March 31, 1987
820K87009
BENZENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is abls to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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This Health Advisory is based on information presented in the Office of
Drinking Water's Draft Health Effects Criteria Documents (CD) for Benzene
(U.S. EPA, 1983b, 1985a). The HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxicological data base or
rationale for risk characterization should consult the CDs. The CDs are
available for review at each EPA Regional Office of Drinking Water counterpart
(e.g., Water Supply Branch or Drinking Water Branch), or for a fee from the
National Technical Information Service, U.S. Department of Commerce, 5285
Port Royal Rd., Springfield, VA 22161, PB # 86-118122/AS. The toll-free
number is (800) 336-4700; in the Washington, D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 71-43-2
Structural Formula
Synonyms
None
Uses
0 Additive to gasoline to increase the octane.
0 Chemical intermediate in the synthesis of compounds such as:
styrene, synthetic rubber, phenol, alkylarnesulfonate detergent,
nitrobenzene (aniline), and cyclohexane.
Properties (Von Gemert and Nettenbreijer, 1977; Windholz, 1983)
Chemical Formula
Physical State
Boiling Point
Freezing Point
Density at 25°C
Vapor Pressure at 26°C
Water Solubility at 25°C
Odor Threshold, in air
Odor Threshold, in water
C6H6
Volatile, colorless flammable liquid,
aromatic hydrocarbon
80.100°C
5.53°C
0.8765 g/mL
100 mmHg
1 .8 g/L
4.9 mg/m3 (characteristic odor)
2.0 mg/L
Occurrence
Benzene is produced at low levels in a number of biological processes
and is a component of petroleum (U.S. EPA, 1983a).
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Benzene is produced in large amounts, e.g., 9 billion Ibs in 1981
(U.S. ITC, 1984), and is used largely as a feedstock on the production
of other chemicals. Small amounts of benzene have been used as a
solvent; however, this use has been discontinued. Benzene also is
produced indirectly in large volumes, such as during gasoline refining
and other operations. The average benzene content of gasoline is
less than 1% (Runion, 1975).
Releases of benzene to the environment are largely to air due to its
volatile nature, with smaller amounts to water and soil. Releases
of benzene to water are mainly due to spills of gasoline and other
petroleum products and from benzene's previous use as a solvent.
Because of the widespread use of petroleum products, releases of
benzene occur nationwide (Mara and Lee, 1978; OSHA, 1978).
Benzene released to surface water rapidly volatilizes to the air.
Benzene degrades rapidly in air with a half life of less than one day.
Benzene released to the ground binds somewhat to soil and slowly
migrates with ground water. Benzene is biodegraded poorly and is
expected to be stable in ground water (Mara and Lee, 1978).
Benzene occurs in drinking water, food, and air (U.S. EPA, 1983b).
Benzene occurs in both ground water and surface public water supplies,
with higher levels occurring in ground water supplies. Based upon
Federal drinking water surveys, approximately 1.3% of all ground
water systems are estimated to contain benzene at levels greater than
0.5 ug/L. The highest level reported in the surveys for ground water
was 80 ug/L. Approximately 3% of all surface water system are esti-
mated to be contaminated at levels higher than 0.5 ug/L. None of the
systems are expected to contain levels higher than 5 ug/L.
Benzene is found at ppb levels in a large number of foods as a naturally
occurring compound (U.S. EPA, 1983b).
Benzene is found in air in urban and suburban areas, generally at
average levels of less than 10 ppb (U.S. EPA, 1983b), but at higher
levels i-n certain metropolitan areas such as Los Angeles where Lonneman
ec al. (1968) measured an average benzene concentration of 15 ppb with
a maximum of 57 ppb. Benzene has been reported to occur in indoor
air at levels higher than those found outdoors. Based upon the
available evidence, the major source of benzene exposure is believed
to be from air.
III. PHARMACOKINETICS
Absorption
0 As a neutral, low molecular weight, lipid soluble material, benzene
is readily absorbed via inhalation and ingestion. It is poorly absorbed
through the intact skin (NIOSH, 1974).
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0 Administration of benzene to rats via inhalation or ingestion results
in its rapid uptake and excretion, mainly via exhalation of unchanged
benzene (Rikert et al., 1979; Parke and Williams, 1953). The exhalation
of unchanged benzene has also been reported in dogs (Schrenk et al.,
1941), rabbits (Parke and Williams, 1953) and mice (Andrews et al.,
1977a) .
0 When humans are exposed to benzene in air, absorption via inhalation
is approximately 50% (Nomiyama and Nomiyama, 1974 a,b).
Distribution
8 Benzene is highly lipid soluble which accounts for its tendency to
accumulate in fatty tissue (U.S. EPA, 1983b).
0 In mice, benzene is stored in the bone marrow, liver and body fat
(Snyder et al., 1978).
Metabolism
8 The metabolic pathway for benzene has been thoroughly delineated
in benzene background documents including U.S. EPA (1983b, 1985a).
In humans, phenol sulfate is the major metabolite of benzene until
400 mg/L levels are reached in the urine. Beyond that level, glucu-
ronide conjugates are also present in the urine (Sherwood, 1972).
Excretion
The rate of elimination of benzene in humans is biphasic with initially
about 16.2% eliminated unchanged via exhalation in 5 hours (Nomiyama
and Nomiyama, 1974a,b). The remainder of the benzene is stored in
the fatty tissues and is excreted much more slowly. Benzene has a
half-life of 0.7 hours in rats (Rickert et al., 1979).
IV. HEALTH EFFECTS
Humans
Acute exposure to high levels of benzene produces primarily central
nervous system effects such as dizziness, giddiness, exhilaration,
nausea, vomiting, headache, drowsiness, staggering, loss of balance,
narcosis, coma and death. Exposure to 25,000 ppm in air is rapidly
fatal (NAS, 1976). At nonlethal levels, mild central nervous system
effects appear to be concentration-dependent and are rapidly reversible.
Lower levels of benzene do not seem to elicit these effects no matter
how long the exposure (U.S. EPA, 1983b).
Benzene has been a known hematological poison since the 19th century
when cases of aplastic anemia in workers fabricating bicycle tires
were described by Santesson (1897).
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Benzene causes bone marrow toxicity resulting in a continuum of
changes in the circulating formed blood elements ranging from a mild
decrease in platelets to aplastic anemia, a rapidly fatal disease.
The lowest level that produced changes in platelet counts in workers
appears to be 10 ppm (Doskin 1971; Chang, 1972).
Benzene causes acute myeloblastic leukemia, acute myelomonocytic
leukemia and erythroleukemia (Rinsky et al., 1981). The exposure
levels resulting in leukemia have not been determined.
Epidemiologic studies show that exposure to benzene via inhalation
at levels of 10 ppm or lower for approximately one year increases
the risk of cancer by 560 fold and exposure for five or more years
increases the risk by 2,100 fold (Rinsky et al., 1981).
Immune system depression resulting from benzene exposure is a well
known toxicological phenomenon. Susceptibility to tuberculosis
(White and Gammon, 1914) and pneumonia (Winternitz and Hirschfelder,
1913) have been demonstrated to be increased in benzene-treated
rabbits.
Serum levels of IgG and IgA (immunoglobulins) were shown to be decreased
in benzene workers (Lange et al., 1973; Smolick et al., 1973).
These observations in conjunction with the well known ability of benzene
to depress leukocytes which play a significant role in protection
against infectious agents, may explain why individuals regularly
exposed to benzene readily succumb to infection and the terminal
event in severe benzene toxicity is often acute overwhelming infection.
Benzene has caused chromosomal aberrations in exposed workers (Kissling
and Speck, 1969; Tough et al., 1970; Forni et al., 1971).
Animals
Short-term Exposure
Dogs exposed to benzene by inhalation at 600 to 1,000 ppm for 12 to
15 days developed leukopenia (reduction in the number of circulating
leukocytes) (Hough and Freeman, 1944).
Mice exposed to benzene by inhalation at 600 to 1,000 ppm developed
fatal anemia within 12 to 15 days (Petrini, 1941).
When exposed to benzene by inhalation at 80 to 85 ppm, rats (136
doses), guinea pigs (193 doses), rabbits (187 doses) and monkeys
(187 doses) developed leukopenia (Wolf et al., 1956).
Deichmann et al. (1963) conducted a series of experiments in which
Sprague-Dawley rats (40/group) were exposed to benzene vapor for 5
hours per day, 4 days per week for 6 to 31 weeks. Average exposure
concentrations ranged from 15 to 831 ppm. Rats exposed to benzene
vapor at 61, 65 or 831 ppm developed severe leukopenia within 2 to 4
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weeks. At 44 and 47 ppm, moderate leukopenia was observed, especially
in females, in 5 to 8 weeks, and no leukopenia was observed when
animals were exposed to 29 or 31 ppm for 4 months. Therefore, 31 ppm
(96 mg/m3) is identified as the NOAEL for this study.
Long-term Exposure
0 Sprague-Dawley rats and both AKR/J and C57BL/6J mice were exposed to
benzene by inhalation at concentrations of either 100 ppm or 300 ppm
6 hours per day, 5 days per week for life by Snyder et al. (1980).
Both rats and mice exhibited lymphocytopenia, anemia and decreased
survival time. In mice these effects were accompanied by granulocytosis
and reticulocytosis. A later evaluation of the same study showed
preliminary evidence of carcinogenic!ty, bone marrow hypoplasia,
anemia and lymphocytopenia (Snyder et al., 1980).
Reproductive Effects
0 There is no strong evidence that benzene produces teratogenic effects.
It is a potent inhibitor of growth in utero (U.S. EPA, 1983b).
Mutagenicity
0 Benzene was found not to be mutagenic in Drosophila melanogaster by
Nylander et al. (1978). In this study, newly hatched larvae were
exposed to media containing benzene at a concentration of 1 % or 2%.
Mutation, as measured by a shift in eye pigmentation, was not noted
at either concentration.
0 Benzene at 20 or 600 ug/plate was shown not to be mutagenic in Salmoneli.
typhimurium when tested with or without metabolic activation in
strains TA100, TA98, TA1535, TA1537 and TA1538. Levels up to 880
ug/plate with activation were not mutagenic in strains TA98 and TA1000
(Dean, 1978).
0 Benzene oxide , the presumed initial metabolite of benzene, was
mutagenic without activation in an Ames test using £. typhimurium
(Pulkrabek et al., 1980).
0 A marked increase in sister chromatid exchanges (SCE) was reported in
DBA/2 mice exposed to benzene at 3100 ppm by inhalation for 4 hours
(Tice et al., 1980).
Carcinogenicity
0 Benzene has produced both solid tumors and leukemias in Sprague-Dawley
rats (Maltoni and Scartano, 1979). Benzene dissolved in olive oil
was administered by gavage to 13 week old Sprague-Dawley rats at
doses of 50 or 250 mg/kg/day 4 to 5 days a week for 52 weeks. The
animals were then allowed to live until spontaneous death. The high
dose group consisted of 35 rats of each sex; the low dose and vehicle
control goups consisted of 30 rats of each sex. After 20 weeks of
exposure, the denominators were corrected (numbers of animals
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surviving) to reflect compound-related deaths. The 250 mgAg group
then consisted of 33, males and 32 female rats; the 50 mgAg and
control groups consisted of 28 male and 30 female rats each. At the
end of 144 weeks, 25% of the females had Zymbal gland tumors, 6.2%
had skin carcinomas and and 12.1% had leukemias.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA _ (NOAEL or LOAEL) x (BW) _ mg/L ( ug/L)
(UF) x ( L/day )
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
Insufficient data are available to calculate a One-day HA for benzene.
Similarly, the National Academy of Sciences (1982) has stated that there are
insufficient data to determine a one-day SNARL. The Ten-day HA (0.235 mg/L
or 235 ug/L) is considered to be adequately protective for a one-day exposure
as well.
Ten-day Health Advisory
The calculation of the Ten-day HA is based on the study of Deichman,
et al. (1963) who exposed Sprague-Dawley rats to benzene by inhalation
6 hours per day, 4 days per week, at a broad range of concentrations and
monitored their hematology weekly. By the second week of treatment, there
was definite hematological impairment, including severe leukopenia, at the
61, 65 and 831 ppm exposure concentration and moderate leukopenia, especially
in females, at the 44 and 47 ppm exposure concentrations. Leukopenia was not
observed, however, at 29 or 31 ppm.
Using the NOAEL of 31 ppm (96 mg/m^), the Ten-day HA is calculated as
follows:
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Step 1: Determination of the Total Absorbed Dose (TAD)
TAD = (96 ^^6 (°>5) 4 =2.35 mg/kg/day
where:
96 mg/m3 = 31 ppm exposure; NOAEL for leukopenia in rats.
6 m3 « volume of air inhaled during 6 hours of exposure; based
upon equivalent lung to whole body ratios for adult humans
and rats (Olson and Gehring, 1976).
0.5 = pulmonary absorption factor for benzene (Nomiyama and
Nomiyama, 1974a,b).
4/7 = conversion of total weekly dose to equivalent daily dose.
Step 2: Determination of the Ten-day Health Advisory
Ten-day HA = (2-35 mg/kg/day )( 10 kg) = 0<235 /L (235 ug/L)
(100) (1 L/day)
where:
2.35 mgAg/day = TAD.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study «.
1 L/day = assumed daily water consumption of a child.
Longer-term Health Advisories
Longer-term Health Advisories have not been calculated because of the
carcinogenic potency of benzene.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake {ADD. The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
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weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
A Lifetime Health Advisory has not been calculated because of the
carcinogenic potency of benzene.
Evaluation of Carcinogenic Potential
0 Benzene is a known human carcinogen.
0 U.S. EPA (1985a) has estimated that excess upper-bound lifetime cancer
risks of 10~4, 1Q-5 and 10-6 correspond to benzene in drinking water
at concentrations of 70, 7 and 0.7 ug/L, respectively.
0 IARC (1982) has classified benzene as a Group 1: Human carcinogen.
8 Applying the criteria in the EPA guidelines for assessment of carcino-
genic risk (U.S. EPA, 1986), benzene may be classified as a Group A:
human carcinogen. This category is for substances for which there is
sufficient evidence from epidemiologic studies to support the causal
association between exposure to the agents and cancer.
VI. OTHER CRITERIA, STANDARDS AND GUIDANCE
0 The National Academy of Sciences has not calculated SNARLS or ADIs for
benzene (NAS, 1982).
0 The current OSHA recommendation for a 10-hour time-weighted average
(TWA) exposure to benzene in air is 3.2 ug/L (1 ppm) and is a lowest
feasible level in the work place. This level would allow a daily
dose of 16 mg.
VII. ANALYTICAL METHODS
Analysis of benzene is by a purge-and-trap gas chromatographic proce-
dure used for the determination of volatile aromatic and unsaturated
organic compounds in water (U.S. EPA, 1985b). This method includes
the bubbling of an inert gas through the sample and trapping benzene
on an adsorbent material which is then heated to drive off benzene onto
a gas chromatographic column. The gas chromatograph is temperature-
programmed to separate the resulting analytes which are then detected
by the photoionization detector. This method is applicable to the
measurement of benzene over a concentration range of 0.02 to 1500 ug/L.
Confirmatory analysis is by mass spectrometry (U.S. EPA, 1985c), which
has a detection limit of 0.2 ug/L for benzene.
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VIII. TREATMENT TECHNOLOGIES
0 Treatment technologies which will remove benzene from water include
granular activated carbon (GAC) adsorption, air stripping and boiling.
0 Dobbs and Cohen (1980) developed adsorption isotherms for several
organic chemicals including benzene. It was reported that Filtrasorb®
300 carbon columns exhibited adsorptive capacities of 0.007 mg, 0.03 mg,
1 mg and 40 mg benzene/g carbon (Beaudet et al., undated, Bilello and
Beaudet, 1981).
0 Air stripping is an effective, simple and relatively inexpensive
process for removing benzene and other organics from water. Benzene
is amenable to air stripping on the basis of its Henry 's Law Constant
of 240 atm at 20°C (Kavanaugh and Trussel, 1980). Cummins (1985)
reported that benzene could be removed from water contaminated by a
gasoline spill by packed column air stripping. In this field study,
24' x 2' columns packed with plastic saddles were used to treat water
containing 190 ug/L benzene and other contaminants. Removal effi-
ciencies of 70 to 100% were obtained using air-to-water ratios of
8.1:1 to 87;1. At air-to-water ratios of 17;1 or greater, efficiencies
were 97% or better. Use of this process, however, transfers the
contaminant directly to the air stream. When considering the use of
air stripping as a treatment process, it is suggested that careful
consideration be given to the overall environmental consequences and
various hazards associated with release of this chemical into the
air.
0 Boiling also is effective in eliminating benzene from water. Studies
have shown that 10 minutes of vigorous boiling will remove 99% of
the benzene (Love et al., 1983).
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IX. REFERENCES
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Effects of toluene on the metabolism, disposition and hemopoietic toxicity
of 3H-benzene. Biochem. Pharmacol. 26:293-300.
Beaudet, B.A., E.M. Keller, L.J. Bilello and R.J. Turner. Undated. Removal
of specific organic contaminants from industrial wastewaters by granular
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Bilello, L.J., and B.A. Beaudet. 1981. Evaluation of activated carbon by
the dynamic mini-column adsorption technique. Incomplete citation.
Chang, I.W. 1972. Study on the threshold limit value of benzene and early
diagnosis of benzene poisoning. J. Cath. Med. Coll. 23:429.
Cummins, M.D. 1985. Field evaluation of packed column air stripping.
U.S. EPA.
Dean. B.J. 1978. Genetic toxicology of benzene, toluene, xylenes and phenols.
Mut. Res. 47:75.
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toxicity of benzene vapors. Toxicol. Appl. Pharmacol. 5:201-224.
Dobbs, R.J., and J.M. Cohen. 1980. Carbon isotherms for toxic organics.
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Doskin, T.A. 1971. Effect of age on the reaction to a combination of hydro-
carbons. Hygiene and Sanitation. 36:379.
Forni, A., E. Pacifico and A. Limonta. 1971. Chromosome studies in workers
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Gerarde, H.W. 1960. Toxicology and biochemistry of aromatic hydrocarbons.
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Hough, H., and S. Freeman. 1944. Relative toxicity of commercial benzene
and a mixture of benzene, toluene and xylene. Fed. Proc. 3:20.
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Kavanaugh, M.C., and R.R. Trussel. 1980. Design of aeration towers to strip
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benzene intoxication. Helv. Med. Acta 36:59.
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Lange, A.R., Smolick, W. Zatonski and J. Syzmanska. 1973. Serum immunoglobulin
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Pulkrabek, P., T. Kinoshita and A.M. Jeffery. 1980. Benzene oxide: In vitro
mutagenic and toxic effects. Proc. 16th Ann. Meeting Amer. Soc. Clin.
Oncol. 21:107.
Rinsky, R.A., R.J. Young, A and B. Smith. 1981. Leukemia in benzene workers.
Amer. J. Ind. Med. 2:217-245.
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Benzene disposition in the rat after exposure by inhalation'. Toxicol.
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36:338-350.
Santesson, C.G. 1897. Uber chronische vergiftung mit steinkohlentheerbenzin;
vir todesfalle. Arch. Hyg. Berl. 31:336.
Schrenk, H.H., W.P. Yant, S.J. Pearce, F.A. Patty and R.R. Sayers. 1941.
Absorption, distribution and elimination of benzene by body tissues and
fluids of dogs exposed to benzene vapor. J. Ind. Hyg. Toxicol. 23:20-34.
Sherwood, R.J. 1972. Benzene: The interpretation of monitoring results.
Ann. Occup. Hyg. 15:409-421.
Smolick, R., K.Grzybek-Hryncewica, A. Lange and W. Zatonski. 1973. Serum
complement level in workers exposed to benzene, toluene and xylene.
Int. Arch. Arbeitmed. 31:243.
Snyder, R., E.W. Lee and J.J. Kocsis. 1978. Binding of labeled benzene
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