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BENZENE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Benzene has a characteristic aromatic odor. It is a clear, colorless liquid that is lighter than water and highly flammable. It is found naturally in such sources as volcanoes and forest fires and produced in high volume in the United States.

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) CAS 71-43-2
    2) 1-chloro-4-(trifluoromethyl)benzene
    3) CAS 98-56-6
    4) Benzene, 1-chloro-4-(trfluoromethyl) (CAS 98-56-6)
    5) Annulene
    6) Benzeen (Dutch)
    7) Benzen (Polish)
    8) Benzol
    9) Benzole
    10) Benzolene
    11) Benzolo (Italian)
    12) Bicarburet of hydrogen
    13) Carbon oil
    14) Coal naphtha
    15) Coal tar naptha
    16) Cyclohexatriene
    17) Fenzen (Czech)
    18) Mineral naptha
    19) Motor benzol
    20) Nitration benzene
    21) Phene
    22) Phenyl hydride
    23) Pyrobenzol
    24) Pyrobenzole
    25) Benzin (obsolete)
    26) Benzine (obsolete)
    1.2.1) MOLECULAR FORMULA
    1) C6-H6

Available Forms Sources

    A) FORMS
    1) Benzene has a characteristic aromatic odor. It is a clear, colorless liquid that is lighter than water (AAR, 2000).
    2) The nitration grade of benzene is greater than 99% pure. 'Benzol 90' contains 80 to 85% benzene, 13 to 15% toluene and 2 to 3% xylene (HSDB , 2001).
    3) Benzene's odor has been described as gasoline-like and pleasantly aromatic (HSDB , 2001).
    B) SOURCES
    1) Natural sources of benzene include volcanoes and forest fires. Benzene is also a natural constituent of crude oil (Howard, 1990).
    2) Benzene is the 16th-highest-volume chemical produced in the United States, according to 1995 data. More than 7 million tons are produced annually (Lewis, 1997; Lewis, 1998).
    3) Benzene can be recovered from coal tar and produced from the hydrodemethylation of toluene under catalytic or thermal conditions (HSDB , 2001).
    4) A chief source of benzene is catalytic reformat, wherein the naphthenes and paraffins contained in naphtha are converted to aromatic hydrocarbons. Solvent extraction is then used to recover the benzene (ATSDR, 1993).
    5) Most of the benzene produced in the United States is derived from the petrochemical and petroleum-refining industries (ATSDR, 1993).
    6) HOOKAH SMOKE: According to a study that measured urinary S-phenylmercapturic acid (SPMA; a metabolite of benzene) levels in hookah smokers (n=105) and non-smokers (n=103) who attended hookah social events at a hookah lounge or in a private home, the urinary SPMA levels were significantly higher in daily hookah smokers than non-smokers after hookah lounge events (27.4 times higher; median 3.56 pmol/mg vs 0.13 pmol/mg, p<0.001) and after home events (7.8 times higher; 1.24 pmol/mg vs 0.16 pmol/mg, p<0.001). In all hookah smokers (daily or occasional smokers), SPMA levels increased 4.2 times and 1.9 times after hookah lounge and home events, respectively, than before the event. In non-smokers, there was no significant change from pre- to post-home event in the urinary SPMA levels (median, 0.14 pmol/mg to 0.16 pmol/mg, p=0.993); however, there was an increase of 2.6 times after hookah lounge events (median, 0.05 pmol/mg to 0.13 pmol/mg, p=0.055), suggesting that secondhand hookah smoke can also be a source of benzene exposure (Kassem et al, 2014).
    C) USES
    1) Benzene is used as solvent, as a gasoline additive, and to make other industrial chemicals including polymers, detergents, pesticides, pharmaceuticals, dyes, plastics and resins. It is also used as a solvent for waxes, resins, oils and natural rubber (AAR, 2000) (Budavari, 2000).
    2) Benzene is added to gasoline and other fuels to act as an octane booster (Lewis, 1998).
    3) Benzene is used for printing, lithography and dry cleaning, and in paint, rubber, adhesives and coatings, and in detergents (HSDB , 2001).
    4) Benzene has been used extensively in shoe factories and in the tire industry. It has also been used as a disinfectant (HSDB , 2001).
    5) The production of ethylbenzene, cumene and cyclohexane constitute the main uses of benzene (ATSDR, 1993).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Most commonly used as an intermediate in the production of other chemicals. Many benzene derivatives, such as styrene and phenol, are used to make a variety of other compounds, such as polymers, plastics, resins, and adhesives.
    B) TOXICOLOGY: Human metabolism of benzene to its principal metabolites (ie, hydroquinone, catechol, and phenol) occurs via cytochrome P450 enzyme 2E1 and quinone oxidoreductase NQ01. It is proposed that these metabolites are responsible for much of the systemic toxicity observed after benzene exposure. Benzene affects many organ systems. Specifically, benzene causes bone marrow suppression and, through its metabolites, disruptions in the cell cycle which can lead to mutagenesis. This effect is further exacerbated by chromosomal aberrations caused by benzene in lymphocytes. As with other solvents, large exposures cause CNS effects.
    C) EPIDEMIOLOGY: Acute exposure is very rare. Found to be an air pollutant found at low levels. Levels have also been found to be higher in smokers than in nonsmokers. Typically patients who present to medical care with symptoms have been exposed chronically.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Benzene is a local irritant. Benzene exposure to the skin causes the development of erythema, burning, and edema. In the gastrointestinal tract, benzene produces a burning sensation of the oral mucous membranes, esophagus, and stomach after ingestion, with associated nausea, vomiting, and abdominal pain. Inhalational exposure causes bronchial irritation, cough, hoarseness, pulmonary edema, and chemical pneumonitis. Exposure to the eyes can cause reversible corneal injury.
    2) SEVERE TOXICITY: Inhalation at moderate concentrations may cause pallor, dizziness and excitation, followed by flushing, dyspnea, chest constriction, headache, and weakness. Higher concentrations may cause euphoria and excitation, followed by fatigue, cardiac dysrhythmias, seizures, coma, and death. Ingestion of benzene can cause vomiting, tachycardia, ataxia, somnolence, loss of consciousness, delirium, chemical pneumonitis with initial excitatory symptoms followed by abrupt CNS and respiratory depression. Transverse myelitis has been reported following occupational exposure. Dermal exposure can cause burns and systemic toxicity.
    3) CHRONIC EXPOSURE: Has been associated with paroxysmal nocturnal hemoglobinuria, various types of leukemia, myeloid metaplasia, aplastic anemia, menstrual cycle disruption, spontaneous abortion, stillbirth, and an increased likelihood of the development of diabetes.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Reversible epithelial cell injury of the eyes may occur after splash contact.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Cardiac dysrhythmias are possible with high concentration exposures.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Inhalation may result in bronchial irritation, cough, hoarseness, pulmonary edema and pneumonitis.
    0.2.7) NEUROLOGIC
    A) Euphoria, headache, giddiness, vertigo, ataxia, narcosis and muscular incoordination are possible. Confusion, seizures and coma may occur after exposure to high concentrations. Fatigue, headache, anorexia, dizziness, neuropathies and abnormal EEG may be noted after chronic exposure. Transverse myelitis may occur.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) A burning sensation of the oral mucous membranes, esophagus and stomach may occur after ingestion, as well as nausea, vomiting and abdominal pain.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Paroxysmal nocturnal hemoglobinuria and other kidney diseases have been reported.
    0.2.13) HEMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Chronic exposure can result in delayed hematopoietic changes, including many types of leukemia, aplastic anemia and myeloid metaplasia.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Erythema, blistering and dermatitis may occur.
    0.2.16) ENDOCRINE
    A) WITH POISONING/EXPOSURE
    1) Diabetes has been linked to benzene exposure.
    0.2.20) REPRODUCTIVE
    A) Benzene has been found in umbilical cord blood. Benzene exposure has been linked to menstrual changes, spontaneous abortion and stillbirth.
    0.2.21) CARCINOGENICITY
    A) Hematologic neoplasms such as leukemia have been associated with benzene exposure.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor CBC with differential and platelet count, and a basic metabolic panel.
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Monitoring benzene in expired air and urine phenol levels may be useful for observing workers exposed to benzene, but is not helpful in the acute setting.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat ventricular dysrhythmias using ACLS protocols. Endotracheal intubation and mechanical ventilation are likely to be necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital GI decontamination is not recommended because of the risk of CNS depression or seizures and subsequent aspiration.
    2) HOSPITAL: Consider insertion of a nasogastric tube to aspirate gastric contents if it can be performed soon (within an hour) after a very large ingestion. Protection of the airway should be ensured as there is a high risk of CNS depression and aspiration.
    D) AIRWAY MANAGEMENT
    1) Monitor for inadequate oxygenation and ventilation due to significant CNS depression and inadequate airway protection. Intubation and assisted ventilation may be necessary.
    E) ANTIDOTE
    1) There is no specific antidote for benzene exposure. The mainstay of therapy is aggressive supportive care.
    F) SEIZURE
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    G) VENTRICULAR ARRHYTHMIA
    1) Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Unstable rhythms require immediate cardioversion.
    H) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with symptoms or a history of more than a sip ingestion should be evaluated in a healthcare facility.
    2) ADMISSION CRITERIA: All symptomatic patients and all those with significant exposures should be admitted for monitoring and laboratory evaluation.
    3) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe signs and symptoms or large exposures.
    I) TOXICOKINETICS
    1) Benzene is absorbed after ingestion, inhalation, and by dermal exposure. Undergoes extensive hepatic metabolism, with subsequent urinary excretion of metabolites.
    J) DIFFERENTIAL DIAGNOSIS
    1) Exposures to many of the heavy metals which exhibit multisystem effects, such as arsenic, thallium, and polonium.
    0.4.3) INHALATION EXPOSURE
    A) First, move the patient to fresh air. Administer supplemental oxygen and assist ventilation as required. Monitor closely for respiratory distress or cough which may be secondary to respiratory tract irritation, bronchitis, or pneumonitis. Treat bronchospasm with inhaled beta-2 agonist and oral or parenteral corticosteroids.
    0.4.4) EYE EXPOSURE
    A) Irrigate exposed eyes with copious amounts of room temperature water or normal saline for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen by an ophthalmologist.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Remove contaminated clothing and wash exposed area thoroughly with soap and water.

Range Of Toxicity

    A) The estimated human oral lethal dose is 50 to 500 mg/kg. The odor threshold is 1.5 to 4.7 parts per million (ppm); CNS effects, including drowsiness, dizziness, headache, vertigo, tremor, delirium, and coma, may occur following inhalation at levels of 300 to 3000 ppm. Inhalation of 20,000 ppm is rapidly fatal. For occupational exposure, the TLV-TWA (threshold limit value time weighted average) is 0.5 ppm and the TLV-STEL (short term exposure limit) is 2.5 ppm; 500 ppm is IDLH (immediately dangerous to life and health).

Clinical Effects

Summary Of Exposure

    A) USES: Most commonly used as an intermediate in the production of other chemicals. Many benzene derivatives, such as styrene and phenol, are used to make a variety of other compounds, such as polymers, plastics, resins, and adhesives.
    B) TOXICOLOGY: Human metabolism of benzene to its principal metabolites (ie, hydroquinone, catechol, and phenol) occurs via cytochrome P450 enzyme 2E1 and quinone oxidoreductase NQ01. It is proposed that these metabolites are responsible for much of the systemic toxicity observed after benzene exposure. Benzene affects many organ systems. Specifically, benzene causes bone marrow suppression and, through its metabolites, disruptions in the cell cycle which can lead to mutagenesis. This effect is further exacerbated by chromosomal aberrations caused by benzene in lymphocytes. As with other solvents, large exposures cause CNS effects.
    C) EPIDEMIOLOGY: Acute exposure is very rare. Found to be an air pollutant found at low levels. Levels have also been found to be higher in smokers than in nonsmokers. Typically patients who present to medical care with symptoms have been exposed chronically.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Benzene is a local irritant. Benzene exposure to the skin causes the development of erythema, burning, and edema. In the gastrointestinal tract, benzene produces a burning sensation of the oral mucous membranes, esophagus, and stomach after ingestion, with associated nausea, vomiting, and abdominal pain. Inhalational exposure causes bronchial irritation, cough, hoarseness, pulmonary edema, and chemical pneumonitis. Exposure to the eyes can cause reversible corneal injury.
    2) SEVERE TOXICITY: Inhalation at moderate concentrations may cause pallor, dizziness and excitation, followed by flushing, dyspnea, chest constriction, headache, and weakness. Higher concentrations may cause euphoria and excitation, followed by fatigue, cardiac dysrhythmias, seizures, coma, and death. Ingestion of benzene can cause vomiting, tachycardia, ataxia, somnolence, loss of consciousness, delirium, chemical pneumonitis with initial excitatory symptoms followed by abrupt CNS and respiratory depression. Transverse myelitis has been reported following occupational exposure. Dermal exposure can cause burns and systemic toxicity.
    3) CHRONIC EXPOSURE: Has been associated with paroxysmal nocturnal hemoglobinuria, various types of leukemia, myeloid metaplasia, aplastic anemia, menstrual cycle disruption, spontaneous abortion, stillbirth, and an increased likelihood of the development of diabetes.

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Reversible epithelial cell injury of the eyes may occur after splash contact.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Splash contact causes a moderate burning sensation, with slight transient epithelial cell injury and rapid recovery (Grant, 1986).
    2) BLURRED VISION may occur with acute exposure (Kaye, 1978).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) CASE REPORT: The autopsy of an 18-year-old man, who died following inhalation of reagent grade benzene, revealed evidence of acute granular tracheitis, laryngitis, and bronchitis (Winek & Collom, 1971).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Cardiac dysrhythmias are possible with high concentration exposures.
    3.5.2) CLINICAL EFFECTS
    A) VENTRICULAR FIBRILLATION
    1) WITH POISONING/EXPOSURE
    a) Cardiac dysrhythmias, including ventricular fibrillation, can occur due to epinephrine sensitization as well as from direct myocardial effects (Kaye, 1978; Nahum & Hoff, 1934).
    b) CASE SERIES: Three people died of ventricular fibrillation after acute benzene poisoning resulting from an industrial accident aboard a chemical cargo ship (Gist & Burg, 1997).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Inhalation may result in bronchial irritation, cough, hoarseness, pulmonary edema and pneumonitis.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) WITH POISONING/EXPOSURE
    a) Respiratory tract irritation may occur after inhalation (Drozd & Bockowski, 1967).
    B) COUGH
    1) WITH POISONING/EXPOSURE
    a) Symptoms after ingestion include chest pain/constriction, coughing, breathlessness, and chemical pneumonitis (Bingham et al, 2001; Lewis, 1998)
    C) APNEA
    1) WITH POISONING/EXPOSURE
    a) Death can occur due to respiratory failure (Kaye, 1978).
    D) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema and hemorrhages of the lungs may occur (Barbera et al, 1998; Winek & Collom, 1971).
    b) Alveolar hemorrhages and pulmonary edema were revealed at the autopsies of 3 crew members who died following exposure to benzene vapors while on a chemical cargo ship (Avis & Hutton, 1993a).

Neurologic

    3.7.1) SUMMARY
    A) Euphoria, headache, giddiness, vertigo, ataxia, narcosis and muscular incoordination are possible. Confusion, seizures and coma may occur after exposure to high concentrations. Fatigue, headache, anorexia, dizziness, neuropathies and abnormal EEG may be noted after chronic exposure. Transverse myelitis may occur.
    3.7.2) CLINICAL EFFECTS
    A) EUPHORIA
    1) WITH POISONING/EXPOSURE
    a) Initially euphoria is seen, followed by headache, giddiness, vertigo and ataxia (Kaye, 1978; Drozd & Bockowski, 1967; Harrington, 1917).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) High doses can result in confusion, seizures and coma (Barbera et al, 1998; Kaye, 1978; Drozd & Bockowski, 1967)
    b) CASE REPORT: Depression, concentration and short-term memory impairment, decreased appetite, headaches, fatigue, decreased libido, and sleep disturbances were reported in seven male boilermakers following occupational exposure to varying amounts of benzene, toluene, and tetraethylene glycol (Leikin et al, 2000).
    C) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headaches have been reported following inhalation (Drozd & Bockowski, 1967).
    D) TRANSVERSE MYELOPATHY SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 25-year-old man, working at a wholesale supplier of chemicals, presented to the hospital with progressive paresis of his upper and lower extremities, bladder and bowel dysfunction, and paresthesias and sensory distortion. Lumbar punctures revealed no abnormalities of the cerebrospinal fluid, and viral tests were normal. A toxicological examination indicated a high urinary phenol concentration (28 mg/L; normal less than 10 mg/L). With supportive care, the patient's condition gradually improved over the next several months, with normal muscle strength in his upper and lower extremities, and the ability to walk without crutches, although bladder dysfunction continued to persist. The urinary phenol level had decreased to 4 mg/L. The patient was subsequently diagnosed with transverse myelitis postulated to be secondary to occupational exposure of benzene (Herregods et al, 1984).
    E) CEREBRAL EDEMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: The autopsy of an 18-year-old man, who died after inhaling reagent grade benzene, revealed the presence of cerebral edema (Winek & Collom, 1971).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) A burning sensation of the oral mucous membranes, esophagus and stomach may occur after ingestion, as well as nausea, vomiting and abdominal pain.
    3.8.2) CLINICAL EFFECTS
    A) ESOPHAGITIS
    1) WITH POISONING/EXPOSURE
    a) A burning sensation in the mouth and stomach can occur following ingestion (Bingham et al, 2001; Lewis, 1998).
    b) Congestive gastritis has been reported following inhalation (Kaye, 1978; Winek & Collom, 1971).
    B) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Stomach pain, nausea and vomiting occur early in intoxication (Drozd & Bockowski, 1967).

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Paroxysmal nocturnal hemoglobinuria and other kidney diseases have been reported.
    3.10.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) WITH POISONING/EXPOSURE
    a) HEMOGLOBINURIA: Paroxysmal nocturnal hemoglobinuria (PNH) has been reported in patients occupationally exposed to benzene. PNH is often associated with aplastic anemia and rarely with acute leukemia (Kwong & Chan, 1993).
    B) KIDNEY DISEASE
    1) WITH POISONING/EXPOSURE
    a) Reports of miscellaneous kidney diseases have been associated with benzene exposure, such as Goodpasture syndrome, antiglomerular basement membrane antibody, and anuric acute renal failure (Gist & Burg, 1997; Winek & Collom, 1971).
    C) ABNORMAL SEXUAL FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Sexual dysfunction, including erectile abnormalities, decreased libido, and Peyronie's disease, has been reported following occupational exposure to varying amounts of benzene and toluene, and may not occur until several months post-exposure (Leikin et al, 2000).

Hematologic

    3.13.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Chronic exposure can result in delayed hematopoietic changes, including many types of leukemia, aplastic anemia and myeloid metaplasia.
    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH POISONING/EXPOSURE
    a) MYELOTOXICITY: Exposures producing acute myelotoxicity can result in delayed hematopoietic changes (Gosselin et al, 1984). Chronic exposure can produce suppression of hematopoiesis, resulting in spontaneous bleeding, anemia and leukopenia. Large single-dose exposure has been postulated to produce acute myelotoxicity or leukemia (Gerarde, 1960).
    B) APLASTIC ANEMIA
    1) WITH POISONING/EXPOSURE
    a) Aplastic anemia and leukemia can occur (Aksoy, 1985a; Aksoy, 1985b; Kuang & Liang, 2005). Work exposure to 100 ppm resulted in 140 excess deaths from leukemia per 1,000 exposed; 10 ppm resulted in 14 excess deaths (Landrigan & Rinsky, 1984). Bone marrow toxicity in exposed individuals may be triggered by individual susceptibility (pregnancy, infection and alcoholism), and affects women more than men. All elements of the marrow are affected.
    C) HEMATOLOGY FINDING
    1) WITH POISONING/EXPOSURE
    a) White blood cell and platelet counts were significantly lower in 250 benzene exposed Chinese shoe workers than 140 controls. This was a persistent finding across all exposure levels from <1 ppm, 1 to <10 ppm, greater than equal 10 ppm. CD4+ counts, CD4+/CD8+ ratio, and B cells were also decreased across all exposure ranges. Hemoglobin was only decreased in workers exposed to 10 ppm or greater air concentrations of benzene. Individuals with two specific genetic variants in two key enzymes (CYP2E1 and myeloperoxidase) that metabolize benzene to toxic quinones and free radicals were more susceptible to benzene induced effects than other genetic subtypes (Lan et al, 2004).
    b) Blood diseases that have been associated with benzene exposure include pancytopenia, leukopenia, bone marrow hypoplasia or aplasia, thrombocytopenia, granulocytopenia, and lymphocytopenia (NTP, 1986). Associations have also been made with benzene exposure (especially chronic exposure) and a reduction in T lymphocytes (Moszczynsky & Lisiewicz, 1984).
    D) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) CHRONIC EXPOSURE/CASE REPORT: One study showed leukocytosis in a 10-year chronically exposed worker with an average benzene exposure level of 0.9 ppm. He also had erythropoietin-independent growth of red cell progenitor colonies on peripheral blood smear. Both conditions began to normalize after benzene exposure was terminated (Froom et al, 1994).
    E) PANCYTOPENIA
    1) WITH POISONING/EXPOSURE
    a) CHRONIC EXPOSURE: Low RBC, WBC, hemoglobin, and platelet counts have been observed in severe cases of chronic benzene poisoning; bone marrow smear and biopsy examinations were not hypocellular. Aplastic anemia, myelodysplastic syndrome, and leukemia have also been reported (Kuang & Liang, 2005).
    F) HEMATOLOGIC NEOPLASM
    1) In a large study of Chinese workers, a cohort of almost 75,000 benzene-exposed and 35,000 unexposed workers were identified and followed. The risk of hematologic neoplasms were increased at average benzene exposure levels of less than 10 ppm (Hayes et al, 1997).
    G) LACK OF EFFECT
    1) CASE SERIES: In a 10-year study of 200 people working with benzene (exposures ranging from 0.01 to 1.4 ppm over 8 hours time-weighted average), results indicated that low level exposure did not seem to produce changes in red blood cell, white blood cell or platelet counts, hemoglobin or mean corpuscular volume when confounding factors (age, sex, race, smoking) were taken into consideration (Collins et al, 1991).
    2) CASE SERIES: Another study of workers exposed to benzene with daily 8-hour time-weighted average exposures of 0.55 ppm found no increase in lymphopenia or other hematologic abnormalities (Collins et al, 1997).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Erythema, blistering and dermatitis may occur.
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) It is a strong irritant of the eyes, skin and respiratory tract, and can cause dermatitis and dehydration, defatting, edema, burning and blistering of the skin (Bingham et al, 2001; Harbison, 1998; Lewis, 1998).
    B) CHEMICAL BURN
    1) WITH POISONING/EXPOSURE
    a) Second degree chemical burns to the face, trunk, and extremities were noted on the autopsy reports of 3 crew members who died following exposure to benzene fumes and dermal contact while on a chemical cargo ship (Avis & Hutton, 1993a).

Endocrine

    3.16.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Diabetes has been linked to benzene exposure.
    3.16.2) CLINICAL EFFECTS
    A) DIABETES MELLITUS
    1) WITH POISONING/EXPOSURE
    a) Insulin-dependent diabetes mellitus was correlated with benzene exposure (Gist & Burg, 1997).

Reproductive

    3.20.1) SUMMARY
    A) Benzene has been found in umbilical cord blood. Benzene exposure has been linked to menstrual changes, spontaneous abortion and stillbirth.
    3.20.2) TERATOGENICITY
    A) BIRTHWEIGHT SUBNORMAL
    1) An epidemiologic study of 792 pregnant women in a large petrochemical industry showed a positive correlation between reduced birth weight and exposure to benzene and work stress. Exposure to either benzene or work stress separately showed a negative correlation (Chen, 2000).
    2) Lower average birth weights in full-term neonates and increased risk for prematurity were seen in infants born to mothers living closest to the highest-ranking hazardous waste site on the US Superfund Priority List.
    a) Risk was increased approximately two-fold for the time period 1971 to 1975, the period corresponding to the highest level of dumping. Chemical hazards, besides benzene, included bis(2-chloroethyl)ether, toluene, methylene chloride, 1,2-dichloroethane, formaldehyde, phenol and heavy metals.
    b) Because of the mixed exposures, these effects cannot be attributed solely to benzene. In addition, critical confounders such as maternal smoking and alcohol consumption, parental occupation and socioeconomic status could not be evaluated (Berry & Bove, 1997).
    B) CONGENITAL ANOMALY
    1) A retrospective, case-control study of 1951 female laboratory workers found no significantly increased risk of major congenital malformations related to laboratory work in general. There was an excess risk with organic solvents, particularly benzene, for major congenital malformations and for neural crest malformations for women who worked with benzene before the end of the second trimester of pregnancy (Wennborg et al, 2005).
    2) Benzene has been mentioned as one of many solvents associated with birth defects in Finland (Kurppa, 1983; Holmberg, 1979). Occupational exposure to benzene, toluene and other aromatic solvents was not associated with abnormal blood loss after labor and delivery (Michon & Tadeusz, 1968).
    C) ANIMAL STUDIES
    1) Benzene has been reported as producing conflicting results in mice and negative results in rats and rabbits in studies of teratogenicity (Schardein, 2000):
    a) Benzene was not teratogenic when inhaled by rats, but was fetotoxic, producing delayed sternebral ossification.
    b) Benzene produced cleft palate and jaw defects when injected parenterally in mice; oral administration did not result in teratogenic effects. Inhalational exposure of mouse dams produced fetal hematopoietic changes.
    c) Congenital malformations resulted in rabbits after inhalational exposure.
    d) Male rats exposed in utero to 10 ppm benzene resulted in decreased numbers of colony-forming uniterythroid (CFU-E) progenitor cells when re-exposed to 10 ppm benzene as adults. Female rats only exhibited these results when also exposed to ethanol (Corti & Snyder, 1990).
    2) Benzene was generally not teratogenic, but was fetotoxic in increasing so-called 'normal skeletal variants' such as delayed ossification and extra ribs, and in stunting the growth of the fetus (Mehlman, 1980).
    3) More animal and epidemiological studies are needed before more definitive conclusions can be made (NTP, 1986).
    3.20.3) EFFECTS IN PREGNANCY
    A) MENSTRUAL DISORDER
    1) Benzene exposure has reportedly induced vaginal bleeding, hemorrhagic complications of pregnancy, heavy menstrual bleeding (at 31 ppm), menstrual cycle disorders and various obstetrical disorders, including miscarriages, premature births and stillbirths (Hunt, 1979; Riera-Bartra & Senor, 1957; Michon, 1965; Mikhailova, 1971; Mukhametova & Vozovaya, 1972).
    2) Menstrual problems, but no effect on fertility, have been described in women after occupational exposure to benzene. Toxicity caused anemia, but no birth defects, in two pregnant women (Forni et al, 1971).
    B) ABORTION
    1) Increased risk for spontaneous abortions occurred in first pregnancies in women with frequent exposure to petrochemical products including benzene, in a retrospective study. The odds ratio for spontaneous abortions overall was 2.9, relative to unexposed controls, and the odds ratio for exposure to benzene was 2.5. Mean exposure to benzene, based on personal sampling, was 0.86 ppm. Increased odds ratios were also seen for exposure to gasoline and hydrogen sulfide (Xu et al, 1998).
    2) Of 15 cases of benzene poisoning in pregnancy, no congenital abnormalities were found in the live births, but there were 7 spontaneous abortions and 1 stillbirth (Schardein, 1985).
    C) PLACENTAL BARRIER
    1) Benzene crosses the human placenta, and similar levels are found in fetal and maternal blood (HSDB , 2001). Benzene is present in cord blood at concentrations at least as high as those in maternal blood (Dowty et al, 1976). However, the reported fetotoxicity of benzene may result from its maternal toxicity (Bingham et al, 2001). In a few cases of benzene poisoning from high-level exposures during pregnancy, the fetus has seemed less sensitive than the mother (Riera-Bartra & Senor, 1957; Messerschmitt, 1972).
    D) ANIMAL STUDIES
    1) Broiler breeder hens exposed to benzene (1.3 ppm) as part of a low concentration chemical mixture (arsenic 0.8 pp, cadmium 5.1 ppm, lead 6.7 ppm and trichloroethylene 0.65 ppm) in water caused significantly decreased egg production and egg weight. It also caused an increased percentage of embryonic mortality (Vodela, 1997).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Discontinuation of breast-feeding 5 days after high exposure to benzene has been recommended (Zenz, 1994).
    3.20.5) FERTILITY
    A) MALE FERTILITY
    1) In a study of 160 industrial workers exposed to benzene and 200 non-exposed control subjects, male fertility, as evaluated by measures of sperm health, seemed to be impaired in the workers exposed to benzene. Although there were no significant differences in macroscopic semen parameters (semen volume, pH, and liquefaction) between the exposed and control groups, there was a statistically significant difference in microscopic semen parameters. A duration-dependent decrease in total sperm count and motility was observed in the exposed group compared with the controls (p less than 0.01). When compared with the control group, a duration-dependent increase in abnormal sperm morphology was reported for the exposed group (p less than 0.01). A significant increase in comet tail length, an indication of sperm DNA damage, was also observed in the exposed groups compared with the controls (p less than 0.01). Regression analysis of the data showed a statistically significant level of p less than 0.05 for the subset of medium-exposed workers with 5 to 10 years of benzene exposure at 8 hours/day (Katukam et al, 2012).
    B) ANIMAL STUDIES
    1) Benzene has had some reproductive effects in laboratory animals, generally at airborne concentrations greater than 200 ppm, which have also been toxic to the mother (Mehlman, 1980). Benzene did not affect the fertility of male or female animals.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS71-43-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Benzene
    b) Carcinogen Rating: 1
    1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    3.21.2) SUMMARY/HUMAN
    A) Hematologic neoplasms such as leukemia have been associated with benzene exposure.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) Benzene has been classified as a human carcinogen by the EPA, IARC, OSHA and NIOSH (Mehlman, 1991; Landrigan, 1996).
    2) NON-HODGKIN'S LYMPHOMA: A meta-analysis of cohort and case control studies, conducted to determine the risk of Non-Hodgkin's Lymphoma (NHL) following occupational exposure to benzene, demonstrated that the overall relative risk from 22 studies was 1.22 (95%CI 1.02 to 1.47; p=0.01). However, in the 13 studies that specifically provided results for highly-exposed workers, the relative risk (RR) increased to 1.49 (95%CI 1.12 to 1.97). When the analysis was adjusted to only include 6 of the studies that did not rely on self-reporting for exposure assessment, the RR again increased to 2.12 (95% CI 1.11 to 4.02), indicating that there is increased risk for development of NHL following benzene exposure (Steinmaus et al, 2008).
    3) GALLBLADDER CANCER: Two patients, a married couple who lived in and operated a dry cleaning facility together, simultaneously developed gall bladder cancer after benzene exposure for a prolonged period of 40 years. Both patients (a 60-year-old man and his 52-year-old wife) presented with jaundice. Laboratory data indicated elevated liver enzyme concentrations , and abdominal CT scans showed gallbladder mass lesions in both patients. The mass lesions metastasized into the abdominal lymph nodes in both patients, and the male patient was specifically diagnosed with stage IV gallbladder cancer, that was confirmed by biopsy and pathology results. To measure the benzene concentrations in the bodies of both patients, urine phenol-benzene and t.t-munoic acid-benzene testing were used. Urine phenol-benzene values were 12.895 mg/g creatinine for the first patient and 2.489 mg/g creatinine for the second patient (normal, less than 50 mg/g creatinine, 10 ppm standard) and urine t.t-munoic acid-benzene values were 0.057 and 0.058 mg/g creatinine, respectively (normal, less than 1 mg/g creatinine, 10 ppm standard). Draining of both intrahepatic ducts was performed in both patients; however, the first patient died 40 days later and the second died 100 days late despite best supportive treatment (Shim et al, 2013).
    B) LEUKEMIA
    1) SUMMARY: The main carcinogenic consequence of benzene exposure is the development of leukemia (Bingham et al, 2001). Acute and chronic lymphocytic leukemias have been reported (Zenz, 1994).
    a) Although benzene consistently produces negative results in most studies for short-term mutagenicity, OSHA assessment has shown that a 40-year exposure to 1 ppm in the workplace doubles the risk of dying from acute myeloid leukemia (Goldstein, 1989). Other studies have shown that concentrations greater than 10 ppm in the workplace over a long period of time results in excess leukemia mortality (Mehlman, 1991).
    b) A large cohort study in China showed that benzene may cause hematologic neoplasms and related disorders at average exposures of less than 10 ppm and cumulative exposures of less than 40 ppm-years (Hayes et al, 1997).
    c) Other previous epidemiological studies on groups of people exposed to benzene have shown a link between relatively high benzene exposure and acute myelogenous leukemia; for other cancers the evidence is weaker (Paustenbach et al, 1993).
    2) A prospective case-cohort study identified a nonsignificant risk of lymphohematopoietic cancers among benzene-exposed versus unexposed offshore workers on the Norwegian continental shelf, most of whom were exposed for less than 15 years. The average intensity level of a 12-hour shift was estimated to be less than 0.040 ppm, while the cumulative level was less than 1 ppm-years. According to intensity and cumulative exposure, a dose-related risk pattern was noted for acute myeloid leukemia and multiple myeloma, while the same was suggested for chronic lymphocytic leukemia (Stenehjem et al, 2015).
    3) The types of leukemia associated with benzene exposure have varied, with heavy exposures being associated more with acute leukemias, mostly myeloblastic, and lighter exposures linked with chronic types (Hathaway et al, 1996).
    4) A latent period of 2 to 50 years can occur between benzene exposure and development of leukemia (OSHA, 1987; (ACGIH, 1991).
    5) RISK ASSESSMENT: Benzene-induced aplastic anemia reportedly results in an increased risk for subsequent leukemia or lymphoma (Hathaway et al, 1996; Aksoy, 1985a; Aksoy, 1985b; Aksoy et al, 1972). Some, but not all, patients developing leukemia have had preexisting blood disorders (Aksoy et al, 1972). Work exposure to 100 ppm resulted in 140 excess deaths from leukemia per 1000 exposed; 10 ppm resulted in 14 excess deaths (Landrigan & Rinsky, 1984). Risk assessment studies have reported estimated lifetime excess deaths due to leukemia of 14 to 104 per 1,000 workers exposed to 10 ppm (Austin et al, 1988).
    a) The Pliofilm group (rubber workers) has the best-defined exposure and incidence data, and is the best for arriving at risk estimates.
    b) The risk from lower exposures depends on the model chosen for low-dose extrapolation, however (Paustenbach et al, 1993).
    c) The Pliofilm group was also the best-studied cohort. However, follow-up studies found no increased risk for any form of cancer other than acute monocytic leukemia, and no increased risk for leukemia in people exposed only to low levels of benzene (Crump, 1996; Paxton, 1996).
    6) SUSCEPTIBLE GROUPS: Bone marrow toxicity in exposed individuals may be governed by individual factors such as pregnancy, infection and alcoholism. In general, women seem to be more susceptible than men. All elements of the marrow are affected.
    7) Acute myeloblastic leukemia has been the most common malignancy associated with benzene exposure (Goldstein, 1977). Chronic lymphocytic leukemias are also reported (Snyder, 1987).
    8) In a large study of 74,825 workers exposed to benzene and 35,805 controls, there were significant excess deaths from leukemia, malignant lymphoma and non-neoplastic blood diseases. With respect to incidence, significant excesses were seen for all lymphohematopoietic malignancies, malignant lymphoma, acute myelogenous leukemia, aplastic anemia and myelodysplastic syndrome (Yin et al, 1996).
    a) A further study of this group of workers demonstrated that benzene may cause hematologic neoplasms at average exposures of 10 ppm and cumulative exposures of 40 ppm-years. Workers with estimated exposures of 25 ppm or more had a relative risk of 7.1 (95 percent CI, 2.1 to 23.7) of developing acute non-lymphocytic leukemia (ANLL) and related myelodysplastic syndromes (MDS).
    1) The risk of developing ANLL or MDS was significantly increased in workers with more-recent benzene exposure (less than 10 years) but not those with distant exposure. The development of non-Hodgkin lymphoma was increased in workers who had been exposed to benzene for 10 or more years (Hayes et al, 1997).
    9) A hospital based multicenter case control study of 280 children with leukemia and 285 controls was conducted. There was a statistically significant trend between duration of childhood exposure to a neighboring petrol station or repair garage and the risk of these children developing leukemia (OR 4.0, 95% CI 1.5 to 10.3). This association appeared particularly strong for acute non-lymphocytic leukemia (OR 7.7, 95% CI 1.7 to 34.3)(Steffen et al, 2004).
    10) Excess mortality from acute non-lymphocytic leukemia was found in a cohort of 5514 benzene-exposed workers followed from 1968 to 2002(Sorahan et al, 2005). Excess mortality from cancer of the lip, and cancer of the lung and bronchus was also found in this group, but was felt to be related to other occupational exposures (asbestos, rubber fumes, polycyclic aromatic hydrocarbons).
    11) Benzene exposure is associated with translocations between chromosomes 8 and 21, and hyperploidy of 8 and 21 in the circulating lymphocytes of workers exposed to benzene. These aberrations may be involved in benzene-induced leukemia (Smith et al, 1998).
    12) In a large cohort study in China, increasing risks for acute myeloblastic leukemia were linked with increasing levels of benzene exposure, particularly for exposure that has occurred within the 10 years before diagnosis. The risk for non-Hodgkin lymphoma increased with duration of exposure and was strongest among workers who had distant (greater than 10 years) of exposure (Hayes et al, 1997).
    13) An association was found between automobile density (highly correlated with gasoline exposure) and risk for acute myelogenous leukemia in Swedish children (Nordlinder & Jarvholm, 1997). However, No excess risk of acute myelogenous leukemia was found in a group of 19,000 former service station attendants exposed to an estimated average of 0.5 to 1 mg/m(3) benzene, with 20 years of follow-up. Risk for kidney cancer and nasal cancer were increased, however (Lynge et al, 1997).
    14) A mortality study that followed coke oven and coal workers for 20 years found no excess leukemias in a group with average exposure to 1.32 ppm benzene (Hurley et al, 1991). The prevailing point of view seems to be that excess risk of leukemia does not exist for exposures at or below 1 ppm.
    15) Some researchers believe that there is still some excess risk, even at 0.1 ppm; however, it is generally agreed that this low level of exposure is not achievable with available control technology. Industrial exposures to benzene have generally averaged less than 1 ppm for some time (Runion & Scott, 1985).
    16) Other epidemiological studies of exposed workers have also indicated involvement of benzene exposure in an increased risk of lymphomas and multiple myeloma (Aksoy et al, 1972; Decoufle, 1983).
    a) In a large study of 74,825 workers exposed to benzene and 35,805 controls, there were significant excess deaths from leukemia, malignant lymphoma and non-neoplastic blood diseases.
    b) With respect to incidence, significant excesses were seen for all lymphohematopoietic malignancies, malignant lymphoma, acute myelogenous leukemia, aplastic anemia and myelodysplastic syndrome (Yin et al, 1996).
    17) Increased deaths from nasal cancer were seen in groups of 4,215 English and 2,008 Florentine shoemakers, with most cases occurring in people with high exposure to leather dust. The Florence cohort had increased leukemia, especially in those with older exposures, when benzene levels were much higher than they are today (Fu et al, 1996).
    18) Chronic low-level benzene exposure in the range of 0.01 to 6.2 ppm was not associated with increased risk for leukemia, non-Hodgkin lymphoma or multiple myeloma in Canadian petroleum distribution workers. The power of this nested case-control study was limited in detecting an increased risk of less than 2-fold, however (Schnatter et al, 1996).
    19) In a meta-analysis of all published cohorts exposed to benzene through petroleum, consisting of more than 208,000 workers, no significant increases in leukemia specific to any cell type were found (Raabe & Wong, 1996). A meta-analysis of all published case-control studies published through mid-1995 found no increased risk for multiple myeloma in relation to benzene exposure (Bezabeh et al, 1996).
    20) A systematic review of the literature through October 2004 examined cohort studies, case-controlled studies, and population-based and nested case-controlled studies. There was a high and significant risk of acute myeloid leukemia with exposure to benzene with a positive dose response relationship across all study designs, especially in highly exposed workers in rubber, shoe and paint industries (Schnatter et al, 2005).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) NTP Toxicology and Carcinogenesis Study (US Dept Health & Human Services, 1986):
    a) CONCLUSIONS - Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene for male F344/N rats, for female F344/N rats, for male B6C3F1 mice, and for female B6C3F1 mice.
    1) In male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. For female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity.
    2) In male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, malignant lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), harderian gland adenomas, and squamous cell carcinomas of the preputial gland.
    3) In female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benign mixed tumors, carcinomas and carcinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcinomas.
    4) Dose-related lymphocytopenia was observed for male and female F344/N rats and male and female B6C3F1 mice.
    2) In a study sponsored by the National Toxicology Program, rats given benzene orally at doses of 50, 100 or 200 mg/kg, and mice administered 25, 50 or 100 mg/kg orally, developed tumors at 5 major sites (OSHA, 1987).
    B) LEUKEMIA
    1) Benzene is one of the few human carcinogens for which it has been difficult to demonstrate carcinogenicity in experimental animals. An animal model of acute myelogenous leukemia induced by benzene has not been developed (Bingham et al, 2001). Experimental animals have not been particularly sensitive to benzene-induced leukemias or other forms of cancers or to its effects on hematopoiesis (Ward, 1975; Cronkite, 1985).
    2) Very high levels of benzene (200 to 300 ppm) are necessary to suppress blood formation and to produce leukemia in mice (Cronkite, 1984; Ward, 1985). Female and obese animals retain benzene longer because of a higher body fat content, and are therefore more sensitive (Calabrese, 1985).
    3) In an Italian study, rats given 50 and 250 mg/kg of benzene for 52 weeks developed leukemias and other tumors (OSHA, 1987). Two of 40 mice inhaling 300 ppm benzene for their lifetime developed leukemia (OSHA, 1987).

Genotoxicity

    A) Micronuclei and DNA damage have been found in human lymphocyteas and in mice. Chromosomal abnormalities have been found in people exposed to benzene. In contrast to results in humans, such chromosomal aberrations have been transient in laboratory animals. Mutational studies have produced negative results.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor CBC with differential and platelet count, and a basic metabolic panel.
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Monitoring benzene in expired air and urine phenol levels may be useful for observing workers exposed to benzene, but is not helpful in the acute setting.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Monitor CBC with differential and platelet count.
    4.1.3) URINE
    A) OTHER
    1) Inoue et al (1986) found a good correlation between urine phenol levels and benzene concentrations in breathing zone air. Monitoring urine phenol levels is useful in monitoring inhalation exposure (Inoue et al, 1986).
    2) Some nonprescription medications containing phenol may give false positive results and/or increased urine phenols. Examples include Pepto Bismol(R) and Chloraseptic(R) (Baselt & Cravey, 1989).
    3) Urine phenol levels in unexposed individuals are less than 10 mg/L. Urine phenol levels after chronic exposure to airborne concentrations of 0.5 to 4 ppm are less than 30 mg/L. Urine phenol levels after exposure to 25 ppm average 200 mg/L (Baselt & Cravey, 1989).
    4) Measurement of phenolic derivatives in urine is most frequently used for biological monitoring, but is unsatisfactory for chronic low level benzene exposure. Analysis of urinary t,t-muconic acid appears to be a better indicator than phenol for assessment of exposure to low levels of benzene (Ghittori et al, 1993).
    5) Urinary levels of muconic and S-phenylmercapturic acids, sampled at the end of a work shift, were better indicators of exposure to benzene in automobile mechanics than phenol. Mean exposures were 2.6 mg/m(3) (Popp et al, 1994). The BEI is 25 mcg/g creatinine collected at the end of shift.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Obtain an ECG, and institute continuous cardiac monitoring. Cardiac dysrhythmias, including ventricular fibrillation, have been reported (Kaye, 1978; Nahum & Hoff, 1934).
    b) Quantification of trans,trans-muconic acid in 50 printing plant workers with low level benzene exposure and 38 matched controls revealed marked elevations in the printing plant workers (1.011 +/- 0.249 and 0.026 +/- 0.028 mg/g creatinine, respectively) (Joo et al, 2004).

Methods

    A) CHROMATOGRAPHY
    1) Benzene is often measured in biological samples by gas chromatography with headspace sampling or after solvent extraction (Baselt & Cravey, 1989).
    2) Direct analysis of benzene in expired air by gas chromatography or gas chromatography-mass spectrometry is less reliable than determination of benzene or its metabolites in blood or urine (Ong & Lee, 1994).
    3) Gas chromatography head-space analysis is the preferred method for determining benzene in blood or urine (Ong & Lee, 1994). The lower limit of detection is 0.64 nmol/L for benzene in blood and 0.51 nmol/L in urine (Kok & Ong, 1994).
    4) Trans,trans-muconic acid is a minor metabolite of benzene that can be detected by high-performance liquid chromatography with ultraviolet detection and can be used for biological monitoring of low-level exposure (Ong & Lee, 1994; Joo et al, 2004).
    5) Urinary S-phenylmercapturic acid can be analyzed only by gas chromatography- mass spectrometry; it is also a useful biomarker for benzene exposure (Ong & Lee, 1994).
    B) OTHER
    1) The ratio of inorganic to total sulfate in urine has been used to indicate occupational exposure.
    a) The normal ratio is 80:20 but may be as high as 92.5:7.5. When the inorganic is 70 to 80 percent, exposure is mild; 60 to 70 percent, it is dangerous; and 0 to 60 percent, it is very dangerous.
    b) More specific blood, urine and breath measurements are available. Exposure to benzene results in an increase in the urinary output of phenol sulfate (greater than 20 mg/day is abnormal) and a decrease in inorganic sulfate.
    2) Benzene can be measured in expired air. It may be useful to use the nitro blue tetrazoli reduction test to monitor benzene's toxic effect on neutrophils. Many use leukocyte acid phosphate in evaluating exposure in workers (Moszczynski & Lisiewicz, 1983; Moszczynski & Lisiewicz, 1983). Expired-air analysis can be used for confirmation of exposure in the first 16 to 24 hours after exposure.
    3) Proteomic analysis by matrix-assisted laser desorption ionizing/time of flight (MALDI-TOF) mass spectrometry with Western blot confirmation described significantly different protein patterns in a group of 50 printing plant workers with low level benzene exposure and 38 matched controls. The benzene exposed group demonstrated up-regulation production of T-cell receptor beta (TCRB) chain, FK506-binding protein, and matrix metalloproteinase-13. TCRB was up-regulated five times over control values. The authors concluded that TCRB protein can be a new marker of benzene exposure (Joo et al, 2004) .

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) All symptomatic patients and all those with significant exposures should be admitted for monitoring and laboratory evaluation.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe signs and symptoms or large exposures.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with symptoms or a history of more than a sip ingestion should be evaluated in a healthcare facility.

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor CBC with differential and platelet count, and a basic metabolic panel.
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Monitoring benzene in expired air and urine phenol levels may be useful for observing workers exposed to benzene, but is not helpful in the acute setting.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital GI decontamination is not recommended because of the risk of abrupt onset decreased mental status or seizures and aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Activated charcoal has been demonstrated to decrease absorption of benzene in animals(Laass, 1980), however the risk of aspiration probably outweighs potential benefits in most circumstances. It can be considered in large, recent ingestions if the patient is alert or the airway is protected.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC ASPIRATION
    1) Consider insertion of a nasogastric tube to aspirate gastric contents if it can be performed soon (within an hour) after a very large ingestion. Protection of the airway should be ensured as there is a high risk of CNS depression and aspiration.
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no specific antidote for benzene exposure. The mainstay of therapy is aggressive supportive care.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor CBC with differential and platelet count and basic metabolic panel.
    3) Obtain an ECG, and institute continuous cardiac monitoring.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    4) PROCAINAMIDE
    a) PROCAINAMIDE/INDICATIONS
    1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010; Vanden Hoek,TL,et al).
    E) CONTRAINDICATED TREATMENT
    1) Avoid epinephrine because of the possibility of myocardial sensitization.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) PULMONARY ABSORPTION
    1) Toxic effects of benzene are produced chiefly by inhalation of the vapor.
    B) SUPPORT
    1) Administer supplemental oxygen and assist ventilation as required. Monitor closely for respiratory distress or cough, which may be secondary to respiratory tract irritation, bronchitis, or pneumonitis. Treat bronchospasm with inhaled beta-2 agonist and oral or parenteral corticosteroids.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Summary

    A) The estimated human oral lethal dose is 50 to 500 mg/kg. The odor threshold is 1.5 to 4.7 parts per million (ppm); CNS effects, including drowsiness, dizziness, headache, vertigo, tremor, delirium, and coma, may occur following inhalation at levels of 300 to 3000 ppm. Inhalation of 20,000 ppm is rapidly fatal. For occupational exposure, the TLV-TWA (threshold limit value time weighted average) is 0.5 ppm and the TLV-STEL (short term exposure limit) is 2.5 ppm; 500 ppm is IDLH (immediately dangerous to life and health).

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Benzene was formerly used in the treatment of leukemia in doses of 3 to 5 grams/day. Chronic therapy led to blood dyscrasias and death (NTP, 1986).

Minimum Lethal Exposure

    A) Oral doses from 9 to 30 grams have proven fatal (HSDB , 2001).
    B) It is estimated that the probable human oral lethal dose is 50 to 500 mg/kg (HSDB , 2001).
    C) It has been estimated that 10 mL benzene is a lethal dose for humans (ATSDR, 1993).
    D) Inhalation of approximately 20,000 ppm (2 percent in air) was fatal in 5 to 10 minutes (Wilbur et al, 2008; HSDB , 2001; ATSDR, 1993; Paustenbach et al, 1993) .
    E) Exposure to benzene is lethal in humans by means of asphyxiation, respiratory arrest, central nervous system depression or cardiac collapse (ATSDR, 1993).

Maximum Tolerated Exposure

    A) The maximum tolerated human exposure to this agent has not been delineated.
    B) CNS effects, including drowsiness, dizziness, headache, vertigo, tremor, delirium, and coma, may occur following inhalation at levels of 300 to 3000 ppm (Wilbur et al, 2008).
    C) Listlessness and confusion were reported following inhalation of approximately 4,700 ppm for 30 minutes (Paustenbach et al, 1993).
    D) One study concluded that a TWA exposure of 3.2 mg/m(3) (1 ppm) for a 40 year working career does not show any statistical increase of leukemia. However, because benzene is a carcinogen, exposure should be limited to the lowest level technically feasible (WHO, 1993).
    E) A study of workers in a Texas refinery indicated that very low levels of benzene exposure (0.5 ppm for 1 to 21 years) resulted in no hematological changes to the workers (ATSDR, 1993).
    F) Two additional studies of workers exposed to low levels of benzene showed that the workers experienced slight decreases in red blood cell counts (ATSDR, 1993).
    G) Headache, lassitude, and fatigue occurred following inhalation of 50 to 150 ppm for 5 hours (Paustenbach et al, 1993).

Workplace Standards

    A) ACGIH TLV Values for CAS71-43-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Benzene
    a) TLV:
    1) TLV-TWA: 0.5 ppm
    2) TLV-STEL: 2.5 ppm
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A1
    2) Codes: BEI, Skin
    3) Definitions:
    a) A1: Confirmed Human Carcinogen: The agent is carcinogenic to humans based on the weight of evidence from epidemiologic studies.
    b) BEI: The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational.
    c) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): Leukemia
    d) Molecular Weight: 78.11
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS71-43-2 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Benzene
    2) REL:
    a) TWA: 0.1 ppm
    b) STEL: 1 ppm
    c) Ceiling:
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix A
    3) IDLH:
    a) IDLH: 500 ppm
    b) Note(s): Ca
    1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

    C) Carcinogenicity Ratings for CAS71-43-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A1 ; Listed as: Benzene
    a) A1 :Confirmed Human Carcinogen: The agent is carcinogenic to humans based on the weight of evidence from epidemiologic studies.
    2) EPA (U.S. Environmental Protection Agency, 2011): A ; Listed as: Benzene
    a) A : Human Carcinogen.
    3) EPA (U.S. Environmental Protection Agency, 2011): A ; Listed as: Benzene
    a) A : Human Carcinogen.
    4) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: Benzene
    a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    5) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Benzene
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    6) MAK (DFG, 2002): Category 1 ; Listed as: Benzene
    a) Category 1 : Substances that cause cancer in man and can be assumed to make a significant contribution to cancer risk. Epidemiological studies provide adequate evidence of a positive correlation between the exposure of humans and the occurence of cancer. Limited epidemiological data can be substantiated by evidence that the substance causes cancer by a mode of action that is relevant to man.
    7) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS71-43-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Benzene; see 29 CFR 1910.1028; see Table Z-2 for the limits applicable in the operations or sectors excluded in 1910.1028
    2) Table Z-1 for Benzene; see 29 CFR 1910.1028; see Table Z-2 for the limits applicable in the operations or sectors excluded in 1910.1028:
    a) 8-hour TWA:
    1) ppm:
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3:
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s):
    a) (d): The final benzene standard in 1910.1028 applies to all occupational exposures to benzene except in some circumstances the distribution and sale of fuels, sealed containers and pipelines, coke production, oil and gas drilling and production, natural gas processing, and the percentage exclusion for liquid mixtures; for the excepted subsegments, the benzene limits in Table Z-2 apply. See 1910.1028 for specific circumstances.
    3) Table Z-2 for Benzene (Z37.40-1969):
    a) 8-hour TWA:10 ppm
    b) Acceptable Ceiling Concentration: 25 ppm
    c) Acceptable Maximum Peak above the Ceiling Concentration for an 8-hour Shift:
    1) Concentration: 50 ppm
    2) Maximum Duration: 10 minutes
    d) Notation(s):
    1) (a): This standard applies to the industry segments exempt from the 1 ppm 8-hour TWA and 5 ppm STEL of the benzene standard at 29 CFR 1910.1028.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Clayton & Clayton, Vol. 2B, 1994; Lewis, 2000; RTECS, 2001; WHO, 1993
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 340 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 4700 mg/kg
    3) LD50- (SKIN)MOUSE:
    a) 48 mg/kg
    4) LD50- (SUBCUTANEOUS)MOUSE:
    a) 0.468 g/kg (Clayton & Clayton, 1994)
    5) LD50- (INTRAPERITONEAL)RAT:
    a) 2890 mcg/kg (Lewis, 2000)
    b) 1100 mcg/kg
    6) LD50- (ORAL)RAT:
    a) <1.0-5 g/kg (Clayton & Clayton, 1994)
    b) 3.4 g/kg (Clayton & Clayton, 1994)
    c) 5.6 g/kg (Clayton & Clayton, 1994)
    d) 3306 mg/kg (Lewis, 2000)
    e) 14 days old, 3000 mg/kg (WHO, 1993)
    f) young adult, 3300 mg/kg (WHO, 1993)
    g) old adult, 4900 mg/kg (WHO, 1993)
    h) 8100 mg/kg (WHO, 1993)
    i) 930 mg/kg -- tremors; affected seizure threshold; convulsions
    7) TCLo- (INHALATION)HUMAN:
    a) 100 ppm -- depressed activity; nausea or vomiting; dermatitis
    b) 10 ppm for 8H/10Y - intermittent -- carcinogenic; leukemia
    c) 150 ppm for 1 Y-intermittent -- blood changes and body temperature increase
    d) 200 mg/m(3) for 78W - intermittent -- carcinogenic; leukemia; thrombocytopenia
    8) TCLo- (INHALATION)MOUSE:
    a) Female, 500 ppm for 7H at 6-15D of pregnancy -- fetotoxicity (except death); musculoskeletal system effects
    b) Female, 500 mg/m(3) for 12H at 6-15D of pregnancy -- fetotoxicity (except death); musculoskeletal system effects
    c) Female, 20 ppm for 6H at 6-15D of pregnancy -- affected blood and lymphatic system
    d) Female, 5 ppm at 6-15D of pregnancy -- cytological changes in embryo; blood and lymphatic system changes
    e) 300 ppm for 6H/16W - intermittent -- tumorigenic agent; lymphomas including Hodgkin's disease
    f) 300 ppm for 6H/13W - intermittent -- blood changes and changes in testicular weight
    g) 300 ppm for 6H/16W - intermittent -- changes in blood; death
    h) 25 ppm for 6H/5D - intermittent -- changes in spleen weight and WBC count
    i) 10 ppm for 6H/26W - intermittent -- changes in spleen, cell count, and RBC count
    j) 48 ppm for 6H/14D - intermittent -- leukopenia; changes in spleen weight; humoral immune responses decrease
    k) 10 ppm for 6H/10W - intermittent -- changes in spleen weight and spleen
    l) 100 ppm for 6H/72W - intermittent -- normocytic anemia; leukopenia; death
    9) TCLo- (ORAL)MOUSE:
    a) 211 ppm for 6H/7D - intermittent -- leukopenia; changes in spleen weight
    10) TCLo- (INHALATION)RAT:
    a) 1200 ppm for 6H/10W - intermittent -- equivocal tumorigenic agent; sense organ tumors
    b) 300 ppm for 6H/13W - intermittent -- leukopenia
    c) 1000 ppm for 7H/28W - intermittent -- unspecified changes in cell count
    d) 500 ppm for 6H/3W - intermittent -- red blood cells pigmented or nucleated; bone marrow changes; WBC changes
    e) 300 ppm for 6H/99W - intermittent -- leukopenia; bone marrow changes; death
    f) 23 mg/m(3) for 4H/8D - intermittent -- changes in liver and pituitary weight
    g) Female, 56,600 mcg/m(3) for 24H at 1-22D of pregnancy -- biochemical and metabolic effects on newborn
    h) Female, 670 mg/m(3) for 24H At 15D prior to mating and 1-22D of pregnancy -- affected female fertility index
    i) Female, 50 ppm for 24H at 7-14D of pregnancy -- extra embryonic structures; fetotoxicity (except death)
    j) Female, 150 ppm for 24H at 7-14D of pregnancy -- effects on fertility; musculoskeletal system abnormalities

Pharmacology Toxicology

Toxicologic Mechanism

    A) Benzene, an aromatic hydrocarbon, is rapidly absorbed after ingestion and inhalation, with most being converted by the liver into water-soluble metabolites that are conjugated with glycine, glucuronic acid or sulfuric acid in the kidney. The hematopoietic effects are due to the metabolites.
    B) The mechanism whereby benzene causes death in acute exposures may be either through its anesthetic properties with resultant respiratory arrest, or through the production of fatal arrhythmia in an adrenalin primed myocardium (Avis & Hutton, 1993).
    C) Exposure to benzene may also stimulate cytochrome P450, which is responsible for the oxygenation of benzene and has a propensity to generate oxygen radicals. These radicals are a chief cause of benzene toxicity (Yardley-Jones et al, 1991).
    D) The mechanism(s) by which benzene can induce leukemia and perhaps other cancers is not known, but may be related to its ability to cause chromosomal aberrations in blood-forming cells. Myelogenous cancer cells often seem to be of common origin, with very high frequencies of abnormal chromosomes (Forni, 1971).
    E) Certain benzene metabolites (1,4-benzoquinone and trans, trans-muconaldehyde) were potent inhibitors of human topoisomerase II in vitro, and other benzene metabolites developed inhibitory activity after activation by peroxidase. Because other topoisomerase II inhibitors are known leukemogens, this finding for benzene metabolites may be relevant to its mechanism of leukemogenesis (Frantz et al, 1996).
    1) Benzene or its metabolites were found to inhibit topoisomerase activity in a leukemia cell line derived from human bone marrow as well as in vivo in the bone marrow of mice treated with benzene (Eastmond et al, 2001).

Physicochemical

Physical Characteristics

    A) Benzene is a colorless, watery liquid with a gasoline-like odor (CHRIS , 2001).
    B) Benzene is a liquid at 15 degrees C and 1 atm (CHRIS , 2001).
    C) Benzene is a clear, colorless liquid (Budavari, 1996).
    D) Benzene is a colorless to light-yellow liquid. Below 42 degrees F, it is a solid (HSDB , 2001).
    E) The taste threshold of benzene in water is 0.5-4.5 mg/L (HSDB , 2001)

Molecular Weight

    A) 78.1

Other

    A) ODOR THRESHOLD
    1) 4.68 ppm (CHRIS , 2001)
    2) 1.5 - 4.7 ppm (ATSDR, 1993)
    3) 2.0 mg/L (in water) (ATSDR, 1993)
    4) 4.9 ppm (mg/m(3)) (Sittig, 1991)
    5) 12 ppm (ACGIH, 1991)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 49 CFR 172.101: Department of Transportation - Table of Hazardous Materials. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 11, 2005.
    5) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    6) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    9) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    10) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    11) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    12) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    13) ACGIH: Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th ed, Am Conference of Govt Ind Hyg, Inc, Cincinnati, OH, 1991.
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    24) Au WW, Ramanujam VMS, & Ward JB Jr: Chromosome aberrations in lymphocytes of mice after sub-acute low-level inhalation exposure to benzene. Mutat Res 1991; 260:219-224.
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