis of the slope estimate for
Inhalation exposure (Aksoy, 1977; Ott et al., 1978; Rlnsky et al., 1981).
The unit risk for oral exposure was calculated to be 8.3xlO~7
(vg/l)"1 (U.S. EPA, 1988). It should be noted that the more recent
study of Rlnsky et al. (1987) has not been reviewed by the U.S. EPA and,
therefore, results -from this study have not been Integrated Into the
quantitative assessment that has been verified by the CRAVE work group.
6.3.2. Inhalation. The U.S. EPA (1980a) derived a cancer-based criterion
for human exposure to benzene from the epidemiology studies of Infante et
al. (1977a,b), Ott et al. (1978) and Aksoy (1977), In which a significantly
Increased Incidence of leukemia was observed for workers exposed to benzene
principally by Inhalation. Using these epidemiology studies, U.S. EPA
(1978b) calculated a dose-response curve with a slope of 0.024074 units of
lifetime risk/unit (ppm) of continuous exposure to atmospheric benzene.
This corresponds to a slope factor of 7.52xlO~3 (mg/m3)"1. Assuming
an Inhalation rate of 20 mVday for a 70 kg man, the unit risk also may be
expressed as 3.76xlO~4 (mg/day)'1 or 2.6xlO~2 (mg/kg/day)'1.
0037H -31- 08/31/89
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In a later evaluation by CAG (U.S. EPA, 1985b), an Inhalation slope
factor of 2.60xlO~2 (ppm)"1 was developed from the epldemlologlcal data
of Rlnsky et al. (1981), Wong et al. (1983) and Ott et al. (1978) (see
Section 6.3.1.). This slope factor transforms to 2.8xlO~2 (mg/kg/day)"1
as determined by U.S. EPA (1986b). The Inhalation carcinogenic: slope factor
for benzene was verified by the CRAVE work group of EPA on March 1, 1988 to
be 2.9xlO"2 (mg/kg/day)"1, based on the occupational results obtained by
Rlnsky et al. (1981), Ott et al. (1978) and Aksoy (1977). The corresponding
Inhalation unit risk Is calculated to be 8.3xlO~* (yg/m3)"1 (U.S.
EPA, 1988).
0037H -32- 08/31/89
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1980.
Documentation of the Threshold Limit Values for Substances In Workroom A1r.
Fourth edition with supplements through 1982. Cincinnati, OH. p. 37-40.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1983.
Threshold Limit Values for Chemical Substances and Physical Agents 1n the
Workroom Environment with Intended Changes for 1984. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986.
Threshold Limit Values and Biological Exposure Indices for 1986-1987.
Cincinnati, OH. p. 10.
Aksoy, M. 1977. Leukemia In workers due to occupational exposure to
benzene. New Istanbul ContMb. Cl1n. Sc1. 12: 3-14. (Cited In IARC, 1982)
Aksoy, M. 1980. Different types of malignancies due to occupational
exposure to benzene: A review of recent observations In Turkey. Environ.
Res. 23: 181-190. (Cited 1n IARC, 1982)
Aksoy, M., K. DlnCol, T. Akgun, S. Erdem and G. DlnCol. 1971. Haemato-
loglcal effects of chronic benzene poisoning 1n 217 workers. Br. J. Ind.
Med. 28: 296-302. (Cited 1n IARC, 1982)
Aksoy, M., K. DlnCol, S. Erdem, T. Akgun and 6. DlnCol. 1972. Details of
blood changes 1n 32 patients with pancytopenla associated with long-term
exposure to benzene. Br. 3. Ind. Med. 29: 56-64. (Cited 1n IARC, 1982)
0037H -33- 08/16/89
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Aksoy, M., S. Erdem and G. DlnCol. 1974. Leukemia 1n shoe workers exposed
chronically to benzene. Blood. 44: 837-841. (Cited 1n U.S. EPA, 1980a)
Anderson, D. and C.R. Richardson. 1979. Chromosome gaps are associated
with chemical mutagenesls (Abstract No. Ec-9). Environ. Mutagen. 1: 179.
(Cited In IARC, 1982)
Andrews, L.S., E.W. Lee, C.H. WHmer, J.J. Kocsls and R. Sriyder. 1977.
Effects of toluene on the metabolism, disposition and hematopoletlc toxldty
of 3H-benzene. Blochem. 3. Pharmacol. 26: 293-300. (Cited In U.S. EPA,
1980a)
Atkinson, R. 1985. Kinetics and mechanisms of the gas-phase reactions of
hydroxyl radical with organic compounds under atmospheric conditions. Chem.
Rev. 85: 69-201.
Banerjee, S., S.H. Yalkowsky and S.C. Valvanl. 1980. Hater solubility and
octanol/water partition coefficients of organlcs. Limitations of the
solubility-partition coefficient correlation. Environ. Scl. Techno!. 14:
1227-1229.
Blattner, W.A., W. Strober, A.V. Huchmore, R.M. Blaese, S. Broder and J.F.
Fraumen. 1976. Familial chronic lymphocytlc leukemia. Ann. Int. Med. 84:
554-557.
Bowdltch, M. and H.B. Elklns. 1939. Chronic exposure to benzene (benzol).
I. The Industrial aspects. J. Ind. Hyg. Toxlcol. 21: 321-330. (Cited In
IARC, 1982)
OQ37H -34- 08/16/89
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Brandt, L., P.G. Nllsson and F. MHelman. 1978. Occupational exposure to
petroleum products 1n men with acute non-lymphocytlc leukemia. Br. Med. J.
1: 553-554. (CHed 1n IARC, 1982)
Bryon, P.-A., P. Coeur, R. Glrard, 0. Gentllhomme and L. Revol. 1969.
Acute erythromyelosls with benzene etiology. J. Med. Lyon. 50: 757-759.
(Fre.) (CHed 1n IARC, 1982)
Callahan, M.A., M.W. Sllmak, N.W. Gabel, et al. 1979. Water-Related
Environmental Fate of 129 Priority Pollutants, Vol. II. Office of Water
Planning and Standards, Office of Water and Waste Management, U.S. EPA,
Washington, DC. EPA 440/4-79-029-b.
Con1gl1o, W.A., K. Miller and 0. MacKeever. 1980. The occurrence of
volatile organlcs 1n drinking water. Briefing prepared for Deputy Assistant
Administrator for Drinking Water, Criteria and Standards Division, Science
and Technology Branch, U.S. EPA, Washington, DC.
Cotruvo, J.A., V.F. Simmon and R.J. Spanggord. 1977. Investigation of
mutagenlc effects of products of ozonatlon reactions 1n water. Ann. NY
Acad. Sc1. 298: 124-140. (Cited 1n IARC, 1982)
Cronklte, E.P, 1986. Benzene hematotoxlclty and leukemogenesls. Blood
Cells. 12: 129-137.
Cronklte, E.P., J.E. BulUs, T. Inoue and R.T. Drew. 1984. Benzene Inhala-
tion produces leukemia 1n mice. Toxlcol. Appl. Pharmacol. 75: 358-361.
0037H -35- 08/17/89
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0037H
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