Benzene
BENZENE
International Programme on Chemical Safety
Poisons Information Monogaph 63
Chemical
1. NAME
1.1 Substance
Benzene
1.2 Group
Aromatic hydrocarbons
1.3 Synonyms
Annulene;
benzeen;
benzen;
benzol;
benzole;
benzolene;
benzolo;
bicarburet of hydrogen;
carbon oil;
coal naphtha;
cyclohexatriene;
fenzen;
mineral naphtha;
phene;
phenyl hydride;
pyrobenzol;
pyrobenzole
1.4 Identification numbers
1.4.1 CAS number
71-43-2
1.4.2 Other numbers
UN: 1114
NCI: C55276
RTECS (NIOSH): CY-1400000
1.5 Main brand names/main trade names
Polystream (IARC, 1982)
1.6 Main manufacturers/main importers:
2. SUMMARY
2.1 Main risks and target organs
Acute exposure to high concentrations of benzene in air
results in neurological toxicity and may sensitize the
myocardium to endogenous catecholamines. Acute ingestion of
benzene causes gastrointestinal and neurological
toxicity.
Chronic exposure to benzene results primarily in
haematotoxicity, including aplastic anemia, pancytopenia, or
any combination of anaemia, leukopenia, and thrombocytopenia.
Chronic benzene exposure is associated with an increased risk
of leukemia.
2.2 Summary of clinical effects
Acute neurological toxicity from benzene exposure may
cause headache, dizziness, drowsiness, confusion, tremors,
and loss of consciousness. Exposure to high concentrations
may have effects on multiple organ systems. Sudden deaths
occurring below anesthetic concentrations of benzene are
apparently due to cardiac dysrhythmias. With ingestion,
toxic signs and symptoms may include nausea, vomiting, and
abdominal pain as well neurological toxicity. Chronic
haematological effects include anaemia, thrombocytopenia,
leukopenia, pancytopenia, chromosomal abberations, and
leukemia. Dermal exposure may cause skin irritation.
2.3 Diagnosis
The diagnosis of acute benzene toxicity depends on a
history of benzene exposure and associated neurological
symptoms improving with removal from exposure, or both
gastrointestinal and neurologic symptoms in the case of
ingestion. Benzene has a sweet aromatic odour which may help
in its detection. Laboratory testing for excess phenol in
the urine will support the diagnosis. Benzene may also be
detected in blood for a short period of time after exposure,
and it may be measured in exhaled breath. Haematological
abnormalities, especially anemia, leukopenia,
thrombocytopenia, pancytopenia, or acute myelogenous
leukemia, associated with chronic use of benzene suggest
benzene poisoning.
2.4 First-aid measures and management principles
Treatment for acute benzene toxicity is supportive. The
patient should be removed from exposure and additional oxygen
administered as necessary. For ingestion of large
quantities, aspiration of stomach contents with a nasogastric
tube and administration of activated charcoal may be
beneficial, especially in suspected combined ingestions.
Emesis is not recommended because of the risk of aspiration,
sudden loss of consciousness, or seizures. Severe poisonings
may required intubation and assisted ventilation. Treatment
of chronic poisoning is supportive care and removal from
exposure.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Benzene occurs naturally but is primarily produced from
petroleum products (ATSDR, 1993). Benzene is produced
commercially through catalytic reforming of light naphtha,
dealkylation of toluene, and as a coking by-product in steel
mills (Weaver et al., 1983).
3.2 Chemical structure
C6H6
Molecular weight 78.11
3.3 Physical properties
3.3.1 Colour
Clear (Budivari, 1996)
3.3.2 State/form
Normal state at 25°C: liquid (Budivari, 1996)
3.3.3 Description
Odour: sweet, aromatic (Budivari, 1996)
Odour threshold: 1.5 to 4.7 ppm (ATSDR, 1993)
Taste threshold: 0.5 to 4.5 ppm (ATSDR, 1993)
Specific gravity: 0.8787 at 15°C (Budivari, 1996)
Viscosity (at 20°C): 0.6468 cP (IARC, 1982)
Vapour pressure (at 25°C): 95.2 mmHg (OHMS/TADS, 1990)
Solubility in water (at 25°C): 1.8 g/L (IARC, 1982)
Soluble in alcohol (Budivari, 1996)
Soluble in ether (Budivari, 1996)
Flammability: high (HSDB, 1992)
Flash point: -11°C (HSDB, 1992)
Melting point: 5.5°C (HSDB, 1992)
Boiling point: 80.1°C (HSDB, 1992)
Conversion factor: 1 ppm = 3.25 mg/m3
3.4 Hazardous characteristics
Stability: stable, combustible (IARC, 1982)
Reactivity undergoes substitution, addition, and cleavage of
the ring (IARC, 1982)
Explosive limits: 1.3% to 7.1% (OHMS/TADS, 1990)
Autoignition temperature: 580°C (OHMS/TADS, 1990))
Safe disposal: incineration (ATSDR, 1993)
4. USES
4.1 Uses
4.1.1 Uses
4.1.2 Description
Benzene is used as an intermediate in the
manufacture of a number of chemicals, including
ethylbenzene (used in the synthesis of styrene),
cumene (used in the synthesis of phenol and for the
manufacture of phenolic resins and nylon
intermediates), cyclohexane (used to make nylon
resins), and nitrobenzene (used in the synthesis of
aniline). Benzene is also a precursor in the
manufacture of urethanes, chlorobenzene, and maleic
anhydride. Benzene was previously used widely as a
solvent, but this use has decreased in many countries
due to the concern over carcinogenic effects. Benzene
is a naturally occurring component of petroleum and is
present in gasoline (ATSDR, 1993). In the United
States benzene averages less than 2% by volume in
gasoline, and in Europe the concentration is often 4
to 5% by volume and may exceed these concentrations
with certain blends. Environmental contamination from
benzene occurs from automobile exhaust, chemical
plants, gasoline spills, and emissions from coke ovens
(Haley, 1977). In some countries, benzene continues
to be used as a household cleaner. Benzene has also
been reported to be abused by sniffing (Winek et al.,
1967).
4.2 High risk circumstances of poisoning
The most common form of exposure to benzene is
occupational, and both occupational and environmental
exposures to benzene are overwhelmingly through inhalation.
Dermal contact is most often only a minor source of exposure.
Environmental exposure is greatest in areas of heavy
automobile use due to the presence of benzene in tailpipe
emissions, near service stations, and from tobacco smoke
(ATSDR, 1993). In the United States, smoking accounts for
approximately half of the total population exposure to
benzene (Wallace, 1989). In countries where benzene is used
as a household cleaner, accidental or suicidal ingestion may
occur.
4.3 Occupationally exposed populations
Individuals working in industries involved with benzene
production (petrochemical industry, coke manufacturing),
rubber tire or cast rubber film manufacturing, transport or
storage of benzene or benzene-containing products, and gas
station employees all are at risk for excess benzene exposure
(ATSDR, 1993). Although in the United States benzene has
been removed from commercial solvents, the use of industrial
solvents may still be a source of exposure. Historically,
benzene used as a solvent in printing inks in the rotogravure
industry (Vigliani & Forni, 1976) and adhesives by shoemakers
(Aksoy et al., 1971) led to a high degree of exposure in
these industries.
In the petrochemical industry, benzene is presently used
primarily in closed system operations, but high time-weighted
average exposure concentrations were previously found in
chlorobenzene and alkylbenzene production plants (Weaver et
al., 1983). In the 1970s, the mean benzene air concentration
in 10 large US tire manufacturing plants was 1.1 ppm with a
range of 0.01 to 16.5 ppm in selected work areas (Van Ert et
al., 1980). Exposure to benzene in industries with poor
workplace controls may still pose a significant hazard to
workers.
5. ROUTES OF ENTRY
5.1 Oral
Acute oral exposure is uncommon and usually results from
accidental ingestion or attempted suicide. Benzene may also
be a contaminant in drinking water (ATSDR, 1993).
5.2 Inhalation
Inhalation is the primary route of exposure for benzene,
both in the occupational and environmental setting (ATSDR,
1993). The relatively high vapor pressure of benzene creates
a significant hazard when adequate workplace safeguards are
not in place.
5.3 Dermal
Dermal exposure may occur in the occupational setting,
although it is quantitatively less important than inhalation
exposure (ATSDR, 1993).
5.4 Eye
Ocular exposure may occur through splashing or high
vapour concentrations.
5.5 Parenteral
Unknown.
5.6 Others
Unknown.
6. KINETICS
6.1 Absorption by route of exposure
In humans absorption by inhalation ranges from 70 to 80%
in the first 5 minutes and then decreases to approximately
50% thereafter (Srbova et al.,1950). In rodents the
percentage of retained benzene decreased as the inhaled vapor
concentration increased from 10 to 1000 ppm (Sabourin et al.,
1987). In animal models, benzene is well absorbed by the
oral route, ranging from over 90% in rabbits (Parke &
Williams, 1953) to over 97% in rats and mice (Sabourin et
al., 1987). In vitro dermal absorption in humans is 0.2%
over a period of 13.5 hours (Loden, 1986). For a worker
exposed to 10 ppm of ambient benzene with his entire skin
exposed, and 100 cm2 of skin exposed directly to 5% benzene
(gasoline), the expected hourly absorption of benzene will be
7.5 µL from inhalation, 1.5 µL from ambient skin absorption,
and 7.0 µL from direct skin contact with the liquid (Blank &
McAuliffe, 1985). At 1 ppm ambient benzene, an unprotected
worker using 0.5% benzene in a rubber solvent could
theoretically absorb 4 to 8 mg of benzene percutaneously as
compared with 14 mg via inhalation (Susten et al.,
1985).
6.2 Distribution by route of exposure
Following inhalation, benzene is distributed throughout
the body, and animal data suggests it may distribute
preferentially to adipose tissue due to its lipophilicity
(Sato & Fujiwara, 1975; Rickert et al., 1979). In human
autopsies on individuals dying shortly after exposure, high
levels of benzene were found in the brain, with lower levels
in the fat, blood, kidneys, and liver (Tauber, 1970; Winek &
Collom, 1971). Exposure to 25 ppm of benzene for two hours
produced an average maximum blood benzene concentration of
0.2 mg/L (Sato & Fujiwara, 1975). No human studies are
available concerning distribution after oral or dermal
exposure (ATSDR, 1993).
6.3 Biological half-life by route of exposure
After inhalation exposure, benzene elimination in humans
appears to follow a two compartment model, with half-lives of
around 1 hour and 24 hours (Sherwood & Carter, 1970). The
half life of exhaled benzene in humans varies depending on
the benzene exposure concentration and duration. Exposure to
99 ppm for 1 hour resulted in an initial phase half-life of
42 minutes, and exposure to 6.4 ppm for 8 hours resulted in
an initial phase half-life of 72 minutes, with a terminal
phase half-life (from 10 to 100 hours after exposure) of 23
to 31 hours (Sherwood, 1988). In analysis of exhaled benzene
in rats, exposure to 500 ppm for 6 hours results in an
initial phase half-life of 42 minutes and a secondary phase
half-life of 13.1 hours (Rickert et al., 1979).
6.4 Metabolism
Benzene is both exhaled unchanged in the lungs and
excreted as metabolites in the urine. Metabolism occurs
primarily in the liver. The first step in benzene metabolism
is the formation of benzene oxide, an epoxide, by cytochrome
P-450 dependent mixed function oxidases. There are at least
two metabolic pathways proceeding from this intermediate.
The first involves hydroxylation of the epoxide to phenol,
which is then excreted as a glucuronide or sulfate conjugate,
or converted to hydroquinone and benzoquinone. Phenol,
hydroquinone glucuronide and hydroquinone sulfate serve as
markers for this enzymatic pathway. The second pathway
involves conversion of benzene oxide to muconic dialdehyde
through an NADPH mediated process, and further conversion to
muconic acid. Catechol is produced via this pathway through
the intermediate benzene glycol, and is excreted as a
glucuronide or sulfate conjugate (Henderson et al., 1989).
In rat bone marrow after a six hour exposure to 500 ppm
inhaled benzene, phenol was initially the main metabolite
followed by catechol and hydroquinine at later times (Rickert
et al., 1979).
6.5 Elimination by route of exposure
In a human study 16.4 to 41.6% of retained benzene was
eliminated through the lungs within five to seven hours after
a two- to three-hour exposure to 47 to 110 ppm and only 0.07
to 0.2% of the remaining benzene was excreted unchanged in
the urine (Srbova et al., 1950). After exposure to 63 to 405
mg/m3 of benzene for 1 to 5 hours, 51 to 87% was excreted in
the urine as phenol over a period of 23 to 50 hours (Hunter &
Blair, 1972). In another human study, 30% of absorbed
dermally applied benzene was excreted as phenol in the urine
(Hanke et al., 1961). No human studies are available for
oral exposure (ATSDR, 1993).
In rabbits within two to three days after oral dosing of 340
to 500 mg/kg of benzene, 43% of benzene was exhaled
unchanged, 23.5% was excreted in the urine as phenol, 4.8% as
quinol, and 2.2% as catechol with a number of other phenolic
compounds excreted as well (Parke & Williams, 1953).
7. TOXICOLOGY
7.1 Mode of action
Acute benzene exposure produces central nervous system
excitation and depression (Gosselin et al., 1984). In
chronic exposures, benzene metabolites are considered the
toxic agents, not the parent compound (Parke & Williams,
1953; Sammett et al., 1979; Morimoto et al., 1983). The
relative contribution of different benzene metabolic pathways
may be dose related, with more toxic agents produced by high
affinity low capacity pathways (Medinsky et al., 1989).
Chronic benzene exposure can cause bone marrow stem cell
depression, apparently through a cytotoxic effect on all
lineages of haematopoietic progenitor cells, although there
is some evidence for a mechanism involving injury to marrow
stromal cells. Bone marrow macrophages have been shown to
metabolize phenol to reactive compounds that bind
irreversibly to protein and DNA (Kalf et al., 1989).
Hydroquinone and phenol are known haematotoxins (Eastmond et
al., 1987).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Inhalation exposure at 20,000 ppm
for five to ten minutes may be fatal (Flury,
1928). Exposure to 150 to 650 ppm for 4
months to 15 years caused pancytopenia (Aksoy
et al., 1972; Aksoy & Erdem, 1978). Chronic
exposure of up to eight years at a mean
benzene concentration of 75 ppm was
associated with the development of anemia and
leukopenia, but no such association was found
at mean exposure concentrations of 15 to 20
ppm for up to 27 years (Kipen et al., 1989).
Acute ingestion of over 10 mL of benzene may
prove lethal (Thienes & Haley,
1972).
7.2.1.2 Children
No data is available for pediatric
exposure levels.
7.2.2 Relevant animal data
The LC50 for rats is in the range of 13700 ppm
over a four hour exposure period (Drew & Fouts,
1974). In rats, the LD50 for oral ingestions in one
study ranged from 710 to 1230 mg/kg in nonfasted rats
to 690 to 950 mg/kg in fasted rats (Cornish & Ryan,
1965).
7.2.3 Relevant in vitro data
None.
7.2.4 Workplace standards
The Occupational Safety and Health
Administration (OSHA) permissible exposure limit (PEL)
is 1 ppm. The National Institute for Occupational
Safety and Health (NIOSH) recommended exposure limit
(REL) is 0.1 ppm (NIOSH, 1990). The American
Conference of Governmental Industrial Hygienists
(ACGIH) threshold limit value-time weighted average
(TLV-TWA) is 10 ppm (ACGIH, 1994).
7.2.5 Acceptable Daily Intake (ADI)
The WHO drinking water standard is 0.01 mg/L
(ATSDR, 1993).
7.3 Carcinogenicity
In epidemiologic studies, chronic exposure to benzene is
associated with the development of acute myelogenous leukemia
and its variants including erythroleukemia (Vigliani & Saita,
1964; Aksoy et al., 1976; Goldstein, 1977; Goldstein, 1988).
Other forms of leukemia including acute lymphoblastic anemia,
acute monocytic leukemia, and preleukemia have also been
reported following benzene exposure (Aksoy et al., 1976).
Other haematopoietic malignancies have been described in
association with benzene exposure including malignant
lymphoma, myeloid metaplasia, and multiple myeloma (Aksoy,
1980).
There are a number of studies of occupational benzene
exposure demonstrating an increased incidence of leukemia.
In a retrospective cohort study of 28,460 workers in China
exposed to benzene at varying concentrations from 10 to 1000
mg/m3, the relative risk for leukemia was 6.97 times the
risk in the unexposed group (Yin et al., 1987a). A group of
748 workers producing rubber hydrochloride exposed to benzene
concentrations of 10 to 100 ppm for up to 9 years had a
relative risk of 10 for acute myelogenous and acute monocytic
leukemia (Infante et al., 1977). 680 workers exposed to
benzene at concentrations exceeding 2 ppm for 30 years had a
relative risk of 3.93 for leukemia and other lymphopoietic
cancers (Wong, 1987). In a study of 1165 workers in a rubber
hydrochloride factory there were 9 deaths from leukemia.
Stratification for level of exposure gave a standard
mortality ratio (SMR) for leukemia of 109 for workers with
< 40 ppm-years of exposure, a SMR of 322 with 40 to 199
ppm-years of exposure, a SMR of 1186 with 200 to 399
ppm-years of exposure, and a SMR of 6637 with > 400
ppm-years of exposure. These ppm-years of exposure
correspond to exposures of <1, 1 to 4.99, 5 to 9.99, and
>10 ppm of benzene over a 40 year working lifetime (Rinsky
et al., 1987). A study of 454 workers exposed to less than 1
ppm of benzene for up to 26 years did not find any deaths
from leukemia out of a total of 34 death certificates, or any
cases of leukemia in a smaller study population (Tsai et al.,
1983).
In a case report, one individual developed acute myelogenous
leukemia after an occupational exposure to 2 ppm of benzene
over an 18 month period, although he had previously worked in
a saw mill which manufactured veneer (Ott et al.,
1978).
7.4 Teratogenicity
Benzene crosses the placenta and is present in cord
blood in concentrations equal to or greater than maternal
blood (Dowty et al., 1976). An increased frequency of
chromatid and isochromatid breaks was found in 14 children of
women exposed during pregnancy to a mix of benzene and other
solvents in chemical laboratories and the printing industry
(Funes-Cravioto et al., 1977).
Animal experiments exposing pregnant mice and rats to inhaled
benzene in general demonstrated increased fetal skeletal
variants and reduced fetal weight, but failed to demonstrate
consistent convincing evidence of teratogenecity. Rats
exposed to 313 ppm for 24 hours/day on days 9 to 14 of
gestation demonstrated reduced fetal weight and increased
skeletal variants (Hudak & Ungvary, 1978). Mice exposed to
500 ppm of benzene for 7 hours/day from days 6 to 15 of
gestation had decreased mean fetal body weight and an
increase in several minor skeletal variants. The same
exposure (500 ppm for 7 hours/day) in rabbits on gestational
days 6 to 18 did not affect fetal body weight, rather a
decrease in two minor skeletal variants (Murray et al.,
1979). In rats exposed to 100, 300, and 2200 ppm of benzene
vapor for 6 hours/day on days 6 to 15 of gestation, an
increase in skeletal variants was seen at all exposure
concentrations, and only the highest exposure concentration
resulted in decreased fetal weight (Green et al., 1978).
Exposure in utero to 20 ppm of benzene for 6 hr/day on days 6
to 15 of gestation in mice resulted in haematopoietic
abnormalities (Keller & Snyder, 1988). Exposures in rats to
less than 10 ppm of benzene during pregnancy did not cause
adverse fetal changes (Kuna & Kapp, 1981).
7.5 Mutagenicity
In studies of occupational exposure, benzene was found
to cause chromosome changes at concentrations that induced
blood dyscrasias (Tough & Court Brown, 1965; Forni et al.,
1971; Ding et al., 1983). At concentrations below 31 ppm,
workers exposed for 10 to 26 years had significantly more
chromosome breaks and gaps in peripheral lymphocytes than
found in controls, and 31 of the 33 workers had no other
evidence of clinical or haematological effects (Sasiadek et
al., 1989). At exposure levels of less than 10 ppm over one
month to 26 years, workers also had a significantly higher
number of chromosomal aberrations in peripheral lymphocytes
than did controls (Picciano, 1979).
7.6 Interactions
Ethanol can increase the extent of hematotoxicity from
benzene exposure (Baarson et al., 1982; Nakajima et al.,
1985; Nakajima et al., 1987). Previous administration of
phenobarbital may decrease benzene hematotoxicity (Ikeda &
Ohtsuji, 1971; Nakajima et al., 1985). Toluene reduces the
metabolism of benzene and reverses the benzene-induced
decrease in incorporation of iron into red blood cells
(Andrews et al., 1976). Hepatitis B may also increase the
incidence of hematopoietic effects from benzene exposure
(Aksoy, 1989).
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological analyses and their interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple qualitative test(s)
8.2.1.2 Advanced qualitative confirmation test(s)
8.2.1.3 Simple quantitative method(s)
8.2.1.4 Advanced quantitative method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple qualitative test(s)
8.2.2.2 Advanced qualitative confirmation test(s)
8.2.2.3 Simple quantitative method(s)
8.2.2.4 Advanced quantitative method(s)
8.2.2.5 Other dedicated method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall interpretation of all toxicological analyses and
toxicological investigations
Sample collection
Urine for phenol measurement should be collected at the end
of the workshift in a standard plastic urinalysis cup in a
volume of at least 50 mL. The sample should be refrigerated.
Breath samples for benzene are collected in standard breath
sampling tubes on a solid sorbent such as activated charcoal,
silica gel, or Tenax GC (ATSDR, 1993). Generally, breath
samples are collected at the start of the next shift (ACGIH,
1993).
Biomedical analysis
Measurement of urine phenol has been the standard bioassay
for benzene exposure, despite the well described limitations
of this test. For a benzene time-weighted average (TWA)
exposure of 10 ppm, an acceptable total phenol in urine
concentration at the end of a workshift is < 50 mg/g
creatinine (ACGIH, 1993). Exposure to 25 ppm of benzene
gives an average end of shift urinary phenol level of 200
mg/L (Walkley et al., 1961). In another study end-shift
urine phenol levels corrected for either creatinine
concentration or specific gravity correlated with exposure to
greater than 10 ppm of benzene. Urine phenol concentrations
of less than 10 mg/L were found in the non-exposed groups
(Inoue et al., 1986). Chronic exposure to 0.5 to 4.0 ppm of
benzene resulted in urine phenol levels that correlated with
benzene exposure, but 5 of 52 workers had baseline levels of
urinary phenol frequently > 30 mg/L (Roush & Ott, 1977). At
benzene exposure concentrations of 8 to 10 ppm or less, urine
phenol monitoring may be of minimal value (Roush & Ott, 1977;
Brief et al., 1980). At exposure concentrations of less than
1 ppm of benzene, urine phenol concentrations do not
correlate with duration of exposure (Drummond et al., 1988;
Perbellini et al., 1988).
Ingestion or inhalation of a variety of substances may
interfere with the use of urine phenol measurement as a
marker for benzene exposure. Certain household products such
as Pepto-Bismol and Chloraseptic contain phenol and their use
may increase urinary phenol levels (Baselt & Cravey, 1989).
Consumption of ethanol, diet, and smoking may also be
potential confounders (Nakajima et al., 1987; Brugnone et
al., 1989). Exposure to toluene decreases the metabolism of
benzene to phenol and quinol but not catechol (Inoue et al.,
1988).
Estimates of benzene exposure can also be made through
measurement of urinary inorganic and organic sulfates.
Unexposed subjects have 80 to 95% of urinary sulfates in the
inorganic form, mild exposure to benzene results in a
decrease to 70 to 80%, higher exposures decrease the
percentage to 60 to 70%, and extremely hazardous exposures
result in a drop to 0 to 60%. However, urinary sulfate
levels are quite variable, nonspecific for benzene, and have
not been used for low levels of benzene exposure (ATSDR,
1993).
Measurement of exhaled benzene has been used to monitor
exposure, but is affected by smoking (Brugnone et al., 1989).
Given a benzene time-weighted average (TWA) exposure of < 10
ppm, the American Conference of Governmental Industrial
Hygienists (ACGIH) recommends exhaled breath monitoring prior
to the next shift, with an acceptable maximum concentration
of 0.08 ppm for mixed-exhaled breath and 0.12 ppm for
end-exhaled breath. However, these concentrations may be
decreased markedly in light of the intended changes in
acceptable workplace benzene levels for 1993 to 1994 (ACGIH,
1993). In one study of coke oven workers exposed to an
average benzene concentration of 1.32 ppm, end-of shift
exhaled breath analysis provided the most useful measurement
of exposure, and measurement of exhaled breath collected just
prior to the next shift was non-specific for smokers
(Drummond et al., 1988). In non-occupationally exposed urban
subjects, average exhaled breath benzene concentrations were
0.38 ppb in nonsmokers in a pristine rural setting, 2.5 ppb
in nonsmokers in an urban area, and 6.8 ppb in smokers
(Wester et al., 1986). At an exposure level of 25 ppm of
benzene in a sedentary individual, exhaled breath was found
to contain 2 ppm of benzene at the end of a 4.5 hour exposure
and 0.2 ppm 16 hours later (Sherwood & Carter, 1970). At an
exposure level of 4 to 7 ppm of benzene for 6 hours a day for
5 days, 4 subjects had a maximum of < 0.05 ppm of benzene in
exhaled breath the following morning (Berlin et al.,
1979).
Benzene concentrations may also be measured in blood, and are
affected by smoking (Brugnone et al., 1989). However,
acceptable occupational limits for blood benzene levels are
not commonly available. The half-life of benzene in blood
varies depending on the duration and magnitude of exposure,
and the concentration may be different in venous and arterial
blood (Schrenk et al., 1941).
In order to detect the haematological effects of chronic
benzene exposure, it is recommended to follow blood counts at
regular intervals. The Occupational Safety and Health
Administration (OSHA) recommends monthly blood counts and
removal from areas with high benzene exposure for white blood
cell counts below 4,000/mm3 or erythrocyte counts below
4,000,000/mm3 (OSHA, 1987).
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Large oral ingestions of benzene have resulted
in nausea, vomiting, ataxia, visual disturbances,
excitement, euphoria, somnolence, delirium, CNS
depression, loss of consciousness, nonreactive pupils,
tachycardia, and pneumonitis (Von Oetingen, 1940;
Thienes & Haley 1972). A non-fatal ingestion
resulted in an intense gastritis followed by pyloric
stenosis, and peripheral swelling and edema
(Greenburg, 1926). Direct aspiration of liquid
benzene into the lungs has resulted in immediate
pulmonary edema and haemorrhage at the site of contact
(Gerarde, 1960).
9.1.2 Inhalation
Acute exposure to 300 to 3000 ppm of benzene
may cause headache, dizziness, drowsiness, vertigo,
delirium, tremor, and loss of consciousness (Cronin,
1924; Greenburg, 1926; Flury, 1928). Nausea,
paralysis, and coma may also occur with significant
exposure (Cronin, 1924; Greenburg, 1926; Tauber,
1970). Additional symptoms may include excitement,
incoherent speech, flushed face, giddiness,
nervousness, insomnia, paresthesias, and fatigue which
may persist for more than two weeks (Hunter, 1978).
Acute benzene exposure has been reported to cause
systemic petechial haemorrhages, as well as
irritability and ataxia which may persist for several
weeks (Gerarde, 1960). One case of sudden fatality
was suggested to be a result of dysrhythmias from the
benzene-sensitized myocardium (Tauber, 1970).
9.1.3 Skin exposure
Dermal exposure to benzene may cause erythema,
vesiculation, dry and scaly dermatitis, and blistering
(Gerarde, 1960; Sandmeyer, 1981).
9.1.4 Eye contact
Ocular burning and transient epithelial injury
may result from exposure to liquid. Exposure to high
concentrations of benzene vapor may cause ocular
irritation (Grant & Schuman, 1993).
9.1.5 Parenteral exposure
Unknown.
9.1.6 Other
Unknown.
9.2 Chronic poisoning
9.2.1 Ingestion
Historic usage of benzene to treat leukemia
resulted in anemia, leukopenia, and multiple
haemorrhages. Dosages generally started at 3 g/day
and were increased to 5 g/day if necessary and
continued for months. The patients developed multiple
hemorrhages and/or menorrhagia associated with anemia,
leukopenia, and purpura followed later by death
(Hunter, 1978). Chronic ingestion studies in animals
have resulted in decreased numbers of erythrocytes and
lymphocytes (Hsieh et al., 1988; Huff et al.,
1989).
9.2.2 Inhalation
Inhalation exposure to benzene over intervals
varying from several months to several years has
resulted in hematologic abnormalities including
pancytopenia, as well as deficits in specific cell
lines, aplastic anemia, and leukemia (Aksoy et al.,
1971; Aksoy et al., 1972; Aksoy et al., 1974; Aksoy &
Erdem, 1978; Aksoy, 1980; Aksoy et al., 1987; Yin et
al., 1987b; Kipen et al., 1989; Yin et al., 1989).
9.2.3 Skin exposure
No information is available on the effects of
chronic dermal exposure to benzene other than the
dermatitis discussed under the acute exposure section
9.1.3.
9.2.4 Eye contact
Unknown.
9.2.5 Parenteral exposure
Unknown
9.2.6 Other
Not relevant.
9.3 Course, prognosis, cause of death
Most cases of acute benzene exposure resolve
spontaneously or with supportive care without long-term
sequela. At extremely high benzene concentrations, death
from acute exposure may occur immediately or within several
hours after exposure (Hamilton, 1922; Cronin, 1924;
Greenburg, 1926; Tauber, 1970). Death may be due to CNS
depression, asphyxiation, or respiratory or circulatory
arrest (Hamilton, 1922; Greenburg, 1926). In fatal cases
autopsy has revealed haemolysis, cyanosis, and multiple organ
haemorrhage. In chronic benzene exposures, patients
developing minor haematologic abnormalities usually recover
completely when removed from the exposure. In cases of
benzene-induced pancytopenia, the patients may recover
completely, die from complications of the pancytopenia, or
develop leukemia at a later time (Aksoy & Erdem, 1978).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Electrocardiographic studies in monkeys and
cats exposed to high concentrations of benzene
revealed ectopic beats and ventricular tachycardia,
which resolved upon excision of the adrenal glands and
stellate ganglion, and recurred with the subcutaneous
administration of adrenaline (Nahum & Hoff, 1934).
One report of sudden death after running and acute
benzene exposure was felt to be due to benzene induced
myocardial sensitivity to endogenous catecholamines
(Tauber, 1970).
9.4.2 Respiratory
Acute exposure may cause irritation, cough, and
hoarseness. At high exposure concentrations
respiratory failure and pulmonary edema may occur
(Ellenhorn & Barceloux, 1988).
9.4.3 Neurological
9.4.3.1 Central Nervous System (CNS)
Signs and symptoms from acute
exposure to benzene include headache,
dizziness, drowsiness, vertigo, delirium,
tremor, seizures, paralysis, and loss of
consciousness (Harrington, 1917; Cronin,
1924; Greenburg, 1926; Flury, 1928; Tauber,
1970). A single case of acute transverse
myelitis was associated with chronic benzene
exposure, possibly due to spinal cord
haemorrhage (Herregods et al.,
1984).
9.4.3.2 Peripheral nervous system
Chronic exposure to mixed solvents
including benzene has been associated with
distal neuropathy of the upper extremities as
demonstrated by electromyographic (EMG) and
nerve conduction velocity (NCV) studies
(Baslo & Aksoy, 1982).
9.4.3.3 Autonomic nervous system
Not known.
9.4.3.4 Skeletal and smooth muscle
Exposure to mixed solvents including
benzene has been associated with global
atrophy of the lower extremities (Baslo &
Aksoy, 1982).
9.4.4 Gastrointestinal
Acute benzene ingestion may cause nausea,
vomiting, and abdominal pain. Ingestion of an unknown
amount of benzene resulted in gastritis followed by
pyloric stenosis (Greenburg, 1926).
9.4.5 Hepatic
No information is available on hepatic effects
in humans from benzene exposure. In rats,
administration of 1.6 mg/kg/day of benzene for three
days resulted in increased liver weight and changes in
metabolic function (Pawar & Mungikar, 1975).
9.4.6 Urinary
9.4.6.1 Renal
No information available.
9.4.6.2 Others
Chronic ingestion of benzene for
therapeutic purposes reportedly led to
bladder irritability and impotence in some
patients (Gerarde, 1960).
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
Acute dermal exposure to benzene may cause
erythema and blistering, and repeated or prolonged
exposures may cause a dry and scaly dermatitis
(Gerarde, 1960). A non-fatal ingestion resulted in a
skin condition characterized by swelling and edema
(Greenburg, 1926).
9.4.9 Eye, ear, nose, throat: local effects
Ocular burning and transient epithelial injury
may result from exposure to liquid. Exposure to high
concentrations of benzene vapor may cause ocular
irritation. There are reports of retrobulbar neuritis
or optic neuritis occurring after inhalation exposure
to benzene (Grant & Schuman, 1993).
9.4.10 Hematological
Very little information is available
concerning acute effects of benzene on the
haematological system. However, there are a multitude
of studies on the haematological effects of
intermediate and chronic exposure, which include
aplastic anaemia, pancytopenia, and varying degrees of
thrombocytopenia and leukopenia mediated through bone
marrow toxicity. Both hypoplasia and hyperplasia of
the bone marrow may be observed, and may vary in
frequency by sex (Hunter, 1978).
Exposure to concentrations of 150 to 650 ppm over a
period of 4 months to 15 years was associated with the
development of pancytopenia (Aksoy et al., 1972).
Bone marrow aspirates in these patients demonstrated a
great range from acellularity to hypercellularity. In
a follow-up study of 44 patients with the same
exposure range and duration, 23 (52%) had complete
remission, 14 (32%) died of complications of
pancytopenia, 6 (14%) developed leukemia after a
period of 6 months to 6 years, and one patient (2%)
with complete remission developed fatal myeloid
metaplasia (Aksoy & Erdem, 1978). Chronic exposure of
1 to 25 years at benzene concentrations of 75 ppm has
been associated with the development of anemia and
leukopenia (Kipen et al., 1989). Anemia and
leukopenia in a group of rubber hydrochloride workers
associated with mean exposures of 75 ppm of benzene
improved as the exposure concentration dropped (Kipen
et al., 1989). A medical surveillance program of 303
workers exposed to less than 1 ppm of benzene for up
to 26 years as a group did not show any evidence of
changes in blood indices or any cases of leukemia
(Tsai et al., 1983). Additional information on
hematological effects of benzene exposure is included
under sections 7.3 and 7.5.
9.4.11 Immunological
Chronic benzene exposure has been shown to
affect both cellular and humoral immunity. In a study
of 35 painters exposed to 3 to 49 ppm of benzene and
higher concentrations of toluene and xylene, increased
serum IgM, and decreased serum IgG and IgA were found
(Lange et al., 1973). Decreases in cellular immunity
have been documented through leukopenia as described
under the hematological section 9.4.10.
Benzene administered to mice by intraperitoneal
injection resulted in a decreased cultured spleen cell
IgM production as demonstrated by plaque-forming cells
assays at a dose of 44 mg/kg for three days, and a
decreased lymphoproliferative response in cultured
spleen lymphocytes exposed to E. coli
lipopolysaccharide or concanavalin A in animals
administered a dose of 264 mg/kg for three days. The
number of circulating lymphocytes was decreased only
at dose of 440 mg/kg or higher (Irons et al., 1983).
Mice given benzene contaminated water had significant
immunotoxic effects on both the humoral and cellular
immune responses at doses of 166 mg/L and higher for a
four week period (Hsieh et al., 1988).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No data available.
9.4.12.2 Fluid and electrolyte disturbances
No data available.
9.4.12.3 Others
Not applicable.
9.4.13 Allergic reactions
None reported.
9.4.14 Other clinical effects
None reported.
9.4.15 Special risks
Pregnancy: Benzene crosses the human placenta
and is present in cord blood in concentrations equal
to or greater than maternal blood (Dowty et al.,
1976). However, effects of benzene exposure in
pregnant women is not well understood. A review of 15
pregnant women exposed to benzene reported one
stillbirth and 7 miscarriages but no congenital
abnormalities, and another study recorded a prevalence
of 4.6% for spontaneous abortions and premature births
in women exposed to benzene and other aromatic
hydrocarbons (Schardein, 1985). An increased
frequency of chromatid and isochromatid breaks was
found in children of women exposed during pregnancy to
a mix of benzene and other solvents in the printing
industry and chemical laboratories (Funes-Cravioto et
al., 1977). One pregnant woman with4 pancytopenia
from occupational exposure to benzene delivered an
apparently normal boy and from a later pregnancy
delivered a normal girl (Forni et al., 1971).
Animal experiments exposing pregnant mice, rats, and
rabbits demonstrated fetotoxicity associated with
maternal toxicity, specifically fetal skeletal
variants and reduced fetal weight (Tatrai et al.,
1980). Exposure in utero to 20 ppm of benzene for 6
hr/day on days 6 to 15 of gestation in mice resulted
in haematopoietic abnormalities (Keller & Snyder,
1988). Exposures in rats to less than 10 ppm of
benzene during pregnancy did not cause adverse fetal
changes (Kuna & Kapp, 1981).
Breast feeding: No data available.
Enzyme deficiencies: No data available.
9.5 Others
Ethanol can increase the extent of hematotoxicity from
benzene exposure (Baarson et al., 1982; Nakajima et al.,
1985; Nakajima et al., 1987). Previous administration of
phenobarbital may decrease benzene hematotoxicity (Ikeda &
Ohtsuji, 1971; Nakajima et al., 1985). Toluene reduces the
metabolism of benzene and reverses the benzene-induced
decrease in incorporation of iron into red blood cells
(Andrews et al., 1976). Hepatitis B may also increase the
incidence of hematopoietic effects from benzene exposure
(Aksoy, 1989).
10. MANAGEMENT
10.1 General principles
For inhalation exposures, it is important to move the
patient to fresh air and administer humidified 100% oxygen as
needed. For ingestions of greater than 1 mL/kg body weight
of benzene presenting less than two hours after ingestion,
gastric aspiration may be useful. Administration of
catecholamines is not recommended due to the possibility of
myocardial sensitization (HSDB, 1992).
10.2 Life supportive procedures and symptomatic treatment
Supportive treatment is adequate for most cases of
benzene exposure. As in all patients, adequate airway,
breathing, and circulation should be assured. The patient
should be removed from the exposure and 100% oxygen
administered as necessary. In severe exposures, endotracheal
intubation and mechanical ventilation may be necessary.
Intravenous crystalloid solutions should be administered for
hypotension. Cardiac monitoring is recommended for severe
exposures, and routine blood tests such as a CBC and
electrolytes should be ordered. Abnormalities should be
corrected. Diazepam is the first line therapy for the
treatment of seizures, and phenobarbital may be a useful
adjunct.
10.3 Decontamination
No decontamination is required for pure inhalation
exposure. For dermal exposure, the patient's clothing should
be removed and discarded. Then the skin should be washed
with soap and copious amounts of tepid water. For oral
exposures, gastric aspiration may be helpful for ingestion of
large quantities of benzene, although there is a risk of
pulmonary aspiration. Gastric lavage should be considered
for the patient who may have ingested other substances.
Ipecac should not be administered due to the risk of sudden
decrease in mental status. Administration of activated
charcoal and sorbitol has not been demonstrated to be
efficacious in humans, although activated charcoal decreased
absorption of benzene into blood from the ligated small
intestines of rats (Laass, 1980). For ocular exposures,
irrigate with copious amounts of water or normal
saline.
10.4 Enhanced elimination
There are no proven means of increasing benzene
elimination once it has been absorbed.
10.5 Antidote treatment
10.5.1 Adults
No proven antidotal therapy is available.
Administration of N-acetyl cysteine may theoretically
be of benefit in limiting haematotoxicity from acute
benzene exposure. In mice, coadministration of
indomethacin (2 mg/kg body weight) with benzene
prevented the bone marrow depression and genotoxicity
seen with the benzene given alone, most likely through
a prostaglandin-mediated process (Kalf et al., 1989),
although use of this therapy has not been reported in
human poisonings.
10.5.2 Children
Adult management guidelines should be followed
with appropriate adjustment of dosages for
children.
10.6 Management discussion
Since the treatment of acute exposure to benzene is
limited to decontamination and supportive care, there are few
controversies over treatment other than the usual discussion
about the risks and benefits of lavage and/or activated
charcoal. The possible beneficial effects of administration
of nonsteriodal antiinflammatory agents and the
administration of N-acetyl cysteine deserve further
investigation prior to their routine use in humans. Further
research should focus on the prevention of injury by blocking
the toxic effects of benzene metabolites.
11. ILLUSTRATIVE CASES
11.1 Case reports from the literature
Tauber reported in 1970 on a fatality from acute
benzene exposure (Tauber, 1970). A 45 year old previously
healthy male collapsed after running 325 feet to shut off an
overflowing benzol plant tank. The tank contained 67.7%
benzene, 14.5% toluene, 5.7% xylene, 4.8% crude solvents, and
7.3% other chemicals. Autopsy was unremarkable except for
elevated benzene levels: blood 0.38 mg%, brain 1.38 mg%, and
liver 0.28 mg%. The suspicion in this case was death from
the benzene-sensitized myocardium and endogenous
catecholamines, as the brain levels were not felt to be high
enough to result in general anesthesia.
A case of multiple fatalities resulted when workers were
exposed to benzene from a previous cargo while opening a
flange valve in the cofferdam of a chemical cargo ship.
Three workers collapsed and one was rescued. The exposure
lasted only a number of minutes. At autopsy all victims had
second degree chemical burns to the face, trunk, and limbs,
confluent alveolar haemorrhages, and pulmonary edema. Blood
benzene levels ranged from 30 to 120 mg/L (Avis & Hutton,
1993).
Hamilton reported on a number of cases of acute benzene
exposure from entry into confined spaces (Hamilton, 1922).
In several of these cases benzene containing tanks had been
washed out thoroughly and in one case additional air was
supplied through a pipe, but despite these precautions
fatalities were reported. In this same article, Hamilton
also reported on nine women aged 15 to 20 years of age who
developed purpura and haemorrhages from the mouth, stomach,
nose or uterus after using benzene-based rubber cement for
three weeks to four months in a velocipede tire factory.
Upon evaluation, they were found to have both marked anemia
and almost complete leukopenia.
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
Benzene should be stored in sealed well marked
containers in locked areas to avoid inadvertent exposure to
children. In occupational settings benzene should be used in
closed-process systems, or in areas with adequate
ventilation. Otherwise appropriate respiratory protection
should be worn at benzene concentrations above occupational
exposure limits. For occupational exposures, annual medical
surveillance examinations including complete blood counts are
recommended.
12.2 Other
No data available.
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14. AUTHOR, REVIEWER(S), DATES (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Author: Dr J.L. Burgess
Washington Poison Center
P.O. Box 5371
Seattle, WA 98105-0371
USA
Tel: 1-206-5172357
Fax: 1-206-5268490
Date: May 1993
Peer
review: Cardiff, United Kingdom, March 1995
(Group members: Mr J. de Kom, Dr R. Dowsett, Dr K.
Hartigan-Go, Dr H. Hentschel, Dr P. Myrenfors, Dr L.
Pinto Pereira, Dr M. Rizk, Dr E. Wickstrom)
Editors: Dr M.J. Ruse (April 1997)
Mrs J. Duménil (June 1999)