EPA-540/1-86-037
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
vvEPA
HEALTH EFFECTS ASSESSMENT
FOR BENZENE
-------
EPA/540/1-86-037
September 1984
HEALTH EFFECTS ASSESSMENT
FOR BENZENE
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
-------
DISCLAIMER
This report has been funded wholly or 1n part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
-------
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 1n
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 Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
basic literature searched supporting this document 1s current up to
September, 1984. 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. 19785. Estimation of Population Cancer Risk from
Ambient Benzene Exposure. Prepared by the Carcinogen Assessment
Group, OHEA, Washington, DC. Internal draft. (Cited In U.S. EPA,
1980b)
U.S. EPA. 1980b. Ambient Water Quality Criteria for Benzene.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-018. NTIS PB 81-117293.
U.S. EPA. 1982. Reportable Quantity for Benzene. Prepared by the
Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA
for the Office of Solid Waste and Emergency Response, Washington,
DC.
U.S. EPA. 1983b. Review of Toxlcologlc Data in Support of Evalua-
tion for Carcinogenic Potential of Benzene. Prepared by the
Carcinogen Assessment Group, OHEA, Washington, DC for the Office of
Solid Waste and Emergency Response, Washington, DC.
The Intent in these assessments is to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data was limited 1n
scope tending to generate conservative (I.e. protective) estimates. Never-
theless, the interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer is not the endpolnt of concern).
The first, the AIS or acceptable intake subchronic, is 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 which
does not constitute a significant portion of the lifespan). 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 in ambient air or water where lifetime exposure is
111
-------
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronic human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, is similar 1n concept to the ADI
(acceptable daily Intake). 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 lifespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable expo-
sure for a given route with the Implicit assumption that exposure by other
routes is insignificant.
Composite scores (CS) for noncardnogens have also been calculated where
data permitted. These values are used for ranking reportable quantities;
the methodology for their development is explained 1n U.S. EPA (1983a).
For compounds for which there is sufficient evidence of carcinogenicity,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer is a
process that is not characterized by a threshold, any exposure contributes
an increment of risk. Consequently, derivation of AIS and AIC values would
be inappropriate. For carcinogens, q-|*s have been computed based on oral
and inhalation data if available.
1v
-------
ABSTRACT
In order to place the risk assessment evaluation In 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 linking Inhalation exposure to
benzene with leukemia. A carcinogenic potency for Inhaled benzene of
2.59xlO~2 {mg/kg/day)~a may be estimated using data from several
ep!dem1olog1cal investigations. Animal data concerning the carclnogeniclty
of Inhaled benzene are equivocal.
Data regarding cancer Incidence In humans following oral exposure to
benzene were not located. Only one animal bloassay for the carclnogeniclty
of orally administered benzene was located (Maltonl and Scarnato, 1979).
Using the linearized multistage model (U.S. EPA, 1980a), a q-|* of
4.4512xlO~2 {mg/kg/day)"1 was computed. This value compares favorably
with the unit risk estimate of 5.2xlO~2 (mg/kg/day)"1 estimated from
human Inhalation data by U.S. EPA (1980b). For the purposes of the present
assessment, the unit risk estimate of 5.2xlO~2 {mg/kg/day)"1 is proposed
to represent the carcinogenic potency of benzene following oral exposure.
As more complete data concerning the carcinogeniclty of orally administered
benzene are available, this estimate should be reviewed.
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was»the Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
-------
TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . .
2.1.
2.2.
ORAL .
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
Page
1
2
. . 2
2
. . 3
, , 3
. . 3
. . 3
5
, . 5
. . 5
7
, . 7
7
, . 9
, . 10
. . 10
. . 10
. . 10
. . 12
. . 12
12
. . 15
. . 16
. . 17
-------
TABLE OF CONTENTS (cent.)
Page
6. RISK ASSESSMENT 20
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 20
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 20
6.3. CARCINOGENIC POTENCY (q-j*) 20
6.3.1. Oral 20
6.3.2. Inhalation 20
7. REFERENCES 22
APPENDIX A: Cancer Data Sheet for Derivation of q^ 41
APPENDIX B: Summary Table for Benzene 42
-------
LIST OF TABLES
No. Title
4-1 Incidences of Leukemia and Zymbal Gland and Mammary
Gland Carcinomas 1n Sprague-Dawley Rats Given Benzene
by Gavage 13
4-2 Incidences of Hematopoletlc Turners 1n Mice Exposed to
Benzene Vapors by Inhalation 14
5-1 National Occupational Exposure Limits for Benzene 18
1x
-------
LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
bw Body weight
CAS Chemical Abstract Service
CS Composite score
NOEL No-observed-effect level
ppm Parts per million
SMR Standardized mortality ratio
STEL Short-term exposure limit
TWA Time-weighted average
-------
1. ENVIRONMENTAL CHEMISTRY AND FATE
The physical and chemical properties and environmental fate of benzene
(CAS No. 71-43-3) are given below:
Chemical class: monocycllc aromatic hydrocarbon
Molecular weight: 78.12 (Callahan et al., 1979)
Vapor pressure: 95.2 mm Hg at 25°C (Callahan et al.,
1979)
Water solubility: 1750 mg/S. at 25°C (Banerjee et al.,
1980)
Octanol/water partition
coefficient: 132 (Banerjee et al., 1980)
B1oconcentrat1on factor: 12.6 (MacKay, 1982)
Half-lives 1n:
A1r: 6 days (Singh et al., 1981)
Water: 1-6 days (estimated)
The half-life of benzene 1n aquatic media has been estimated from the
reaeratlon rate ratio of 0.574 and the oxygen reaeratlon rate of 0.19
day-1 to 0.96 day'1 (Mabey et al., 1981).
An estimate for the half-life for benzene 1n soil was not located 1n the
available literature. By analogy with Us probable fate In aquatic media,
evaporation 1s expected to be the predominant loss mechanism from the soil
surface. Considering Us reasonably high water solubility and reasonably
low soil-water distribution coefficient (Chlou et al., 1983), benzene 1s
expected to leach from soil. Con1gl1o 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 1t has the chance to leach appreciably from soil to
groundwater.
-1-
-------
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Although quantitative data regarding the rate and extent of benzene
absorption from the gastrointestinal tract are not available, absorption can
be Inferred from oral toxldty and cardnogenlcHy studies (Chapters 3
and 4).
2.2. INHALATION
Although quantitative data regarding the rate and extent of pulmonary
benzene absorption are not available, absorption can be Inferred from
studies reporting effects 1n humans and animals following exposure to
benzene vapors (Chapters 3 and 4).
-2-
-------
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 levels of 1, 10, 50 or 100 mg/kg by
gavage 5 days/week for a period of 187 days. 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. Hematopoletlc
effects were reported for all dose levels except the lowest one. No effect
on the hematopoletlc system was seen at the 1 mg/kg level, while very slight
leukopenla was recorded at the 10 mg/kg level, and leukopenla and erythro-
cytopenla were noted at both the 50 and 100 mg/kg levels. From this study,
the 1 mg/kg dose level of benzene can therefore be suggested as a NOEL for
leukopenla and/or erythrocytopenla 1n female rats.
Pertinent data regarding the effects of subchronlc oral exposure of
humans to benzene were not located In.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 for 5-13 weeks. After 1-4 weeks of exposure, significant leuko-
penla was recorded for those animals exposed to >61 ppm for 5 hours/day, -5
days/week over a period of 38-46 days. Rats exposed to benzene vapors at a
level of 47 ppm for 7 hours/day on 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, leukopenla was observed among
rats exposed to 44 ppm benzene for 7 hours/day, 5 days/week, for 8 weeks.
Leukopenla was not observed 1n groups of rats exposed to benzene levels <31
ppm for 7 hours/day, -5 days/week for periods of 88-126 days. There were no
-3-
-------
overt signs of toxlclty, effects on body weight gain, anemia or gross patho-
logic changes at any exposure level (15-831 ppm of benzene). Rats exposed
to either 61 or 831 ppm of benzene vapors were examined for bone marrow
changes, but there were no differences when compared with control animals.
No differences between treated and control animals were observed during
extensive hlstopathologlcal examination of control rats and those exposed to
15, 31 or 47 ppm of benzene. From this study, 31 ppm of benzene can be
suggested as the NOEL for leukopenla 1n rats.
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, 88 and 80 ppm, respectively, for 7 hours/day, 5 days/week for 204-269
days. Leukopenla was seen 1n all three species at the lowest exposure
levels tested. In addition, rats exposed to 88 ppm of benzene had Increased
spleen weights; guinea pigs exposed to 88 ppm had depressed growth,
Increased spleen and testes weights and unspecified hlstopathologlc changes
In the bone marrow; and rabbits exposed to 80 ppm had unspecified hlsto-
pathologlc changes 1n the kidneys and testes. Rats exposed to benzene
vapors at a level of 2200 ppm had signs of necrosis, depressed growth and
unspecified hlstopathologlc changes In the spleen and bone marrow, 1n
addition to the effects also seen at the lower exposure level.
No hematologlc effects were seen In rats, guinea pigs or dogs exposed to
benzene vapors at a level of 17.6 ppm continuously for up to 127 days
(Jenkins et al., 1970).
Green et al. (1981) exposed 11 or 12 male CD-I mice to benzene vapors at
a level of 302 ppm for 6 hours/day, 5 days/week for 26 weeks. Treatment-
related effects Included nearly 50% mortality by the end of the study, as
well as marked lymphocytopenla, anemia and reduction of bone marrow, spleen
cellularlty and spleen weight.
-4-
-------
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. Pertinent data regarding the chronic toxldty of benzene
following oral exposure of either animals or humans were not located 1n the
available literature.
3.2.2. Inhalation. Snyder et al. (1980) examined the hematotoxlc and
carcinogenic effects of benzene to mice by exposing groups of 50 male AKR/J
mice to filtered air or 100 ppm of benzene, and groups of 40 male C57B1/6J
mice to filtered air or 300 ppm of benzene, for 6 hours/day, 5 days/week for
life (up to 505 days for C57B1 mice). For AKR mice, there was no signifi-
cant difference In median survival or rate of weight gain between treated
and control animals. From the first week of exposure through the end of the
experiment, marked lymphocytopenla and slight but statistically significant
anemia were reported for treated AKR mice relative to controls. Bone marrow
hypoplasla was observed 1n 10/50 treated AKR mice and 1n 1/50 controls.
Similar, but more severe, effects on these parameters 1n AKR mice were
reported In an earlier study conducted at a higher exposure level of 300 ppm
of benzene 1n the same laboratory (Snyder et al., 1978).
A decreased survival rate was reported for treated C57B1 mice, with a
median survival of 41 weeks for the treated group and 75 weeks for the
control group. Body weight gain of treated C57B1 mice was depressed rela-
tive to controls. From the first week of exposure through the end of the
experiment, marked lymphocytopenla and anemia were observed 1n treated C57B1
mice relative to controls. Bone marrow hyperplasla was observed In 13/40
benzene-exposed C57B1 mice and 1n none of the corresponding control mice.
-5-
-------
In an earlier experiment by Snyder et al. (1978), Sprague-Dawley rats,
tested similarly at 300 ppm of 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. 1s a reduction of blood erythrocytes, leukocytes and
thrombocytes (platelets) (U.S. EPA, 1980b; IARC, 1982; AC6IH, 1980; NIOSH,
1974). In early (mild) cases of chronic benzene poisoning, a decrease in
only one type of blood element may occur (I.e., anemia, leukopenla or throm-
bocytopenla), and the disease appears to be reversible on cessation of
exposure. Severe pancytopenla (aplastlc anemia) as a result of exposure to
benzene Is often associated with a marked reduction In bone marrow cellular-
1ty (U.S. EPA, 1980b; IARC, 1982). The best evidence for the causal rela-
tionship between benzene exposure and pancytopenla 1s derived from occupa-
tional studies 1n which the appearance of pancytopenla 1n workers occurred
after the use of benzene was Instituted, and ceased after benzene was
replaced with another solvent (U.S. EPA, 1980b). According to NIOSH (1974),
occupational exposures to benzene at 300-700 ppm have been linked consis-
tently with blood dyscraslas (Greenburg, 1926; Sav1laht1, 1956; Vlgllanl and
Salta, 1964). The lower limit of exposure that will result In hematologlc
effects 1n humans 1s not well defined, but Is thought to be <100 ppm (Hardy
and Elkins, 1948; Pagnotto et al., 1961; Pagnotto, 1972). There 1s some
evidence for Impairment of the Immune system 1n humans chronically exposed
to benzene (Lange et al., 1973; Smollk et al., 1973).
-6-
-------
An additional consequence of chronic benzene exposure 1s the Induction
of acute myelogenous leukemia 1n humans (Section 4.1.) (U.S. EPA, 1980b;
IARC, 1982). According to IARC (1982), there is sufficient evidence that
benzene Is 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 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 all dose levels. 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 teratogenldty experiments,
benzene was not teratogenlc and was fetotoxlc only at levels of exposure
that were also maternotoxlc (U.S. EPA, 1980b; IARC, 1982). In one study,
however, evidence of fetotoxldty was observed 1n mice In the absence of
maternotoxlclty (Murray et al., 1979), and In another study, suggestive
evidence of teratogenlc potential was observed 1n rats at maternotoxlc
exposure levels (Kuna and Kapp, 1981). Only the studies of Murray et al.
(1979) and Kuna and Kapp (1981), summarized by U.S. EPA (1982), will be
discussed here; further Information Is available 1n U.S. EPA (1980b) and
IARC (1982).
Murray et al. (1979) exposed CF-1 mice and New Zealand rabbits to
benzene vapors at a concentration of 500 ppm. 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. Changes 1n body
weight and overt signs of toxldty were not observed In exposed animals of
either species, nor were differences In numbers of resorptlons or viable
-7-
-------
fetuses observed. Mean fetal body weight was significantly lower (p<0.05)
1n Utters from benzene-exposed mice, but not In Utters from benzene-
exposed rabbits. Litters of benzene-exposed mice had statistically signifi-
cant Increases In several minor skeletal variants considered to be Indica-
tive of delayed development, but not In major malformations. 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. Animals were exposed to 0 ppm (17
females), 10 ppm (18 females), 50 ppm (20 females) or 500 ppm (19 females)
for 7 hours/day. No overt signs of toxldty were seen 1n any of the preg-
nant dams except for reduced weight gains on days 5-15 of gestation In the
50 and 500 ppm groups. No differences were seen 1n 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 litters of dams exposed to 500 ppm, and mean fetal body weights
were reduced (p<0.05) In both the 50 and 500 ppm groups. Delayed ossifica-
tion 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 ribs and two had out-of-sequence ossification of the fore-
feet. 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 In control
rats; these specific abnormalities had not previously occurred together 1n a
single experiment. In the 50 ppm group, delayed ossification of the Mb
cage and extremities was seen. No anomalies were noted 1n the lowest dose
or control Utters. This study suggests a NOEL of 10 ppm for fetotoxlc
effects 1n rats.
-8-
-------
3.4. TOXICANT INTERACTIONS
Benzene metabolism, and therefore benzene toxIcHy, 1s altered by simul-
taneous exposure to some other solvents (e.g., xylene, toluene) because
these aromatic solvents are oxidized by many of the same hepatic enzyme
systems (Ikeda et a!., 1972; U.S. EPA, 1980b). Reported hematotoxlc effects
of benzene 1n humans may be a synerglstlc result of simultaneous exposure to
other solvents (e.g., xylene, toluene), as benzene Itself does not Induce
leukemia 1n animals (NAS, 1976; U.S. EPA, 1980b). Since benzene metabolites
rather than the parent compound are suspected of Inducing bone marrow toxlc-
Ity, Inhibition of benzene metabolism (hydroxylatlon) by toluene may result
1n Increased toxic effects of the parent compound Instead of benzene metabo-
lites (Andrews et al., 1977; U.S. EPA, 1980b).
-9-
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the carclnogenldty of benzene via
oral exposure to humans were not located 1n 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; DeGowIn, 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 Trolsi, 1950; Nlssen
and Soeborg Ohlsen, 1953; 01 Gugllelmo and lannaccone, 1958; Rozman et al.,
1968; Bryon et al., 1969; Fornl and Moreo, 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.
Instead, the reader 1s referred to the reviews 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) by
Inhalation with an Increased Incidence of leukemia (Aksoy, 1977; Infante et
al., 1977a,b; Ott et al., 1978; Ishlmaru et al., 1971; Vlgllanl, 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; Hardell et al., 1981; Greene et al., 1979; Rushton and Alderson, 1980,
1981; Tabershaw and Lamm, 1977; Rlnsky et al., 1981). Since the U.S. EPA
(1980b) used the studies of Aksoy et al. (1974), Infante et al. (1977a,b)
and Ott et al. (1978) to derive a human cancer-based criterion for exposure
-10-
-------
to benzene, only these studies will be discussed further. The other epide-
miology studies are reviewed In IARC (1982) and U.S. EPA (1978a, 1980b).
Aksoy et al. (1974) examined the effect of benzene exposure on the Inci-
dence 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,
respectively. Benzene exposure was reported to have occurred 1n small,
poorly ventilated work areas, with peak exposures of 210-650 ppm (670-2075
mg/m3). Of the 28,500 subjects studied, 26 were reported to have leukemia
(34 cases of leukemia or preleukemla 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 the cohort through mid-1975. When compared with either of two
separate control populations, the general American population and workers In
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 myelocytlc
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 monccytlc leukemia
(six cases) was 10-21 years. The work environment was reported to be free
-11-
-------
of contamination by solvents other than benzene. The air concentrations of
benzene were generally below the recommended limits 1n effect 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 In 1969).
Ott et al. (1978) used a retrospective cohort analysis to examine the
mortality experience of 594 Individuals occupatlonally exposed to benzene In
chemical manufacture during the period 1940-1973. Three deaths attributable
to leukemia (one myelogenous and one myeloblastlc) and one to aplastlc
anemia were reported among the 594 workers. Only 0.8 deaths from leukemia
(excluding lymphocytlc or monocytlc cell types) were expected, based on
Incidence data from the third National Cancer Survey (SMR=375); the differ-
ence had marginal statistical significance (p<0.05). The TWA benzene con-
centration to which the three subjects who died of leukemia were exposed was
estimated to be <10 ppm.
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 1n 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 In Table 4-1.
4.2.2. Inhalation. Slight Increases 1n hematopoletlc neoplasms were
reported for male C57B1 mice (N=40) exposed by Inhalation to 300 ppm of
benzene for 6 hours/day, 5 days/week for 488 days (Snyder et al., 1980).
These tumor Incidences are summarized In Table 4-2. In the same study,
there was no Increase 1n tumors 1n 50 male AKR mice exposed to 100 ppm of
benzene under the same exposure schedule. Snyder et al. (1980) also failed
-12-
-------
TABLE 4-1
Incidences of Leukemia and Zymbal Gland and Mammary Gland Carcinomas In Sprague-Dawley Rats Given Benzene by Gavage3
CJ
i
Sex
N
N
N
F
{
r
Dose or
Exposure
0.0 rag
50 mg/kg
4-5 times/week
250 mg/kg
4-5 times/week
0.0 mg
50 mg/kg
4-5 times/week
250 mg/kg
4-5 times/week
Duration
of
Treatment
(weeks)
NA
52
52
NA
52
52
Duration
of Study
llfespan
llfespan
llfespan
llfespan
Hfespan
llfespan
Purity
of
Compound
NA
NR
NR
NA
NA
NA
Vehicle or
Physical
State
olive oil
olive oil
olive oil
olive oil
olive oil
olive oil
Target Organ
hematopoletlc
hematopoletlc
hematopoletlc
zymbal gland
mammary gland
zymbal gland
mammary gland
zymbal gland
mammary gland
Tumor
Type
leukemia
leukemia
leukemia
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
Tumor
Incidence
(p value)
0/30
0/30
4/35
0/30 (NA)
3/30
2/30 (NS)b
4/30
8/35 (p<0.05)b
7/35
aSource: Hal ton1 and Scarnato, 1979
bF1sher exact test
NA = Not applicable; NR » not recorded; NS - not significant
-------
TABLE 4-2
Incidences of Hematopoletlc Tumors In Nice Exposed to Benzene Vapors by Inhalation9
Strain
C57B1
C57B1
AKR
AKR
Sex
N
N
N
N
Dose or
Exposure
0.0 ppm
300 ppm
6 hours/day,
5 days /week
0.0 ppm
100 ppm
6 hours/day,
5 days/week
Duration
of
Treatment
(days)
NA
488
NA
SOS
Duration
of Study
llfespan
llfespan
llfespan
llfespan
Purity
of
Compound
MA
NR
NA
NR
Vehicle or
Physical
State
NA
vapor
NA
vapor
Target Organ
hematopoletlc
hematopoletlc
hematopoletlc
hematopoletlc
Tumor
Tumor Type Incidence
(p value)
all tumors 2/40
all tumors B/40
all tumors NR
all tumors NS
aSource: Snyder et al.. 1980
bLymphomas occurred In two of the control and six of the treated CS7B1 mice.
NA - Not applicable; NR = not reported; NS * not significant
-------
to find a statistically significant Increased Incidence In 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. A leukemlc response was not observed 1n 45 male Sprague-
Dawley rats exposed to benzene vapors at a level of 300 ppm for 6 hours/day,
5 days/week for life.(Snyder et a!., 1980).
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 typh1mur1um both 1n the presence and absence of an exogenous metabolic
activating system (Lyon, 1976; Dean, 1978; Shahln and Fournler, 1978;
Lebowltz et a!., 1979; Kaden et al., 1979), Saccharomyces cerevlslae
(Cotruvo et al., 1977) and Escher1ch1a coll (Rosenkranz and Lelfer, 1980).
Benzene was also negative 1n the sex-linked recessive lethal mutation assay
with DrosophUa 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 ±n vitro, but 1t
appears that benzene metabolites are responsible 1n those cases with posi-
tive results (IARC, 1982; Koizumi et al., 1974; MoMmoto, 1976; Gerner-Smldt
and FMedrlch, 1978; D1az et al., 1979; Morlmoto and Wolff, 1980). Several
Investigators have reported positive results for benzene In mouse micro-
nucleus assays (Lyon, 1976; D1az et al., 1980; Hlte et al., 1980; Meyne and
Legator, 1980). Benzene Induced chromosomal aberrations 1n bone marrow
cells from rabbits (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).
-15-
-------
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 1n chromosomal aberrations In both symptomatic and asymptomatic
groups, some of which persisted for years after cessation of exposure (IARC,
1982; Polllnl 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; Plcdano, 1979;
Hartwlch and Schwanltz, 1972; Khan and Khan, 1973; Fredga et al., 1979).
4.4. WEIGHT OF EVIDENCE
The case reports reviewed by IARC (1982) and Goldstein (1977) relating
cardnogenlcHy 1n humans with exposure to benzene, coupled with the eplde-
mlologlcal studies by Aksoy et al. (1974), Infante et al. (1977a,b) and Ott
et al. (1978) provide sufficient evidence for the cardnogenlcHy of benzene
to humans.
Animal bloassays, which demonstrate Increased Incidence of zymbal and
mammary gland carcinoma 1n orally exposed rats (Maltonl and Scarnato, 1979)
and suggest Increased Incidence of hematopoletlc tumors 1n C57B1 mice
exposed via Inhalation, may be considered corroborative data supportive of a
carcinogenic role for benzene. Applying the criteria for weight of evidence
proposed by the Carcinogen Assessment Group of the U.S. EPA (Federal
Register, 1984), benzene 1s most appropriately designated a Group A human
carcinogen.
-16-
-------
5. REGULATORY STANDARDS AND CRITERIA
Regulations and recommended guidelines have been reported by 15
countries for limiting occupational exposure to benzene (IARC, 1982). These
regulations and guidelines are summarized In Table 5-1. Six countries
(Finland, the Federal Republic of Germany, Italy, Japan, Sweden and Switzer-
land) recognize benzene as being carcinogenic to humans, and two others
(Australia, the United States) have designated benzene as a suspected human
carcinogen'(IARC, 1982).
The U.S. EPA (1980b) has estimated water criteria for the consumption of
benzene through water andd life time contaminated fish for Increased risk
levels of 10"7, 10~6 and 10"s of 0.066, 0.66 and 6.6 pg/l, respec-
tively.
-17-
-------
TABLE 5-1
National Occupational Exposure Limits for Benzene3
Concentration
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
1983
1980
(mg/m3)
30
30
50
80
32
20
30
80
30
30
50
15
30
6.5
NR
NR
NR
30
75
3.2
(ppm)
10
10
NR
NR
10
NR
10
25
10
NR
NR
5
10
2
10
25
50
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
celling (60 minutes)
Status
guideline
regulation
regulation
regulation
regulation
regulation
guideline
guideline
guideline
regulation
regulation
guideline
guideline
regulation
regulation
regulation
regulation
guideline
guideline
guideline
-18-
-------
TABLE 5-1 (cont.)
Concentration
Country
USSR
Yugoslavia
Year
1980
1971
(mg/m3)
5
50
(ppm)
NR
15
Interpretation
celling5
ce111ngb
Status
regulation
regulation
aSources: ACGIH, 1983; International Labour Office, 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
-19-
-------
6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Benzene 1s a known carcinogen for which data are sufficient for comput-
ing a q *. Therefore, It 1s Inappropriate to calculate an oral or Inhala-
tion AIS for benzene.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Benzene 1s a known carcinogen for which data are sufficient for comput-
ing a q,*. Therefore, 1t 1s Inappropriate to calculate an oral or Inhala-
tion AIC for benzene.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. In the only oral cancer bloassay, Maltonl and Scarnato
(1979) observed an Increased Incidence of zymbal gland carcinoma 1n female
rats given benzene by gavage 1n olive oil at levels of 0, 50 or 250 mg/kg bw
(equivalent to 0, 11.6 or 58.0 mg/kg/day, respectively), 4-5 days/week for
52 weeks. The Incidences of zymbal gland carcinoma were 0/30 controls, 2/30
low dose and 8/35 high dose. Using the cancer data from this study, a
quantitative risk criterion can be derived for benzene. Based on the zymbal
gland carcinoma response of female rats, and using the linearized multistage
model adopted by the U.S. EPA (1980a), a carcinogenic potency factor (q *)
of 4.4512xlO~2 (mg/kg/day)'1 can be derived for humans. The human q,*
1s calculated from the animal q * by applying the cube root of the ratio
of the body weight of humans to rats. Complete data for derivation of this
q * are presented In Appendix A.
This value compares favorably with the unit risk estimate developed for
oral exposure based upon human occupational exposure (U.S. EPA, 1980b).
This Inhalation-based oral estimate of 5.2xlO~* (mg/kg/day)"1 was
derived as described 1n section 6.3.2. of this document with the additive of
-20-
-------
an absorption factor of 0.5 to estimate oral exposure from enhalation data
It Is proposed that the unit risk value of 5.2xlO~2 (mg/kg/day)"1 as
estimated by U.S. EPA (1980b) be used as an estimate of the oral carcino-
genic potency of benzene for the purposes of the present assessment.
6.3.2. Inhalation. The U.S. EPA (1980b) 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 et al. (1974), 1n which a signif-
icantly Increased Incidence of leukemia was observed for workers exposed to
benzene principally by Inhalation. Using these epidemiology studies, the
U.S. EPA Carcinogen Assessment Group (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 unit risk
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 3.76x10"*
mg/day~a or 2.6xlO~2 mg/kg/day'1.
-21-
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1980.
Documentation of the Threshold Limit Values for Substances 1n Workroom A1r.
Fourth edition with supplements through 1982. Cincinnati, OH. p. 37-40.
ACGIH (American Conference of Governmental Industrial Hyglenists). 1983.
Threshold Limit Values for Chemical Substances and Physical Agents In the
Workroom Environment with Intended Changes for 1984. Cincinnati, OH.
Aksoy, M. 1977. Leukemia 1n workers due to occupational exposure to
benzene. New Istanbul ContMb. Cl1n. Scl. 12: 3-14. (Cited In IARC, 1982)
Aksoy, M. 1980. Different types of malignancies due to occupational expo-
sure 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. 3. Ind.
Med. 28: 296-302. (Cited In IARC, 1982)
Aksoy, M., K. DlnCol, S. Erdem, T. Akgun and G. DlnCol. 1972. Details of
blood changes 1n 32 patients with pancytopenla associated with long-term
exposure to benzene. Br. J. Ind. Med. 29: 56-64. (Cited 1n IARC, 1982)
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, 1980b)
-22-
-------
Anderson, D. and C.R. Richardson. 1979. Chromosome gaps are associated
with chemical mutagenesls (Abstract No. Ec-9). Environ. Mutagen. 1: 179.
(Cited 1n IARC, 1982)
Andrews, L.S., E.W. Lee, C.M. WHmer, J.J. Kocsls and R. Snyder. 1977.
Effects of toluene on the metabolism, disposition and hemopoletlc toxldty
of 3H-benzene. Blochem. J. Pharmacol. 26: 293-300. (Cited In U.S. EPA,
1980b)
Banerjee, S., S.H. Yalkowsky and S.C. Valvanl. 1980. Water solubility and
octanol/water partition coefficients of organlcs. Limitations of the
solubility-partition coefficient correlation. Environ. Scl. Techno!. 14:
1227-1229.
BowdHch, M. and H.B. Elklns. 1939. Chronic exposure to benzene (benzol).
I. The Industrial aspects. J. Ind. Hyg. Toxlcol. 21: 321-330. (CHed 1n
IARC, 1982)
Brandt, L., P.6. NHsson and F. Mltelman. 1978. Occupational exposure to
petroleum products 1n men with acute non-lymphocyt1c 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. (Fre.) J. Med. Lyon. 50:
757-759. (Cited 1n IARC, 1982)
-23-
-------
Callahan, M.A., M.W. SUmak, 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.
Chlou, C.T., P.E. Porter and D.W. Schmeddlng. 1983. Partition equilibrium
of nonlonlc organic compounds between soil, organic matter and water.
Environ. Sd. Technol. 17: 227-231.
Con1gl1o, W.A., K. Miller and D. MacKeever. 1980. The occurrence of
volatile organlcs In 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. Sci. 298: 124-140. (Cited In IARC, 1982)
Dean, B.J. 1969. Chemical-Induced chromosome damage. Lab. An1m. 3:
57-174. (Cited 1n IARC, 1982)
Dean, B.J. 1978. Genetic toxldty of benzene, toluene, xylenes and
phenols. Mutat. Res. 47: 75-97. (Cited In IARC, 1982)
DeGowIn, R.L. 1963. Benzene exposure and aplastlc anemia followed by
leukemia 15 years later. J. Am. Med. Assoc. 185: 748-751. (Cited 1n IARC,
1982)
-24-
-------
Delchmann, W.B., W.E. MacDonald and E. Bernal. 1963. The hemopoletlc
tissue tox1c1ty of benzene vapors. Toxlcol. Appl. Pharmacol. 5: 201-224.
(Cited 1n U.S. EPA, 1982)
Delore, P. and C. Borgomano. 1928. Acute leukemia following benzene poi-
soning. On the toxic origin of certain acute leukaemias and their relation
to serious anaemias. (Fre.) J. Med. Lyon. 9: 227-233. (CUed 1n IARC,
1982)
D1az, M., N. Fljtman. V. Carrlcarte, L. Braler and J. 01ez. 1979. Effect
of benzene and Us metabolites on SCE 1n human lymphocytes cultures
(Abstract No. 23). In Vitro. 15: 172. (Cited 1n IARC, 1982)
D1az, M., A. Reiser, L. Braler and J. 01ez. 1980. Studies on benzenes
mutagenesls. I. The mlcronucleus test. Exper1ent1a. 36: 297-299. (Cited
In IARC, 1982)
01 Gugllelmo, G. and A. lannaccone. 1958. Inhibition of mitosis and
regressive changes of erythroblasts In acute erythropathy caused by occupa-
tional benzene poisoning. Acta Haematol. 19: 144-147. (Cited In IARC,
1982)
Oobrokhotov, V.B. and M.I. Enlkeev. 1977. Mutagenlc effect of benzene,
toluene and a mixture of these hydrocarbons 1n a chronic experiment. (Rus.)
G1g. SanH. 1: 32-34. (Cited 1n IARC, 1982)
-25-
-------
Erdogan, G. and M. Aksoy. 1973. Cytogenetlc studies In thirteen patients
with pancytopenla and leukemia associated with long-term exposure to
benzene. New Istanbul. ContMb. Cl1n. Sd. 10: 230-247. (Cited In IARC,
1982)
Federal Register. 1984. Environmental Protection Agency. Proposed
Guidelines for Carcinogenic Risk Assessment. Federal Register. 49:
46294-46299.
Flshbeck, W.A., J.C. Townsend and M.G. Swank. 1978. Effects of chronic
occupational exposure to measured concentrations of benzene. J. Occup. Med.
20: 539-542. (Cited 1n IARC, 1982)
Flodln, U., L. Andersson, C.G. Anjou, U.B. Palm, 0. Vlkrot and 0. Axelson.
1981. A case-referent study on acute myelold leukemia, background radiation
and exposures to solvents and other agents. Scand. J. Work Environ. Health.
7: 169-178. (Cited 1n IARC, 1982)
Fornl, A. and L. Moreo. 1967. Cytogenetlc studies 1n a case of benzene
leukemia. Eur. J. Cancer. 3: 251-255. (Cited In IARC, 1982)
Fornl, A. and L. Moreo. 1969. Chromosome studies In a case of benzene-
Induced erythroleukaemla. Eur. J. Cancer. 5: 459-463. (Cited In IARC,
1982)
-26-
-------
Fornl, A.M., A. Cappelllnl, E. Pac1f1co and E.G. V1gl1an1. 1971a. Chromo-
some changes and their evolution 1n subjects with past exposure to benzene.
Arch. Environ. Health. 23: 385-391. (Cited In IARC, 1982}
Fornl, A., E. Padflco and A. Llmonta. 1971b. Chromosome studies 1n
workers exposed to benzene or toluene or both. Arch. Environ. Health. 22:
373-378. (Cited 1n IARC, 1982)
Fredga, K., J. Reltalu-and M. Berlin. 1979. Chromosome studies In workers
exposed to benzene. In: Genetic Damage In Man Caused by Environmental
Agents. Academic Press, NY. p. 187-203. (Cited 1n IARC, 1982)
Funes-Cravloto, F., B. Kolmodln-Hedman, J. Llndsten, et al. 1977. Chromo-
some aberrations and sister-chromatid exchange 1n workers In chemical
laboratories and a rotoprlntlng factory and 1n children of women laboratory
workers. Lancet, p. 322-325. (Cited in IARC, 1982)
Galavottl, B. and F.M. Tro1s1. 1950. Erythroleukemla myelosls 1n benzene
poisoning. Br. J. Ind. Med. 7: 79-81. (Cited 1n IARC, 1982)
Gerner-Smldt, P. and U. FMedrlch. 1978. The mutagenlc effect of benzene,
toluene and xylene studied by the SCE technique. Mutat. Res. 58: 313-316.
(Cited 1n IARC, 1982)
Glrard, R. and L. Revol. 1970. The Incidence of exposure to benzene In
severe haemopathies. Nouv. Rev. Fr. Hematol. 10: 477-484. (Cited 1n IARC,
1982)
-27-
-------
Goguel, A., A. Cavlgneaux and J. Bernard. 1967. Benzene leukemlas. (Fre.)
Bull. Inst. Natl. Sante Rech. Med. 22: 421-441. (CHed in IARC, 1982)
Goldstein, B.D. 1977. Hematotoxldty 1n humans. J. Toxlcol. Environ.
Health Suppl. 2: 69-105. (Cited in IARC, 1982}
Green, J.O., C.A. Snyder, J. LoBue, B.D. Goldstein and R.E. Albert. 1981.
Acute and chronic dose/response effect of benzene Inhalation on the
peripheral blood, bone marrow, and spleen cells of CD-I male mice. Toxlcol.
Appl. Pharmacol. 59(2): 204-214. (CHed in U.S. EPA, 1982)
Greenburg, L. 1926. Benzol poisoning as an Industrial hazard. VII.
Results of medical examination and clinical tests made to discover early
signs of benzol poisoning 1n exposed workers. Public Health Reports. 41:
1526-1539. (Cited 1n NIOSH, 1974; U.S. EPA, 1982)
Greene, M.H., R.N. Hoover, R.L. Eck and J.F. Fraumeni, Jr. 1979. Cancer
mortality among printing plant workers. Environ. Res. 20: 66-73. (CHed
in IARC, 1982)
Hardell, L., H. Eriksson, P. Lenner and E. Lundgren. 1981. Malignant
lymphoma and exposure to chemicals, especially organic solvents, chloro-
phenols and phenoxy acids: A case-control study. Br. J. Cancer. 43:
169-176. (Cited 1n IARC, 1982)
-28-
-------
Hardy, H.L. and H.B. Elklns. 1948. Medical aspects of maximum allowable
concentrations -- Benzene. J. Ind. Hyg. Toxlcol. 30: 196-200. (Cited 1n
NIOSH, 1974; U.S. EPA, 1982}
Hartwlch, 6. and G. Schwanitz. 1972. Chromosome studies after chronic
benzene exposure. (Ger.) Dtsch. Med. Wochenschr. 97: 45-49. (Cited 1n
IARC, 1982)
Hartwlch, G., G. Schwanitz and J. Becker. 1969. Chromosomal aberrations 1n
a leukaemia due to benzene. (Ger.) Dtsch. Med. Wochenschr. 94: 1228-1229.
(Cited 1n IARC, 1982)
HHe, M., M. Pecharo, I. Smith and S. Thornton. 1980. Effect of benzene 1n
the micronucleus test. Mutat. Res. 77: 149-155. (Cited In IARC, 1982)
Hudak, A. and K. Gombosl. 1977. Chromosome Impairment of workers 1n
research laboratories under uncontrolled benzene exposure. (Hung.)
Munkavedelem. 23: 50-51. (Cited 1n IARC, 1982)
Hunter, F.T. 1939. Chronic exposure to benzene (benzol). II. The clinical
effects. J. Ind. Hyg. 21: 331-354. (Cited 1n IARC, 1982)
IARC (International Agency for Research on Cancer). 1982. Benzene. Jji;
Some Industrial Chemicals and Dyestuffs. IARC Monographs on the Evaluation
of Carcinogenic Risk of Chemicals to Humans. IARC, WHO, Lyon, France. Vol.
29. p. 93-148.
-29-
-------
Ikeda, M., H. Ohtsuji and T. Imamura. 1972. in vivo suppression of benzene
and styrene oxidation by co-administered toluene 1n rats and effects of
phenobarbltal. Xenob1ot1ca. 2: 101-106. (Cited 1n U.S. EPA, 1980b)
Infante, P.P., R.A. Rlnsky, J.K. Wagoner and R.J. Young. 1977a. Leukemia
1n benzene workers. Lancet. 2: 76. (Cited 1n U.S. EPA, 1980b)
Infante, P.P., R.A. Rlnsky, J.K. Wagoner and R.J. Young. 1977b. Benzene
and leukemia. Lancet. 2: 867-869. (Cited 1n U.S. EPA, 1980b)
International Labour Office. 1980. Occupational Exposure Limits for
Airborne Toxic Substances, 2nd (rev.) ed. Occupational Safety and Health
Series No. 37. Geneva, p. 48-49, 271-290. (Cited in IARC, 1982)
Ishlmaru, T., H. Okada, T. Tomlyasu, T. Tsuchimoto, T. Hoshino and M.
Ichimaru. 1971. Occupational factors In the epidemiology of leukemia 1n
Hiroshima and Nagasaki. Am. J. Epidemic!. 93: 157-165. (Cited 1n U.S.
EPA, 1980b)
Jenkins, L.J., R.A. Jones and J. Siegel. 1970. Long-term inhalation
screening studies of benzene, toluene, o-xylene, and cumene on experimental
animals. Toxlcol. Appl. Pharmacol. 16: 818-823. (Cited in IARC, 1982;
U.S. EPA, 1980b, 1982)
Kaden, O.A., R.A. Hites and W.G. Thilly. 1979. Mutagenicity of soot and
associated polycycllc aromatic hydrocarbons to Salmonella typhimurium.
Cancer Res. 39: 4152-4159. (Cited in IARC, 1982)
-30-
-------
Khan, H. and M.H. Khan. 1973. Cytogenetlc studies following chronic expo-
sure to benzene. (Ger.) Arch. Toxlcol. 31: 39-49. (Cited 1n IARC, 1982)
K1ssl1ng, M. and B. Speck. 1971. Chromosome aberrations In experimental
benzene Intoxication. Helv. Med. Acta. 36: 59-66. (Cited 1n IARC, 1982)
Koizumi, A., Y. Dobashl, Y. Tachlbana, K. Tsuda and H. Katsunuma. 1974.
Cytok1net1c and cytogenetlc changes 1n cultured human leukocytes and HeLa
cells Induced by benzene. Ind. Health. 12: 23-29. (Cited In IARC, 1982)
Kuna, R.A. and R.W. Kapp, Jr. 1981. The embryotoxlc/teratogenlc potential
of benzene vapor 1n rats. Toxlcol. Appl. Pharmacol. 57(1): 1-7. (Cited 1n
U.S. EPA, 1982)
Lange, A., R. Smollk, W. Zatonskl and J. Szymanska. 1973. Serum Immuno-
globulln levels In workers exposed to benzene, toluene, and xylene. Int.
Arch. Arbeltsmed. 31: 37-44. (CHed In U.S. EPA, 1980b, 1982)
Lebowltz, H., 0. Bruslck, D. Matheson, et al. 1979. Commonly used fuels
and solvents evaluated In a battery of short-term bloassays (Abstract No.
Eb-8). Environ. Mutagen. 1: 172-173. (Cited 1n IARC, 1982)
Ludwlg, H. and A. Werthemann. 1962. Benzene myelopathy. (Ger.) Schwelz.
Med. Wochenschr. 13: 378-384. (Cited In IARC, 1982)
Lyapkalo, A.A. 1973. Genetic activity of benzene and toluene. (Rus.)
G1g. Tr. Prof. Zabol. 17: 24-28. (CHed In IARC, 1982)
-31-
-------
Lyon, J.P. 1976. Mutagenldty studies with benzene (Abstract). Dlss.
Abstr. Int. B. 36: 5537. (Cited 1n IARC, 1982)
Mabey, W.R., J.H. Smith, R.J. Podoll, et al. 1981. Aquatic Fate Process
Data for Organic Priority Pollutants. U.S. EPA, Monitoring and Data Support
Division, Office of Water Regulations and Standards, Washington, DC. EPA
440/4-81-014.
HacKay, D. 1982. Correlation of bloconcentratlon factors. Environ. Sd.
Techno!. 16: 274-278.
Mallory, T.B., E.A. Gall and W.J. BMckley. 1939. Chronic exposure to
benzene (benzol). III. The pathologic results. J. Ind. Hyg. Toxlcol. 21:
355-377. (Cited In IARC, 1982)
Maltonl, C. and C. Scarnato. 1979. First experimental demonstration of the
carcinogenic effects of benzene. Long-term bloassays on Sprague-Dawley rats
by oral administration. Med. Lav. 70: 352-357. (Cited 1n U.S. EPA, 1983b)
McMlchael, A.J., R. Splrtas, L.L. Kupper and J.F. Gamble. 1975. Solvent
exposure and leukemia among rubber workers: An epidemiology study. J.
Occup. Med. 17: 234-239. (Cited 1n IARC, 1982)
Meyne, J. and M.S. Legator. 1978. Cytogenetlc analysis after an acute
1ntraper1toneal exposure of mice to benzene. Mamm. Chromosomes Newsl. 19:
38. (Cited 1n IARC, 1982)
-32-
-------
Meyne, J. and M.S. Legator. 1980. Sex-related differences In cytogenetlc
effects of benzene In the bone marrow of Swiss mice. Environ. Mutagen. 2:
43-50. (Cited 1n IARC, 1982)
Monson, R.R. and K.K. Nakano. 1976. Mortality among rubber workers. I.
White male union employees 1n Akron, OH. Am. J. Ep1dem1ol. 103: 284-296.
(Cited 1n IARC, 1982)
MoMmoto, K. 1976. Analysis of combined effects of benzene with radiation
on chromosomes 1n cultured human leukocytes. Jap. J. Ind. Health. 18:
23-24. (Cited In IARC, 1982)
MoMmoto, K. and S. Wolff. 1980. Increase of slster-chromatld exchanges
and perturbations of cell division kinetics In human lymphocytes by benzene
metabolites. Cancer Res. 40: 1189-1193. (Cited 1n IARC, 1982)
Murray, F.J., J.A. John, L.W. Rampy, R.A. Kuna and B.A. Schwetz. 1979.
Embryotoxldty of Inhaled benzene 1n mice and rabbits. Am. Ind. Hyg. Assoc.
J. 40: 993-998.
NAS (National Academy of Sciences). 1976. Health effects of benzene: A
review. Washington, DC. (Cited 1n U.S. EPA, 1980b)
Nawrot, P.S. and R.E. Staples. 1979. No title provided. Teratology. 19:
41. (Cited In U.S. EPA, 1980b, 1982)
-33-
-------
NIOSH (National Institute for Occupational Safety and Health). 1974.
Criteria for a Recommended Standard...Occupational Exposure to Benzene.
U.S. DHEW, PHS, CDC, Cincinnati, OH. Publ. No. 74-137. (Cited In U.S. EPA,
1982)
NIOSH (National Institute for Occupational Safety and Health). 1980. Sum-
mary of NIOSH Recommendations for Occupational Health Standards, Rockvllle,
MD. (Cited 1n IARC, 1982)
Nlssen, N.I. and A. Soeborg Ohlsen. 1953. Erythromyelosls (morbus d1
Gugllelmo). Review and report of a case 1n a benzene (benzol) worker. Acta
Med. Scand. 145: 56-71. (Cited 1n IARC, 1982)
Nylander, P.O., H. Olofsson, B. Rasmuson and H. SvahUn. 1978. Mutagenlc
effects of petrol 1n Drosophlla melanogaster. I. Effects of benzene and
l,2-d1chloroethane. Mutat. Res. 57: 163-167. (Cited 1n IARC, 1982)
OSHA (Occupational Safety and Health Administration). 1980. Benzene. U.S.
Code of Federal Regulations, Tl'tle 29, Parts 1910.19, 1910.1000, 1910.1028.
(Cited 1n IARC, 1982)
Ott, M.G., J.C. Townsend, W.A. Flshbeck and R.A. Langner. 1978. Mortality
among Individuals occupatlonally exposed to benzene. Arch. Environ. Health.
33: 3-10. (Cited 1n U.S. EPA, 1980b)
Pagnotto, H.L. 1972. Written communication to NIOSH. (Cited 1n NIOSH,
1974; U.S. EPA, 1982)
-34-
-------
Pagnotto, L.O., H.B. Elklns, H.G. Brugsch and E.J. Walkley. 1961. Indus-
trial benzene exposure from petroleum naphtha. I. Rubber coating Industry.
Am. Ind. Hyg. Assoc. J. 22: 417-421. (CHed In NIOSH, 1974; U.S. EPA,
1980b, 1982)
Philip, P. and M. Krogh Jensen. 1970. Benzene Induced chromosome abnor-
malities 1n rat bone marrow cells. Acta. Pathol. M1crob1ol. Scand. 78:
489-490. (Cited 1n IARC, 1982)
Plcclano, D. 1979. Cytogenetlc study of workers exposed to benzene.
Environ. Res. 19: 33-38. (CHed In IARC, 1982)
t
Polllnl, G. and G.P. B1scald1. 1976. Persistence of karyotype alterations
1n lymphocytes 10 years after benzene poisoning. (Ital.) Med. Lav. 67
(SuppK 5): 465-472. (Cited In IARC, 1982)
Polllnl, G. and G.P. B1scald1. 1977. Investigations of karyotype In the
lymphocytes of subjects with benzene hemopathy twelve years after poisoning.
(Ital.) Med. Lav. 68: 308-312. (CHed In IARC, 1982)
Polllnl, G. and R. Colombl. 1964a. Damage to bone-marrow chromosomes In
benzollc aplastlc anaemia. (Hal.) Med. Lav. 55: 241-255. (CHed 1n
IARC, 1982)
PolUnl, G. and R. Colombl. 1964b. Chromosomal damage 1n lymphocytes
during benzene haemopathy. (Ital.) Med. Lav. 55: 641-655. {CHed 1n
IARC, 1982)
-35-
-------
Polllnl, G., E. Strosselll and R. Colombl. 1964. The relationship between
chromosomal alterations 1n haemopoletlc cells and the severity of benzene
haemopathy. (Hal.) Med. Lav. 55: 735-751. (Cited 1n IARC, 1982)
Polllnl, G., G.P. B1scald1 and G. RobustelH della Cuna. 1969. Chromosome
changes In lymphocytes five years after benzene haemopathy. (Ital.) Med.
Lav. 60: 743-758. (Cited In IARC, 1982)
Rlnsky, R.A., R.J. Young and A.B. Smith. 1981. Leukemia 1n benzene
workers. Am. J. Ind. Med. 2: 217-245. (Cited In IARC, 1982)
Rosenkranz, H.S. and Z. Lelfer. 1980. Determining the ONA-mod1fy1ng
activity of chemicals using ONA-polymerase-def1c1ent Escher1ch1a coll. In.:
Chemical Mutagens. Principles and Methods for their Detection, Vol. 6, F.J.
de Serres and A. Hollaender, Ed. Plenum Press, NY. p. 109-147. (Cited 1n
IARC, 1982)
Rozman, C., S. Woessner and J. Saez-Serran1a. 1968. Acute erythromyelosls
after benzene poisoning. Acta Haematol. 40: 234-237. (Cited In IARC, 1982)
Rushton, L. and M. Alderson. 1980. The Influence of occupation on
health — Some results from a study 1n the UK oil Industry. Cardnogenesls.
1: 739-743. (Cited 1n IARC, 1982)
Rushton, L. and M.R. Alderson. 1981. A case-control study to Investigate
the association between exposure to benzene and deaths from leukemia 1n oil
refinery workers. Br. J. Cancer. 43: 77-84. (Cited 1n IARC, 1982)
-36-
-------
Sav1laht1, M. 1956. More than TOO cases of benzene poisoning 1n a shoe
factory. Arch. Gewerbepathol. Gewerbehyg. 15: 147-157. (Ger.) (Cited In
NIOSH, 1974; U.S. EPA, 1982}
Sellyel, M. and E. Kelemen. 1971. Chromosome study 1n a case of granulo-
cytlc leukemia with 'pelgerlsatlon1 7 years after benzene pancytopenla.
Eur. J. Cancer. 7: 83-85. (CHed 1n IARC, 1982)
Shahln, M.M. and F. Fournler. 1978-. Suppression of mutation Induction and
failure to detect mutagenlc activity with Athabasca tar sand fractions.
Mutat. Res. 58: 29-34. (CHed 1n IARC, 1982)
Singh, H.B., L.O. Salas, A.J. Smith and H. Shlgelshl. 1981. Measurements
of some potentially hazardous organic chemicals 1n urban environments.
Atmos. Environ. 15: 601-612.
Smollk, R., et al. 1973. Serum complement level In workers exposed to
benzene, toluene, and xylene. Inc. Arch. Arbeltsmed. 31: 243. (CHed 1n
U.S. EPA, 1980b, 1982)
Snyder, C.A., B.D. Goldstein, A. Sellakumar, et al. 1978. Hematotoxlclty
of Inhaled benzene to Sprague-Dawley rats and AKR mice at 300 ppm. J.
Toxlcol. Environ. Health. 4: 605-618. (Cited in Snyder et al., 1980; U.S.
EPA, 1982)
-37-
-------
•k >
Snyder, C.A., B.C. Goldstein, A.R. Sellakumar, I. Bromberg, S. Laskln and
R.E. Albert. 1980. The Inhalation toxicology of benzene: Incidence of
hematopoletlc neoplasms and hematotox1c1ty 1n AKR/J and C57B1/6J mice.
Toxlcol. Appl. Pharmacol. 54(2): 323-331. (Cited 1n U.S. EPA, 1982, 1983b)
Tabershaw, I.R. and S.H. Lamm. 1977. Benzene and leukemia. Lancet. 11:
867 868. (Cited 1n JARC, 1982)
Tareeff, E.M., N.H. Kontchalovskaya and L.A. Zorlna. 1963. Benzene leuke-
mlas. Acta Un1o. Int. Cancru. 19: 751-755. (Cited in IARC, 1982)
Thorpe, J.J. 1974. Ep1dem1olog1c survey of leukemia In persons potentially
exposed to benzene. J. Occup. Med. 16: 375-382. (Cited 1n IARC, 1982)
Tough, I.M. and W.M. Court Brown. 1965. Chromosome aberrations and
exposure to ambient benzene. Lancet. 1: 684. (Cited 1n IARC, 1982)
Tough, I.M., P.G. Smith, W.M. Court Brown and D.G. Harnden. 1970. Chromo-
some studies on workers exposed to atmospheric benzene. The possible Influ-
ence of age. Eur. J. Cancer. 6: 49-55. (Cited 1n IARC, 1982)
Tyroler, H.A., D. Andjelkovlc, R. Harris, W. Lednar, A. McMlchael and M.
Symons. 1976. Chronic diseases 1n the rubber Industry. Environ. Health
Perspect. 17: 13-20. (CHed 1n IARC, 1982)
-38-
-------
U.S. EPA. 1978a. Assessment of Health Effects of Benzene Germane to Low-
Level Exposure. Office of Health and Ecological Effects, U.S. EPA, Washing-
ton, DC. EPA 600/1-78-061.
U.S. EPA. 1978b. Estimation of Population Cancer Risk from Ambient Benzene
Exposure. Prepared by the Carcinogen Assessment Group, OHEA, Washington,
DC. Internal draft. (Cited 1n U.S. EPA, 1980b)
U.S. EPA. 1980a. Guidelines and Methodology Used 1n the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Quality
Criteria. Federal Register. 45: 79347-79357.
U.S. EPA. 1980b. Ambient Water Quality Criteria for Benzene. Environ-
mental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-018.
NTIS PB 81-117293.
U.S. EPA. 1982. Reportable Quantity for Benzene. Prepared by the Environ-
mental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office
of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1983a. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty Data. Prepared by the Environmental
Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid
Waste and Emergency Response, Washington, DC.
-39-
-------
U.S. EPA. 1983b. Review of Tox1colog1c Data 1n Support of Evaluation for
Carcinogenic Potential of Benzene. Prepared by the Carcinogen Assessment
Group, OHEA, Washington, DC for the Office of Solid Waste and Emergency
Response, Washington, DC.
Van den Berghe, H., A. Louwagle, A. Broeckaert-Van Orshoven, G. David and R.
Verwllghen. 1979. Chromosome anaylsls 1n two unusual malignant blood dis-
orders presumably Induced by benzene. Blood. 53: 558-566. (CHed In IARC,
1982)
V1gl1an1, E.C. 1976. Leukemia associated with benzene exposure. Ann. NY
Acad. Sd. 271: 143-151. (CHed 1n IARC, 1982)
V1gl1an1, E.C. and G. SaHa. 1964. Benzene and leukemia. N. Engl. J. Med.
271: 872-876. (CHed In NIOSH, 1974; U.S. EPA, 1982)
Wolf, M.A., V.K. Rowe, D.D. McColHster, R.L. Holllngsworth and F. Oyen.
1956. lexicological studies of certain alkylated benzenes and benzene.
Arch. Ind. Health. 14: 387-398. (CHed In U.S. EPA, 1982)
-40-
------- |