Everything You Need To Know About Benzene

What is benzene? Benzene is a colorless liquid with a sweet odor. It evaporates into the air very quickly and dissolves slightly in water. It is highly flammable and is formed from both natural processes and human activities.

Bensene is also a toxic, volatile liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide.

Benzene is widely used in the United States; it ranks in the top 20 chemicals for production volume. Some industries use benzene to make other chemicals which are used to make plastics, resins, and nylon and synthetic fibers. Benzene is also used to make some types of rubbers, lubricants, dyes, detergents, drugs, and pesticides. Natural sources of benzene include volcanoes and forest fires. Benzene is also a natural part of crude oil, gasoline, and cigarette smoke. Benzene is also known as: (6)Annulene, AI3-00808, Benceno [Spanish], Benzeen [Dutch], Benzen [Polish], Benzene, Benzin, Benzin (Obs.), Benzine, Benzine (Obs.), Benzol, Benzol 90, Benzole, Benzolene, Benzolo [Italian], Bicarburet of hydrogen, CCRIS 70, Carbon oil, Caswell No. 077, Coal naphtha, Cyclohexatriene, EINECS 200-753-7, EPA Pesticide Chemical Code 008801, Fenzen [Czech], HSDB 35, Mineral naphtha, Motor benzol, NCI-C55276, NSC 67315, Nitration benzene, Phene, Phenyl hydride, Polystream, Pyrobenzol, Pyrobenzole, RCRA waste number U019, UN 1114, Systematic Names: Benzene, Benzene, pure, Superlist Names: Benzene, Benzene (including benzene from gasoline), Benzene [UN1114] [Flammable liquid], Benzol diluent, RCRA waste no. U109, UN1114

What happens to benzene when it enters the environment? Industrial processes are the main source of benzene in the environment. Benzene can pass into the air from water and soil. It reacts with other chemicals in the air and breaks down within a few days. Benzene in the air can attach to rain or snow and be carried back down to the ground. It breaks down more slowly in water and soil, and can pass through the soil into underground water. Benzene does not build up in plants or animals.

How might I be exposed to benzene? Outdoor air contains low levels of benzene from tobacco smoke, automobile service stations, exhaust from motor vehicles, and industrial emissions. Vapors (or gases) from products that contain benzene, such as glues, paints, furniture wax, and detergents, can also be a source of exposure. Air around hazardous waste sites or gas stations will contain higher levels of benzene. Working in industries that make or use benzene.

Percent Benzene Contained in Specific Brands with category, and form of Products: Champion Sprayon Flush Off Degreaser -Auto products -aerosol <1%, Parks Adhesive Remover-09/04/1998 Hobby/Craft liquid, Glidden Ultra Hide Alkyd Semi Gloss Interior Deep Tint Base- Home maintenance- liquid- 0.1-1.0%, Glidden Ultra Hide Alkyd Semi Gloss Interior Intermediate Tint Base -Home maintenance -liquid -0.1-1.0%

Benzene was used in the past as a solvent in inks, rubber, lacquers, and paint removers. Today, it is used mainly in closed processes to synthesize organic chemicals. Gasoline in some countries contains a high concentration of benzene (as high as 30%); the U.S. average is 1-3%. Workers who remove or clean underground storage tanks may be exposed to significant levels. Gasoline in North America now contains about 1% benzene.

Industrial Processes with risk of exposure to Benzene: Burning Synthetic Polymers, Firefighting, Metal Preparation and Pouring, Petroleum Refining, Working with Glues and Adhesives

Activities with risk of exposure of Benzene: Preparing, stuffing, and mounting the skins of animals (taxidermy), Smoking cigarettes

How can benzene affect my health? Breathing very high levels of benzene can result in death, while high levels can cause drowsiness, dizziness, rapid heart rate, headaches, tremors, confusion, and unconsciousness. Eating or drinking foods containing high levels of benzene can cause vomiting, irritation of the stomach, dizziness, sleepiness, convulsions, rapid heart rate, and death.

The major effect of benzene from long-term exposure is on the blood. Benzene causes harmful effects on the bone marrow and can cause a decrease in red blood cells leading to anemia. It can also cause excessive bleeding and can affect the immune system, increasing the chance for infection.

Diseases associated with exposure to Benzene: Aplastic anemia, Encephalopathy, chronic solvent Erythroleukemia, Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, acute toxic solvent effects

Some women who breathed high levels of benzene for many months had irregular menstrual periods and a decrease in the size of their ovaries. It is not known whether benzene will affect fertility in men.

How likely is benzene to cause cancer? Long-term exposure to high levels of benzene in the air can cause leukemia, particularly acute myelogenous leukemia, often referred to as AML. This is a cancer of the blood-forming organs. The Department of Health and Human Services (DHHS) has determined that benzene is a known carcinogen. The International Agency for Research on Cancer (IARC) and the EPA have determined that benzene is carcinogenic to humans.

How can benzene affect children? Children can be affected by benzene exposure in the same ways as adults. It is not known if children are more susceptible to benzene poisoning than adults.

Benzene can pass from the mother's blood to a fetus. Animal studies have shown low birth weights, delayed bone formation, and bone marrow damage when pregnant animals breathed benzene.

How can families reduce the risks of exposure to benzene? Benzene exposure can be reduced by limiting contact with gasoline and cigarette smoke. Families are encouraged not to smoke in their house, in enclosed environments, or near their children.

Is there a medical test to show whether I've been exposed to benzene? Several tests can show if you have been exposed to benzene. There is a test for measuring benzene in the breath; this test must be done shortly after exposure. Benzene can also be measured in the blood; however, since benzene disappears rapidly from the blood, this test is only useful for recent exposures.

In the body, benzene is converted to products called metabolites. Certain metabolites can be measured in the urine. The metabolite S-phenylmercapturic acid in urine is a sensitive indicator of benzene exposure. However, this test must be done shortly after exposure and is not a reliable indicator of how much benzene you have been exposed to, since the metabolites may be present in urine from other sources.

Has the federal government made recommendations to protect human health? The EPA has set the maximum permissible level of benzene in drinking water at 5 parts benzene per billion parts of water (5 ppb).

The Occupational Safety and Health Administration (OSHA) has set limits of 1 part benzene per million parts of workplace air (1 ppm) for 8 hour shifts and 40 hour work weeks.

References Agency for Toxic Substances and Disease Registry (ATSDR). 1997. Managing Hazardous Materials Incidents. Volume III – Medical Management Guidelines for Acute Chemical Exposures: Benzene. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.

Agency for Toxic Substances and Disease Registry (ATSDR). 2005. Toxicological Profile for benzene. (Draft for Public Comment). Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.

Where can I get more information? ATSDR can tell you where to find occupational and environmental health clinics. Their specialists can recognize, evaluate, and treat illnesses resulting from exposure to hazardous substances. You can also contact your community or state health or environmental quality department if you have any more questions or concerns.

For more information, contact:

Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road NE, Mailstop F-32 Atlanta, GA 30333 Phone: 1-888-42-ATSDR (1-888-422-8737) FAX: (770)-488-4178 Email: ATSDRIC@cdc.gov

Benzene MSDS Information:

Contents:

Human Health Effects
Emergency Medical Treatment
Animal Toxicity Studies
Metabolism/Pharmacokinetics
Pharmacology
Environmental Fate & Exposure
Environmental Standards & Regulations
Chemical/Physical Properties
Chemical Safety & Handling
Occupational Exposure Standards
Manufacturing/Use Information
Laboratory Methods
Special References
Synonyms and Identifiers

BENZENE

CASRN: 71-43-2
Human Health Effects:

Toxicity Summary:

IDENTIFICATION: Benzene is an aromatic hydrocarbon used as a solvent. It is a clear liquid with a sweet odor. Origin of the substance: Benzene occurs naturally but is primarily produced from petroleum products. Uses: 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. HUMAN EXPOSURE: 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 hematotoxicity, including aplastic anemia, pancytopenia, or any combination of anemia, leukopenia, and thrombocytopenia Chronic benzene exposure is associated with an increased risk of leukemia. 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 hematological effects include anemia, thrombocytopenia, leukopenia, pancytopenia, chromosomal abberations, and leukemia. Dermal exposure may cause skin irritation. 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. In the United States, smoking accounts for approximately half of the total population exposure to benzene. In countries where benzene is used as a household cleaner, accidental or suicidal ingestion may occur. 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. 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 and adhesives by shoemakers led to a high degree of exposure in these industries. Routes of entry Oral: Acute oral exposure is uncommon and usually results from accidental ingestion or attempted suicide. Benzene is a contaminant in drinking water. Inhalation: Inhalation is the primary route of exposure for benzene, both in the occupational and environmental setting. The relatively high vapor pressure of benzene creates a significant hazard when adequate workplace safeguards are not in place. Dermal: Dermal exposure may occur in the occupational setting, although it is quantitatively less important than inhalation exposure. Eye: Ocular exposure may occur through splashing or high vapor concentrations. 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. In rodents the percentage of retained benzene decreased as the inhaled vapor concentration increased from 10 to 1000 ppm. In vitro dermal absorption in humans is 0.2% over a period of 13.5 hours. Distribution by route of exposure: 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. Exposure to 25 ppm of benzene for two hours produced an average maximum blood benzene concentration of 0.2 mg/L. 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. 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. 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. 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. 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. 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. In another human study, 30% of absorbed dermally applied benzene was excreted as phenol in the urine. Mode of action: Acute benzene exposure produces central nervous system excitation and depression. In chronic exposures, benzene metabolites are considered the toxic agents, not the parent compound. The relative contribution of different benzene metabolic pathways may be dose related, with more toxic agents produced by high affinity low capacity pathways. Chronic benzene exposure can cause bone marrow stem cell depression, apparently through a cytotoxic effect on all lineages of hematopoietic 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. Hydroquinone and phenol are known hematotoxins. Toxicity: Human data: Adults: Inhalation exposure at 20,000 ppm for five to ten minutes may be fatal. Exposure to 150 to 650 ppm for 4 months to 15 years caused pancytopenia. 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. Carcinogenicity: In epidemiologic studies, chronic exposure to benzene is associated with the development of acute myelogenous leukemia and its variants including erythroleukemia. Other forms of leukemia including acute lymphoblastic anemia, acute monocytic leukemia, and preleukemia have also been reported following benzene exposure. Other hematopoietic malignancies have been described in association with benzene exposure including malignant lymphoma, myeloid metaplasia, and multiple myeloma. The relative risk for leukemia was 6.97 times the risk in the unexposed group. 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. 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. In a study of 1165 workers in a rubber hydrochloride factory there were 9 deaths from leukemia. 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. Teratogenicity: Benzene crosses the placenta and is present in cord blood in concentrations equal to or greater than maternal blood. 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. Mutagenicity: In studies of occupational exposure, benzene was found to cause chromosome changes at concentrations that induced blood dyscrasias. 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 hematological effects. 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. Interactions: Ethanol can increase the extent of hematotoxicity from benzene exposure. Previous administration of phenobarbital may decrease benzene hematotoxicity. Toluene reduces the metabolizm of benzene and reverses the benzene induced decrease in incorporation of iron into red blood cells. Hepatitis B may also increase the incidence of hematopoietic effects from benzene exposure. 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. 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. Death may be due to CNS depression, asphyxiation, or respiratory or circulatory arrest. In fatal cases autopsy has revealed haemolysis, cyanosis, and multiple organ hemorrhage. In chronic benzene exposures, patients developing minor hematologic 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. Chronic ingestion of benzene for therapeutic purposes reportedly led to bladder irritability and impotence in some patients. 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. Decreases in cellular immunity have been documented through leucopenia. ANIMAL STUDIES: In animal models, benzene is well absorbed by the oral route, ranging from over 90% in rabbits to over 97% in rats and mice. 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. Metabolism: 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. 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. 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. 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. 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. Exposure in utero to 20 ppm of benzene for 6 hr/day on days 6 to 15 of gestation in mice resulted in hematopoietic abnormalities. Exposures in rats to less than 10 ppm of benzene during pregnancy did not cause adverse fetal changes. 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. One report of sudden death after running and acute benzene exposure was felt to be due to benzene induced myocardial sensitivity to endogenous catecholamines. Immunological: 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 Eschericha 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. 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. Animal experiments exposing pregnant mice, rats, and rabbits demonstrated fetotoxicity associated with maternal toxicity, specifically fetal skeletal variants and reduced fetal weight.
[International Programme on Chemical Safety; Poisons Information Monograph: Benzene (PIM 063) (1999) Available from http://www.inchem.org/pages/pims.html as of October 24, 2005. ]**PEER REVIEWED**

Evidence for Carcinogenicity:

Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient; Overall summary evaluation of carcinogenic risk to humans is group 1: The chemical is carcinogenic to humans. /From table/
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. S7 120 (1987)]**PEER REVIEWED**

A1; Confirmed human carcinogen.
[ American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinatti, OH, 2005, p. 13]**QC REVIEWED**

WEIGHT-OF-EVIDENCE CHARACTERIZATION: Benzene is classified as a "known" human carcinogen (Category A) under the Risk Assessment Guidelines of 1986. Under the proposed revised Carcinogen Risk Asessment Guidelines (USEPA, 1996), benzene is characterized as a known human carcinogen for all routes of exposure based upon convincing human evidence as well as supporting evidence from animal studies. Epidemiologic studies and case studies provide clear evidence of a causal association between exposure to benzene and acute nonlymphocytic leukemia and also suggest evidence for chronic nonlymphocytic leukemia and chronic lymphocytic leukemia. Other neoplastic conditions that are associated with an increased risk in humans are hematologic neoplasms, blood disorders such as preleukemia and aplastic anemia, Hodgkin's lymphoma, and myelodysplastic syndrome. These human data are supported by animal studies. The experimental animal data add to the argument that exposure to benzene increases the risk of cancer in multiple species at multiple organ sites (hematopoietic, oral and nasal, liver, forestomach, preputial gland, lung, ovary, and mammary gland). It is likely that these responses are due to interactions of the metabolites of benzene with DNA ... Recent evidence supports the viewpoint that there are likely multiple mechanistic pathways leading ... to leukemogenesis from exposure to benzene. HUMAN CARCINOGENICITY DATA: Benzene is a known human carcinogen based upon evidence presented in numerous occupational epidemiological studies. Significantly increased risks of leukemia, chiefly acute myelogenous leukemia, have been reported in benzene-exposed workers in the chemical industry, shoemaking and oil refineries. ANIMAL CARCINOGENICITY DATA:... many experimental animal studies, both inhalation and oral, also support the evidence that exposure to benzene increases the risk of cancer in multiple organ systems, including the hematopoietic system, oral and nasal cavities, liver, forestomach, preputial gland, lung, ovary, and mammary gland ....
[U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Benzene (71-43-2). Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000]**PEER REVIEWED**

Human Toxicity Excerpts:

Benzene is irritant to skin, & by defatting the keratin layer may cause erythema, vesiculation, & dry & scaly dermatitis.
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1308]**PEER REVIEWED**

AFTER A SHORT EXPOSURE TO A LARGE AMT OF BENZENE, BY INGESTION OR BY BREATHING CONCENTRATED VAPORS, THE MAJOR TOXIC EFFECT IS ON THE CNS. SYMPTOMS FROM MILD EXPOSURE INCL DIZZINESS, WEAKNESS, EUPHORIA, HEADACHE, NAUSEA, VOMITING, TIGHTNESS IN CHEST, & STAGGERING. IF EXPOSURE IS MORE SEVERE, SYMPTOMS PROGRESS TO BLURRED VISION, TREMORS, SHALLOW & RAPID RESP, VENTRICULAR IRREGULARITIES, PARALYSIS, & UNCONSCIOUSNESS.
[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1683]**PEER REVIEWED**

Long-term exposure to benzene usually is due to the inhalation of vapor or to contact with the skin. Signs and symptoms of long-term exposure to benzene incl effects on the CNS & the GI tract (headache, loss of appetite, drowsiness, nervousness, & pallor), but the major manifestation of toxicity is aplastic anemia. Bone marrow cells in early stages of development are most the sensitive ... & arrest of maturation leads to gradual depletion of circulating cells.
[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1683]**PEER REVIEWED**

BENZENE (BENZOL) ... HAS SPECIFIC TOXIC EFFECT ON BLOOD FORMATION, CAUSING APLASTIC ANEMIA & TENDENCY TO HEMORRHAGE. OCCASIONALLY HEMORRHAGES IN RETINA & IN CONJUNCTIVA ARE FOUND IN SYSTEMIC POISONING BY BENZENE. IN RARE INSTANCES NEURORETINAL EDEMA & PAPILLEDEMA HAVE BEEN DESCRIBED ACCOMPANYING RETINAL HEMORRHAGES. IT HAS NOT BEEN ESTABLISHED THAT BENZENE CAN INDUCE RETROBULBAR NEURITIS OR OPTIC NEURITIS ...
[Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 140]**PEER REVIEWED**

PATHOLOGICAL FINDINGS FROM ... INHALATION INCL ACUTE GRANULAR TRACHEITIS, LARYNGITIS & BRONCHITIS, MASSIVE HEMORRHAGE OF LUNG, CONGESTIVE GASTRITIS, INFARCT OF SPLEEN, ACUTE CONGESTION OF KIDNEYS, & MARKED CEREBRAL EDEMA.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 906]**PEER REVIEWED**

Many acute deaths /from benzene exposure at high concn have been/ ... due to ventricular fibrillation ... /caused by exertion/ & release of epinephrine. This was probably the mechanism involved in the death of workers in tank cars which had contained benzene. Frequently, the man who went into the tank car to carry out an unconscious worker died during the effort of lifting the unconscious man up the ladder.
[Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972., p. 124]**PEER REVIEWED**

... A large number of workers exposed to but not seriously intoxicated by benzene /were studied & results showed/ that serum complement levels, IgG, & IgA, were depressed but that IgM levels did not drop & were in fact slightly higher (Lange et al 1973; Smolik et al 1973). ... These /& other/ observations, taken together with well-known ability of benzene to depress leukocytes ... may explain why benzene-intoxicated individuals readily succumb to infection & why terminal event in severe ... toxicity is often an acute, overwhelming infection.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 116 (1982)]**PEER REVIEWED**

IN EXPT IN VITRO, BENZENE DID NOT CHANGE THE NUMBER OF SISTER-CHROMATID EXCHANGES OR THE NUMBER OF CHROMOSOMAL ABERRATIONS IN HUMAN LYMPHOCYTES.
[GERNER-SMIDT P, FRIEDRICH U; MUTAT RES 58 (2-3): 313-6 (1978)]**PEER REVIEWED**

THE MUTAGENIC ACTIVITY UPON HUMAN LYMPHOCYTES WAS STUDIED AFTER ITS ADDN TO CULTURE ON THE 28TH HR OF CULTIVATION (G1-S PERIODS). CONCN OF 1, 10, 25, 50, 100, & 250 UG/ML WERE STUDIED. BENZENE IS A WEAK MUTAGEN. IT CAUSED ELONGATION OF CENTROMERE PORTIONS OF CHROMOSOMES & CHROMOSOMAL ABERRATIONS WERE MAINLY OF SINGLE & PAIRED FRAGMENT TYPE. MUTAGENIC ACTIVITY WAS ABOUT THE SAME IN THE G0 & G1-S PERIODS.
[MNATSAKANOV ST, POGOSYAN AS; BIOL ZH ARM 26 (12): 38-43 (1973)]**PEER REVIEWED**

A major concern is the relationship between long-term exposure to benzene & leukemia. Epidemiological studies have been conducted on workers in the tire industry & in shoe factories, where benzene was used extensively. Among workers who died from exposure to benzene, death was caused by either leukemia or aplastic anemia, in approx equal proportions.
[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1683]**PEER REVIEWED**

CHRONIC BENZENE TOXICITY IS EXPRESSED AS BONE MARROW DEPRESSION RESULTING IN LEUCOPENIA, ANEMIA, OR THROMBOCYTOPENIA (LEUKEMOGENIC ACTION). WITH CONTINUED EXPOSURE THE DISEASE PROGRESSES TO PANCYTOPENIA RESULTING FROM BONE MARROW APLASIA. EVIDENCE HAS ACCUM IMPLICATING BENZENE IN THE ETIOLOGY OF LEUKEMIAS IN WORKERS IN INDUSTRIES WHERE BENZENE WAS HEAVILY USED. IT HAS BEEN SUGGESTED THAT LEUKEMIA IS AS FREQUENT A CAUSE OF DEATH FROM CHRONIC BENZENE EXPOSURE AS IS APLASTIC ANEMIA.
[SNYDER R ET AL; LIFE SCIENCES 21 (12): 1709-22 (1977)]**PEER REVIEWED**

MANY CASES OF ACUTE LEUKEMIA DEVELOPING AS TERMINAL STAGE OF APLASTIC ANEMIA RESULTING FROM EXPOSURE TO BENZENE MAY HAVE BEEN MISSED BECAUSE BONE MARROW PUNCTURE WAS NOT PERFORMED. BENZENE LEUKEMIA IS ACUTE STEM CELL OR MYELOBLASTIC LEUKEMIA, SOMETIMES ALEUKEMIA. THERE MAY BE A LATENT PERIOD EXTENDING OVER SEVERAL YEARS BETWEEN CESSATION OF EXPOSURE WITH MORE OR LESS PRONOUNCED ANEMIA, & THE ONSET OF LEUKEMIA.
[VIGLIANI EC, FORNI A; ENVIRON RES 11 (1): 122-7 (1976)]**PEER REVIEWED**

A dose-related increase in the number of cells with chromosomal aberrations occurred in human lymphocyte cultures treated with 4X10-5 M and 3.0X10-3 M benzene for 53 hr prior to metaphase analysis. Cells in late G2 stage were the most susceptible to the effect of benzene.
[Morimoto K; Japan J Ind Health 8: 23-5 (1976)]**PEER REVIEWED**

Epidemiological studies (exposure to high concn is associated with hematotoxicity and acute myelocytic leukemia in humans ...)
[European Chemical Industry, Ecology and Toxicology Center p.44 (1984)]**PEER REVIEWED**

Italian shoemakers exposed to 200-500 ppm benzene in inks and glues showed an incidence of leukemia of 1 per 1,000.
[Vigliani EC; Ann NY Acad Sci 271: 143 (1976)]**PEER REVIEWED**

Follow up study at Massachusetts rubber coating plants of 38 workers exposed over 1-24 yr at 5-50 ppm (140 ppm peak) showed no evidence of blood dyscrasias or leukemia.
[Pagnotto LD et al; Am Ind Hyg Assoc J 40: 137 (1979)]**PEER REVIEWED**

A significantly incr frequency of chromatid and isochromatid breaks in the cultured lymphocytes of workers in chemical laboratories and in the printing industry has been reported.
[USEPA; Ambient Water Quality Criteria for Benzene p.C-46 (1980) EPA 440/5-80-018]**PEER REVIEWED**

A significant incr of peripheral blood lymphocyte chromosomal aberrations in workers exposed to benzene was reported, but not in those exposed to toluene and xylene.
[Vigliani EC, Forni A; J Occup Med 11 p.148 (1969) as cited in USEPA; Ambient Water Quality Criteria for Benzene p.C-46 (1980) EPA 440/5-80-018]**PEER REVIEWED**

A report on 52 workers exposed to benzene found chromosomal aberrations (chromosome breaks, dicentric chromosomes, translocations, and exchange figures) in peripheral lymphocytes at 2-3 times the rates found in controls. The 8 hr TWA exposure was 2-3 ppm, the average concn determined by 15 min sampling was 25 ppm, and the peak concn was 50 ppm.
[USEPA; Ambient Water Quality Criteria for Benzene p.C-47 (1980) EPA 440/5-80-018]**PEER REVIEWED**

An epidemiological study implicating benzene as a leukemogen (acute myelocytic leukemia) followed 748 white males exposed to benzene in the manufacture of a rubber product from 1940-1949. A statistically significant (p < or = 0.002) excess of leukemia was found when compared against two control populations. There was a 5 fold excessive risk of all leukemias and a 10 fold excessive risk of myelocytic and monocytic leukemias combined.
[USEPA; Ambient Water Quality Criteria: Benzene p.C-58 (1980) EPA 440/5-80-018]**PEER REVIEWED**

A hematological investigation was carried out on 147 workers (employed for +10 years) exposed to high benzene levels (320-470 ppm). Abnormalities were noted in at least one parameter in 73%, the most common one being thrombocytopenia, which occurred in 62% followed by anemia (35%) and leucopenia (32%). Pancytopenia occurred in 21% of the workers. During the 3 months following removal from exposure, hematological parameters returned to normal in 120 workers, and one subject died. After one year, 20 of the remaining workers had only minor abnormalities, six were still off work, and one was still hospitalized.
[Savilahti M; Arch Gewerbpathol Gewerbhyg 15: 147-57 (1956)]**PEER REVIEWED**

A retrospective mortality study of a cohort of 594 men exposed to benzene at levels ranging between 2 and 25 ppm (TWA) was carried out at the Dow Chemical Co between 1940-1973. No incr in total mortality was noted with 102 observed/128 expected (Standard Mortality Ratio (SMR) 80). A slight increase was noted in total deaths due to malignancies (30 observed/22.8 expected, SMR 132) and suicide (5 observed/3.2 expected, SMR 147) as well as deaths from leukemia (3 observed/0.8 expected) and cancers of the digestive organs and peritoneum (9 observed/6.9 expected, SMR 125). If 53 workers exposed to other chemicals are excluded from malignancies, the results would then be 24 observed/20.3 expected, SMR 108.
[Ott MG et al; Arch Environ Health 33: 3-10 (1978)]**PEER REVIEWED**

/A subset of 292 men of the 594 in the benzene exposure of Dow cohort who were still employed in 1967/ had an examination of the health status /evaluation/ carried out between 1967-1974 and compared to a control population selected from employees not exposed to benzene, using a matched pair design (matched for age, cigarette smoking habits and length of employment). No clinically significant differences were reported although slight decr in total bilirubin levels and red blood cell counts were noted.
[Towsent et al; J Occup Med 20: 543-8 (1978)]**PEER REVIEWED**

Thirty two patients who had recovered from a blood disease (bone marrow impairment) caused by benzene poisoning had significantly increased rates of "unstable" and "stable" chromosomes. Aberrations of chromosomes were present for several years after cessation of the exposure and after recovery from poisoning. Persistence of an increase of the "stable" changes was particularly remarkable.
[Waldbott GL; Health Eff of Envir Poll p.214 (1973)]**PEER REVIEWED**

NUMEROUS STUDIES HAVE BEEN CARRIED OUT ON THE CHROMOSOMES OF BONE-MARROW CELLS & PERIPHERAL LYMPHOCYTES FROM PEOPLE KNOWN TO HAVE BEEN EXPOSED TO BENZENE. ... IN MANY OF THESE STUDIES, SIGNIFICANT INCR IN CHROMOSOMAL ABERRATIONS HAVE BEEN SEEN, WHICH IN SOME CASES HAVE PERSISTED FOR YEARS AFTER CESSATION OF EXPOSURE. ... BONE-MARROW CELLS & PERIPHERAL LYMPHOCYTES /HAVE BEEN EXAM/ FROM WORKERS WITH CURRENT SEVERE BLOOD DYSCRASIAS, & ... /FOLLOW-UP STUDIES HAVE BEEN DONE ON/ SEVERAL WORKERS BY REPEATED CYTOGENETIC STUDIES UP TO 12 YR AFTER RECOVERY FROM BENZENE-INDUCED PANCYTOPENIA. GROSS CHROMOSOMAL ABNORMALITIES WERE CHARACTERISTIC OF THESE CELLS; 70% OF THE BONE-MARROW CELLS & LYMPHOCYTES IN PT WITH ACUTE POISONING SHOWED KARYOTYPIC ABNORMALITIES. THE AUTHORS COULD NOT RELATE THE FREQUENCY OR TYPE OF CHROMOSOMAL ALTERATIONS TO THE SEVERITY OF BLOOD DYSCRASIA. FIVE YR AFTER POISONING, ALL ... 5 PATIENTS STUDIED STILL SHOWED STABLE (Cs) & UNSTABLE (Cu) CHROMOSOMAL ABERRATIONS IN ... LYMPHOCYTES, ALTHOUGH ONLY 40% OF CELLS WERE NOW ABNORMAL. BY 12 YR ... NO CYTOGENETIC ABNORMALITIES REMAINED IN THE 4 PATIENTS STUDIED.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 118 (1982)]**PEER REVIEWED**

METABOLIC ACTIVATION OF BENZENE BY RAT LIVER MICROSOMES & A REDUCED NADP-GENERATING SYSTEM (S-9 MIX) INDUCED SISTER CHROMATID EXCHANGES (SCE) & CELL DIVISION DELAYS IN CULTURED HUMAN LYMPHOCYTES. THERE WERE OPTIMAL CONCN OF S-9 MIX FOR THE CONVERSION OF BENZENE INTO THE ACTIVE METABOLITES THAT EXERTED THESE CYTOTOXIC EFFECTS.
[MORIMOTO K; CANCER RES 43 (3): 1330-4 (1983)]**PEER REVIEWED**

... INCIDENCE OF ACUTE LEUKEMIA OR 'PRELEUKEMIA' AMONG 28,500 SHOE-WORKERS IN TURKEY /WAS ESTIMATED/ ON BASIS OF CASE ASCERTAINMENT BY CONTACT WITH MEDICAL CARE. THIRTY FOUR CASES WERE IDENTIFIED. ... INCIDENCE OF ACUTE LEUKEMIA WAS SIGNIFICANTLY GREATER AMONG WORKERS CHRONICALLY EXPOSED TO BENZENE, WHICH WAS USED AS A SOLVENT BY THESE WORKERS, THAN IN THE GENERAL POPULATION. OCCUPATIONAL EXPOSURES WERE DETERMINED BY WORK HISTORIES & BY ENVIRONMENTAL MEASUREMENTS. THERE WAS SAID TO BE EXPOSURE ONLY TO BENZENE IN SMALL, POORLY VENTILATED WORK AREAS; PEAK EXPOSURES ... WERE REPORTED TO BE 210-650 PPM (670-2075 MG/CU M). DURATION ... WAS EST TO HAVE BEEN 1 TO 15 YR (MEAN 9.7 YR). ANNUAL INCIDENCE WAS EST TO BE 13/100000, GIVING APPROX RELATIVE RISK OF 2 WHEN COMPARED WITH ANNUAL EST FOR GENERAL POPULATION, 6/100000. (THESE EST ARE LIMITED BY STUDY DESIGN CHARACTERISTICS & BY UNCERTAINTY ABOUT THE WAY IN WHICH CASES WERE ASCERTAINED, & HOW MANY OF THE STUDY POPULATION WERE EXPOSED & HOW MANY UNEXPOSED).
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 121 (1982)]**PEER REVIEWED**

OCCUPATIONAL EXPOSURES WERE IDENTIFIED IN ROTOGRAVURE PLANTS & SHOE FACTORIES. BENZENE CONCN NEAR ROTOGRAVURE MACHINES WERE 200-400 PPM (640-1280 MG/CU M), WITH PEAKS UP TO 1500 PPM (4800 MG/CU M); BENZENE CONCN IN AIR NEAR WORKERS HANDLING GLUE IN SHOE FACTORIES WERE 25-600 PPM (80-1920 MG/CU M), BUT WERE MOSTLY AROUND 200-500 PPM (640-1600 MG/CU M). EST LATENCY (YEARS FROM START OF EXPOSURE TO CLINICAL DIAGNOSIS OF LEUKEMIA) RANGED FROM 3-24 YR (MEDIAN, 9 YR). ... THE RELATIVE RISK OF ACUTE LEUKEMIA WAS /EST TO BE/ AT LEAST 20:1 FOR WORKERS HEAVILY EXPOSED TO BENZENE IN ROTOGRAVURE & SHOE INDUSTRIES IN THE PROVINCES STUDIED, WHEN COMPARED WITH GENERAL POPULATION. (THE RELATIVE RISK IS BASED ON A NON-VALIDATED ESTIMATE).
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 122 (1982)]**PEER REVIEWED**

A HISTORICAL COHORT MORTALITY STUDY WAS CONDUCTED OF 259 MALE EMPLOYEES OF A CHEM PLANT WHERE BENZENE HAS BEEN USED IN LARGE QUANTITIES. THE STUDY GROUP INCL ALL PERSONS WHO WERE EMPLOYED BY THE COMPANY ANY TIME BETWEEN JAN 1, 1947 & DEC 31, 1960. THE COHORT WAS FOLLOWED THROUGH DEC 31, 1977 AT WHICH TIME 58 KNOWN DEATHS WERE IDENTIFIED. THE ONLY UNUSUAL FINDING WAS FOUR DEATHS FROM LYMPHORETICULAR CANCERS WHEN 1.1 WOULD HAVE BEEN EXPECTED ON THE BASIS OF NATIONAL MORTALITY RATES. THREE OF THE DEATHS WERE DUE TO LEUKEMIA & 1 WAS CAUSED BY MULTIPLE MYELOMA. IN ADDN, 1 OF THE LEUKEMIA DEATHS HAD MULTIPLE MYELOMA LISTED ON THE DEATH CERTIFICATE. THE FINDINGS ARE CONSISTENT WITH PREVIOUS REPORTS OF LEUKEMIA FOLLOWING OCCUPATIONAL EXPOSURE TO BENZENE & RAISE THE POSSIBILITY THAT MULTIPLE MYELOMA COULD BE LINKED TO BENZENE, ALSO.
[DECOUFLE P ET AL; ENVIRON RES 30 (1): 16-25 (1983)]**PEER REVIEWED**

HEMATOLOGIC & IMMUNOCHEMICAL INVESTIGATIONS CARRIED OUT IN 270 WORKERS WITH CHRONIC EXPOSURE TO BENZENE DEMONSTRATED CHANGES OF THE NUCLEOLOGRAM & OF THE AREA OF LYMPHOCYTE NUCLEOLI & DISORDERS OF THE HUMORAL IMMUNE RESPONSE REVEALED BY RADIAL IMMUNODIFFUSION. THE NUMERICAL RISE OF BI- & POLYNUCLEOLATED CELLS, OF CELLS WITH IRREGULAR MACRONUCLEOLI & AN ENLARGEMENT OF THE NUCLEOLAR AREA REFLECTED INCR ENDOLYMPHOCYTIC AMT OF RNA. AN INCR CAPACITY OF IG FORMATION, PARTICULARLY OF IGM, WAS ALSO OBSERVED.
[CHIRCU V ET AL; REV ROUM MED INTERNE 19 (4): 373-8 (1981)]**PEER REVIEWED**

SOME ASPECTS OF QUANTITATIVE CANCER RISK ESTIMATION: ... RISK IS GREATEST AMONG THOSE WITH LONGEST EXPOSURE, RELATIVE RISKS OF APPROX 2, 14 & 32 BEING OBSERVED FOR EXPOSURES OF LESS THAN 5 YR (2 CASES), 5-9 YR (2 CASES) & 10+ YR (3 CASES), RESPECTIVELY. THE RELATIVE RISK ASSOC WITH AT LEAST 5 YR OF EXPOSURE IS THUS LIKELY TO BE LOWER BOUND FOR RISK ASSOC WITH LIFETIME EXPOSURE AT SIMILAR LEVELS. FOR THOSE WITH AT LEAST 5 YR EXPOSURE, 5 CASES WERE OBSERVED COMPARED WITH AN EXPECTED NUMBER OF 0.237, GIVING A RELATIVE RISK OF 21.1. SINCE THE EXPECTED CUMULATIVE MALE ADULT LIFETIME (FROM 20 YR TO END OF LIFE, TAKEN AS AGE 75) PROBABILITY OF DYING FROM LEUKEMIA IS APPROX 7 PER 1000 IN THE GENERAL POPULATION OF THE USA, AN EXPECTED RELATIVE RISK OF 21.1 WOULD GIVE AN EXTRA (21.1-1.0)X7= 141 CASES OF LEUKEMIA PER 1000 EXPOSED POPULATION.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 395 (1982)]**PEER REVIEWED**

The hematotoxicity of benzene is expressed primarily as a bone marrow effect leading eventually to complete destruction of myeloid and erythroid marrow components. This is manifested as a marked decrease in circulating formed elements, ie red blood cells, and platelets. The resultant aplastic anemia is a potentially fatal disorder which in its severe form has better than a fifty percent mortality rate. In both man and laboratory animals the extent of bone marrow damage appears proportional to the dose of benzene. Lesser degrees of bone marrow toxicity than aplastic anemia are more common in occupational exposure situations. Classically, the discovery of one individual with significant bone marrow toxicity has led to evaluation of the exposed work force and the finding of a wide variation in the extent of hematotoxicity. This has ranged from clinically significant pancytopenia, in which are decreases in white blood cells (leukopenia), red blood cells (anemia), and platelets (thrombocytopenia) to a situation in which only one of these is slightly below normal range. In the latter case it is of course difficult to distinguish a benzene effect from that due to the extremes of normal variation or to mild intercurrent disease.
[Mehlman MA, ed; Adv Mod Environ Toxicol Vol IV: Carcinogenicity and Toxicity of Benzene p.52 (1983)]**PEER REVIEWED**

The type of leukemia most commonly associated with benzene is acute myelogenous leukemia and its variants, including erythroleukemia and acute myelomonocytic leukemia. Acute myelogenous leukemia is the adult form of acute leukemia and, until recent advances in chemotherapy, it was a rapidly fatal disease. The other major acute form of leukemia, acute lymphocytic leukemia, has been reported to be associated with benzene exposure but evidence of a causal association is weak. There is a somewhat stronger, although still inconclusive, association in the literature between benzene exposure and the two common forms of chronic leukemia: chronic myelogenous leukemia and chronic lymphocytic leukemia. Other hematological disorders possibly associated with benzene exposure include Hodgkin's disease, lymphocytic lymphoma, myelofibrosis and myeloid metaplasia, paroxysmal nocturnal hemoglobinuria, and multiple myeloma.
[Mehlman MA, ed; Adv Mod Environ Toxicol Vol IV: Carcinogenicity and Toxicity of Benzene p.52 (1983)]**PEER REVIEWED**

An acute hemorrhagic pneumonitis is highly likely if ... aspirated into lung.
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-398]**PEER REVIEWED**

Three cases of chronic leukemia were presented which had a history of chronic benzene exposure. These three patients were part of a larger group of 58 leukemia patients with benzene exposure histories. Case 1 presented at age 43 due to cardiac complaints. The patient owned a printing shop at which he mixed pigmented dyes with solutions of toluene or methyl alcohol ketone. The individual had a practice of sniffing the solutions as control measure. The toluene solution on analysis was shown to contain 2.8% benzene 95.3% toluene. Blood and bone marrow examination revealed chronic lymphatic leukemia. Case 2 was a 51 year old man with pain in the right quadrant. This individual had owned a small plastics facility between 1955 and 1965 where he was intermittently exposed to thinners containing 27.3% benzene. Subsequent exposure included cleaning solutions without benzene. He was also diagnosed with chronic lymphatic leukemia. The third case was a 50 year old manager of a plastic facility who was diabetic for 15 years and was hospitalized due to recurrent gluteal and inguinal furunculosis during the last 3 years. He had been heavily exposed to benzene between 1957 and 1965. He admitted having removed the dirt from his hands using thinners containing benzene. Hairy cell leukemia was diagnosed. The data suggests that differences in distribution of acute or chronic leukemias in chronic benzene exposure may be related to exposure levels, mode of exposure, or exposure to benzene homologs or other chemicals.
[Askoy M; Brit J Haematol 66 (2): 209-11 (1987)]**PEER REVIEWED**

A study conducted to measure the concentration of benzene in the air and solvents at 40 small and large workplaces in Turkey where workers had contracted leukemia and lymphoma. In addition, hematological examinations were performed on the 231 workers employed at the facilities. The facilities manufactured and repaired shoes, tires, leather works, automobiles, and farm equipment. The age of the workers ranged from 14 to 57 years and the mean duration of exposure was 8.8 years (range 1 month to 40 years). Case reports were presented for five workers with 2 to 15 years of exposure who had developed acute myeloblastic leukemia, acute lymphoblastic leukemia, acute myelomonocytic leukemia, Hodgkin's disease and poorly differentiated lymphoma. Benzene concentrations in the solutions and thinners used ranged from 3 to 7.5%. The concn of benzene in air samples from the plants ranged from 0 to 110 ppm while 76.4% of solvents contained more than 1% of benzene. Hematological examinations of the workers showed that 32% of them had abnormal values. There has been a decline in the use of benzene in Turkey since an earlier study in 1972, but that the percentages of benzene in most of the materials are still above permissible limits.
[Askoy M et al; Brit J Indust Med 44 (11): 785-7 (1987)]**PEER REVIEWED**

Benzene is widely recognized as a leukemogen, and the Occupational Safety and Health Administration is currently attempting to limit exposure to it more strictly. The proposed new regulation is a limit of an eight hr time-weighted average of 1 ppm in place of the current limit of 10 ppm. The fundamental rationale for the change is a perception that the current standard is associated with an inordinate excess of leukemia. The epidemiologic literature on benzene and leukemia supports the inference that benzene causes acute myelocytic leukemia. However, the available data are too sparse, or /have/ other limitations, to substantiate the idea that this causal association applies at low levels (ie, 1-10 ppm) of benzene. Nonetheless, under the assumption that causation does apply at such low levels, a number of researchers have performed risk assessments using similar data but different methodologies. The assessments that is considered acceptable suggest that, among 1,000 men exposed to benzene at 10 ppm for a working lifetime of 30 years, there would occur about 50 excess deaths due to leukemia in addition to the baseline expectation of seven deaths. However, this estimate is speculative and whether or not enough confidence can be placed in it to justify a lower occupational benzene standard remain a decision for policy makers.
[Austin H et al; Am J Epidemiol 127 (3): 419-39 (1988)]**PEER REVIEWED**

Results of epidemiologic studies indicating an association between solvent exposure and the development of malignancies affecting hematopoietic and lymphatic tissues are reviewed. Clinical and cytogenetic data supporting this association are discussed. A variety of malignant disorders have been associated with solvent exposure, ie acute leukemia, Hodgkin's disease (odds ratio 2.8-6.6), non-Hodgkin's lymphoma (odds ratio 3.3) and myeloma, and there are some indications that solvent exposure may be a risk factor for myelofibrosis. The carcinogenic effect of benzene is epidemiologically and experimentally well documented and there are some indications that other solvents may also be hazardous. Possible mechanisms bringing about malignant transformation are discussed. The need for further epidemiologic, cytogenetic and clinical studies on the association between solvent exposure and malignant diseases is emphasized.
[Brandt L; Med Oncol Tumor Pharmacother 4 (3/4): 199-205 (1987)]**PEER REVIEWED**

Currently the most applied technique for monitoring biological effects of exposure to genotoxic chemicals in industrial workers is the measurement of chromosome aberrations in peripheral blood lymphocytes. In the Shell petrochemical complex in the Netherlands cytogenetic monitoring studies have been carried out from 1976 till 1981 inclusive, in workers potentially exposed to a variety of genotoxic chemicals, ie vinyl chloride, ethylene oxide, benzene, epichlorohydrin, epoxy resins. Average exposure levels to these chemicals were well below the occupational exposure limits. Results of thesse studies indicate that no biologically significant increase in the frequencies of chromosome aberrations in the exposed populations occurred compared with control populations. ... Experience with this methodology has shown that the results of chromosome analyses are difficult to interpret, due to the variable and high background levels of chromosome aberrations in control populations and in individuals. It is concluded that the method is not sufficiently sensitive for routine monitoring of cytogenetic effect in workers exposed to the low levels of genotoxic compounds.
[deJong G et al; Mutat Res 204 (3): 451-64 (1988)]**PEER REVIEWED**

The possibility of there being a link between the apparent predominance of men with specific on the job exposures to toxic materials among patients with hairy cell leukemia was explored. Of a total of 105 hairy cell leukemia patients, eight were in the medical profession (two X-ray technicians, one radiologist, two pneumologists, two orthopedists, and one internist), 21 were garage mechanics or divers of trucks or other heavy vehicles, eight worked in construction as painters, decorators or masons, three were in the printing industry as photogravure and equipment maintenance workers, ten were farmers, six were engineers and 49 held various technical or office positions. Interviews were conducted with 69 of the patients. All those in medicine had used radioscopy for periods exceeding 10 years. Exposure to petroleum derived substances was high not only among the garage mechanics and drivers, but among those 49 individuals whose occupations did not have particular exposure, but whose hobbies and paraprofessional activities involved use of benzene or other solvents. Of the 69 interviewed, 52 were able to document exposure to benzene or other solvents.
[Flandrin G, Collado S; Brit J Haematol 67 (1): 119-20 (1987)]**PEER REVIEWED**

The case of a 55 year old male with hairy cell leukemia associated with chronic exposure to benzene in an occupational setting was described. The subject had been employed as a coach paint sprayer for over 25 years at the time of diagnosis. When that patient was questioned, it was admitted that at the job site he did not usually take the normal protective measures to prevent exposure to the chemicals in the paints. The /investigators noted/ that spray painting is the one of the occupations which can involve exposure to benzene, due to the use of benzene containing solvents. The /researchers/ concluded that since three other cases of chronic leukemia have been previously associated with exposure to benzene, more retrospective demographic studies which take occupational exposures into account confirm the possible link between chronic benzene toxicity and leukemia, particularly the very rare hairy cell leukemia.
[Ng JP et al; Brit J Haematol 67 (1): 116 (1987)]**PEER REVIEWED**

The mutual metabolic suppression between benzene and toluene was studied. The subjects, 190 male Chinese workers employed in shoe manufacturing, printing, audio equipment manufacture, and automobile industries, were divided into four groups based on occupational exposure: 65 were exposed to benzene, 35 to toluene, 55 to both compounds, and 35 served as comparisons. The arithmetic mean exposure level of benzene was 31.9 and of toluene 44.7 ppm. The mixture contained benzene at 17.9 + - 29.3 and toluene at 20.5 + - 25.8 ppm. The exposure levels were measured using individual diffusive samplers. The geometric mean levels of the metabolites, phenol, catechol, hydroquinone, hippuric acid, and o-cresol, in unexposed workers were 6.9, 9.4, 4.8, 72.5, and 0.066 mg/l, respectively. Values corrected for creatinine and specific gravity were different from the values cited above. Multiple correlation coefficients for benzene exposure versus its three metabolites were for phenol, 0.740; for catechol, 0.629; and for hydroquinone, 0.762. Multiple correlation coefficients for toluene and its two metabolites were 0.649 for hippuric acid and 0.583 for o-cresol. The slopes of regression lines for the exposure to benzene in the presence of toluene were less than half of those obtained when the workers were exposed to benzene alone; however, the regression lines for benzene in mixture versus catechol were out 80% of higher than the lines observed with benzene as the sole pollutant. The regression lines for toluene in the mixture and excretion level of hippuric acid and hydroquinone showed reduced metabolic conversion compared to when exposure was limited to toluene alone.
[Inove O et al; Internat Arch Occupat Environ Health 60 (1): 15-20 (1988)]**PEER REVIEWED**

A retrospective cohort study was conducted in 233 benzene factories and 83 control factories in 12 cities in China. The benzene cohort and the control cohort consisted of 28,460 benzene exposed workers (178,556 person-years in 1972-81) and 28,257 control workers (199,201 person-years). Thirty cases of leukemia (25 dead and 5 alive) were detected in the former and four cases (all dead) in the latter. The leukemia mortality rate was 14/100,000 person-years in the benzene cohort and 2/100,000 person-years in the control cohort; the standardized mortality ratio was 5.74 (p less than 0.01 by U test). The average latency of benzene leukemia was 11.4 years. Most (76.6%) cases of benzene leukemia were of the acute type. The mortality due to benzene leukemia was high in organic synthesis plants followed by painting and rubber synthesis industries. The concentration of benzene to which patients with a leukemia were exposed ranged from 10 to 1000 mg/cu m (mostly from 50 to 500 mg/cu m). Of the 25 cases of leukemia, seven had a history of chronic benzene poisoning before the leukemia developed.
[Jin C et al; Br J Ind Med 44 (2): 124-8 (1987)]**PEER REVIEWED**

Cytogenetic and environmental factors in the etiology of acute leukemias in adults were discussed. Epidemiological aspects of leukemia were considered. The leukemias currently account for approximately 3% of the total cancer incidence and 4% of the cancer deaths in the USA. The average annual incidence is eight cases per 100,000 for females and 11 cases per 100,000 for males. Leukemia is more common in whites than nonwhites and more common in males. Acute nonlymphocytic accounts for about 30% of the total leukemia incidence and for over 85% of the acute leukemia seen in persons over 40 years of age. Recent mortality data show very little change in leukemia death rates except for acute nonlymphocytic leukemia which increased by 20% from 1969 to 1977. Genetic and environmental factors were considered. Chromosome disorders and a family history may be etiological factors in both acute nonlymphocytic leukemia and lymphocytic leukemia. Exposures to benzene, ionizing radiation, and antineoplastic agents are known to cause chromosomal aberrations and leukemia; however, no evidence of a causal sequence of events has been obtained. Environmental risk factors such as ionizing radiation, cigarette smoke, and chemicals were described. Benzene is considered the best known and most widely occurring human leukemogen. A number of case reports and cohort studies have linked benzene exposure and acute leukemias. Benzene associated relative risk for overall leukemia generally range from 1.5 to 2.0. Cytogenetic aspects of leukemia were considered. Some studies have shown that prior chemical exposures are associated with chromosome aberrations in acute nonlymphocytic leukemic patients. Suggestions for improving epidemiological studies of leukemia were discussed.
[Sandler DP, Collman GW; Amer J Epidemiol 126 (6): 1017-32 (1987)]**PEER REVIEWED**

A study of mortality in automobile mechanics and gasoline service station workers in New Hampshire was conducted. A proportionate mortality ratio analysis of all deaths occurring among male residents 20 years or older who lived in New Hampshire between 1975 and 1985 was performed. Occupation, industry, age, and date and cause of death were obtained from death certificates. A total of 37,426 deaths were recorded. Of these, 453 were automobile mechanics and 134 were persons who had been employed in the gasoline service station industry. Automobile mechanics had statistically significant proportionate mortality ratio elevations for suicide. Nonsignificant increases in proportionate mortality ratio for leukemia, cancers of the oral cavity, lung, bladder, rectum and lymphatic tissue, and nonmalignant blood dyscrasias and cirrhosis of the liver were observed. Workers in the gasoline service station industry had statistically significant increases in mortality from leukemia and mental and psychoneurotic and personality disorders, proportionate mortality ratio 328 and 394, respectively; however, the number of deaths was small. Proportionate mortality ratio increases were also observed for emphysema and suicide. One or more of the exposures experienced by automobile mechanics and service station workers presents a carcinogenic risk. The finding of excess mortality from leukemia in both groups is consistent with exposure to benzene, a component of gasoline. ... Workers who pump gasoline should be informed of the potential cancer hazard. Gasoline should not be used as a solvent for removing grease and cleaning hands, and gasoline should not be siphoned by mouth.
[Schwartz E; Amer J Indust Med 12 (1): 91-9 (1987)]**PEER REVIEWED**

This paper presents a critical review more than 100 references on the possible leukemogenic (blastomogenic) effects of benzene, based upon clinical, epidemiological and experimental /studies/. /Evidence supports the conclusion that/ there exists reliable clinical and epidemiological /studies/, concerning increased leukemogenic risk on working place with high benzene concentrations in past years (tens and even hundreds of ppm). Most epidemiological studies, indicate now that this risk is also elevated in more favorable working conditions, although practical valuable dose-effect relationship between benzene concentrations and rate of leukemogenic risks is still unknown. Results of experimental investigations on problem of leukemogenic effects of benzene are contradictory. It was stated recently that there is a lack of adequate experimental models of benzene blastomogenesis. Taking into consideration increasing economic significance of benzene and existence of large contingents of workers dealing with benzene, it is necessary to continue appropriate experimental and epidemiological investigations.
[Sokolov VV, Frasch VN; J Hyg Epidemiol Microbiol Immunol 31 (2): 135-43 (1987)]**PEER REVIEWED**

The possible association of thinner, a mixture of seven organic solvents used in the Mexican auto and paint industry, with the frequency of sister chromatid exchanges in the peripheral lymphocytes of 24 industrial workers was investigated. The subjects worked in a factory and three workshops in which no protective measures against inhalation of vapors were taken. A matched comparison group consisted of 24 administrative and outdoor workers. Use of cigarettes, alcohol, and medicines, and presence of viral infections within the 3 previous months were determined by questionnaire. Blood was cultured for 72 hr with phytohemagglutinin, with 5-bromodeoxyuridine added at 24 hr and colchicine at 70 hr. Sister chromatid exchanges were scored from 50 metaphases from each individual. Air samples to determine concentrations of thinner components in the working atmosphere were taken on the day of blood sampling and analyzed by gas chromatography. Solvent concentrations in the samples from the factory air were methyl isobutyl ketone 2.4 ppm, methanol 0.6 ppm, isopropanol 3.3 ppm, toluene 3.3 ppm, benzene 6.0 ppm, and hexane 3.3 ppm. The concentrations were below the limits recommended by NIOSH ... except for benzene which was six times the NIOSH limit. One way analysis of variance of the sister chromatid exchanges frequency for the exposed and comparison groups showed no differences for exposures of either 5 years or less of 6 to 35 years. However, a significant increase of sister chromatid exchanges was found for tobacco use in the exposed group but not for the comparison group. The implications of this result were discussed principally in relation to benzene. ... Working conditions should be improved by a ventilation system and that a benzene free thinner be substituted for the one being used.
[Souza V, Puig M; Mutat Res 189 (3): 357-62 (1987)]**PEER REVIEWED**

Dose response analyses for a cohort study of chemical workers exposed to benzene were reported. Exposure information included 8 hour time-weighted averages and peak exposures and was used to calculate the latency, duration of exposure, and peak exposure for several types of lymphatic and hematopoietic cancers. The cohort included 4,602 male chemical workers from seven companies who were occupationally exposed to benzene for at least 6 months between 1946 and 1975. A comparison group included 3,074 workers at the same plants who were employed for at least 6 months without exposure to benzene. Workers exposed to benzene 5 and 14 years showed an increased risk of lung cancer with a statistically significant enhancement of the standardized mortality ratio. Increased in reticulosarcoma and lymphosarcoma were related to the duration of continuous benzene exposure. Increased latency was related to a slight enhancement for all cancers among the exposed workers. Analysis by cumulative exposure demonstrated an increasing trend for death due to lymphatic and hematopoietic cancer, lymphosarcoma, reticulosarcoma, and leukemia. Workers with a cumulative exposure of 180 to 719 ppm month showed a significant increase in lung cancer. No dose response relation was detected for any other causes of death.
[Wong O; Brit J Indust Med 44 (6): 382-95 (1987)]**PEER REVIEWED**

A mortality study of 7,676 male chemical workers occupationally exposed to benzene was described. The subjects were employed at nine plants belonging to seven member companies of the Chemical Manufacturers Association. Workers were classified according to their benzene exposure into occupationally exposed or comparison groups. Occupationally exposed workers received at least 6 months of continuous or intermittent job exposure to benzene between 1946 and 1975. The comparison group comprised workers with at least 6 months of employment at the same plant with no benzene exposure. Approximately 40% of the cohort were not occupationally exposed to benzene, and about 46% of the cohort had received continuous exposure to benzene. The remaining 14% fell into the intermittent exposure group. The observed mortality of the cohort was compared with the expected based on the United States mortality rates appropriately standardized. Standardized mortality ratios were determined for lymphatic and hematopoietic cancer, leukemia, non Hodgkin's lymphoma, and non-Hodgkin's lymphopoietic cancer. The number of observed deaths in the continuous exposure group was slightly but not significantly greater than expected. Deaths from lymphatic and hematopoietic cancers and from leukemia were greater than expected in the continuous exposure group. The mortality of the intermittent exposure group was comparable to the expected mortality. The standardized mortality ratios of the total group were greater than the comparison group. Statistically significant associations were demonstrated between benzene exposure and both lymphopoietic cancer and leukemia.
[Wong O; Brit J Indust Med 44 (6): 365-81 (1987)]**PEER REVIEWED**

Comprehensive comparative studies were conducted on the three groups of 148 male and 167 female workers exposed to benzene, toluene, or a combination of the two to evaluate subjective symptoms and hematologic effects of the compounds. Exposed workers were compared to 127 unexposed referents. The exposure intensity of the workers was estimated by diffusion dosimetry, and their subjective symptoms were obtained from questionnaires. The workers in the benzene group were engaged in shoe making and printing; the toluene group was engaged in shoe making and audio equipment production, and the mixed exposure group was employed in spray painting in automobile body shops. The mean age of the workers ranged from 26.7 to 39.0 years. The average 7 hr time weighted exposure to benzene was 33 and 59 ppm for men and women, respectively; the exposure concentrations of toluene were 46 and 41 ppm for men and women, respectively. In the mixed exposure group, men were exposed to 14 ppm of benzene and 18 ppm of toluene; the female mixed exposure was 18 ppm of benzene and 21 ppm of toluene. Hematological examinations showed no significant differences between exposed and nonexposed workers, although leukocytes were marginally decreased. The prevalence of subjective symptoms was dose related and statistically significant for both men and women. The number of symptoms per person during work was at least ten fold higher in the exposed than in the nonexposed groups. The most frequent symptoms were dizziness, sore throat, and headache which occurred during work as well as during non work time. This study provides no indication of pancytopenia, and that both liver and kidney functions are unchanged under exposure conditions.
[Yin S et al; Indust Health 25 (3): 113-30 (1987)]**PEER REVIEWED**

Of a total of 528,729 workers exposed to benzene or benzene mixtures in China, 508,818 (96.23%) were examined. Altogether 2,676 cases of benzene poisoning were found, a prevalence of 0.15%. A higher prevalence of benzene poisoning was found in the cities of Hangjou, Hefei, Nanjing, Shenyang, and Xian. The geometric mean concentration of benzene in 50,255 workplaces was 18.1 mg/cu m but 64.6% of the workplaces had less than 40 mg/cu m. There was a positive correlation between the prevalence of benzene poisoning and the concentration in shoemaking factories. The prevalence of benzene induced aplastic anemia in shoemakers was about 5.8 times that occurring in the general population. The results of this investigation show the need for a practicable hygiene standard to prevent benzene poisoning.
[Yin SN et al; Br J Ind Med 44 (3): 192-5 (1987)]**PEER REVIEWED**

... CYTOGENETIC APPROACHES APPEAR TO BE NEAREST TO ROUTINE SURVEILLANCE IN DETECTING EARLY BIOLOGIC EFFECTS IN EXPOSED HUMANS. BENZENE SHOWED CONTRADICTORY RESULTS IN CHROMOSOME ABERRATION TESTS & WAS NEGATIVE FOR SISTER CHROMATID EXCHANGE.
[SORSA M ET AL; TERATOG CARCINOG MUTAGEN 2 (2): 137-50 (1982)]**PEER REVIEWED**

Investigations on the association between environmental hazards and the development of various /forms/ of leukemia are reviewed. Regarding acute non-lymphocytic leukemia exposure to ionizing radiation is a well documented risk factor. According to several recent studies exposure to strong electronmagnetic fields may be suspected to be of etiologic importance for acute non-lymphocytic leukemia. There is evidence that occupational handling of benzene is a risk factor and other organic solvents may be leukemogenic. Occupational exposure to petroleum products has been proposed to be a risk factor although the hazardous substances have not yet been defined. Results of cytogenic studies in acute non-lymphocytic leukemia suggest that exposure to certain environmental agents may be associated with relatively specific clonal chromosome aberrations. These results are of interest because it has been proposed that chromosomal rearrangements may play a role in the activation of cellular oncogens. Exposure in utero to ionizing radiation has been proposed to be a risk factor for acute lymphocytic leukemia in children. Unlike acute non-lymphocytic leukemia there seems at present to be little evidence that acute lymphocytic leukemia is related to exposure to some chemicals. Chronic myleoid leukemia may follow exposure to high doses of ionizing radiation whereas such exposure seems to be of insignificant importance in the development of chronic lymphocytic leukemia. According to some studies an abnormally high incidence of chronic lymphocytic leukemia may be found among farmers in the USA. These results have not been confirmed in Scandinaavian studies. There seems to be little evidence that chronic myleoid leukemia or chronic lymphocytic leukemia are related to occupational handling of some chemicals.
[Brandt L; Med Oncol Tumor Pharmacother 2 (1): 7-10 (1985)]**PEER REVIEWED**

Personal air monitors and breath samples were used to measure benzene and other volatile compounds in the breath of 200 smokers and 322 nonsmokers in New Jersey and California during 12 hr sampling periods. The monitor measured only sidestream and exhaled mainstream smoke. Concentrations were also measured in a subsample of homes and outdoor air. Compared to nonsmokers, benzene was significantly higher in the breath of persons who had smoked tobacco the day they were monitored (p< 0.001); values for smokers were 12 to 16 ug/cu m, nearly 10 times the breath level of nonsmokers. Values for personal air samplers were not always significantly higher. Benzene in breath was related to number of cigarettes smoked. Based on direct measurements of mainstream smoke, it was calculated that the typical smoker inhales 2 mg/day compared to the nonsmokers' intake of <0.2 mg/day. Both smokers and nonsmokers exposed to passive smoking at home or work had increased levels of benzene compared to nonsmoking situations (p< 0.05). Indoor air levels in homes with smokers were significantly greater than in nonsmoking homes in fall and winter but not during spring and summer.
[Wallace L et al; Arch Environ Health 42 (5): 272-9 (1987)]**PEER REVIEWED**

In both human and animal studies, it appears that benzene-induced bone marrow depression is a dose-dependent phenomenon.
[Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 742]**PEER REVIEWED**

Toxicities from inhalation /of benzene include/: irritation of conjunctiva and visual blurring, mucous membranes, dizziness, headache, unconsciousness, convulsions, tremors, ataxia, delirium, tightness in chest, irreversible brain damage with cerebral atrophy, fatigue, vertigo, dyspnea, respiratory arrest, cardiac failure and ventricular arrhythmias, leukopenia, anemia, thrombocytopenia, petechiae, blood dyscrasia, leukemia, bone marrow aplasia, fatty degeneration and necrosis of heart, liver, adrenal glands, fatal overdose. /From table/
[Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 1494]**PEER REVIEWED**

Single exposures to concentrations of 66,000 mg/cu m (20,000 ppm) commercial benzene have been reported to be fatal in man within 5-10 minutes. At lower levels, loss of consciousness, irregular heart-beat, dizziness, headache and nausea are observed.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 116 (1982)]**PEER REVIEWED**

In general, acute symptoms are dependent on both the concentration and duration of exposure. Exposure to 7500 ppm for 30 min is life-threatening; 1500 ppm for 60 min produces significant symptoms; 50-150 ppm for 5 hr results in headache and weakness; whereas exposure to 25 ppm or less for 8 hr results in no demonstrable acute effect.
[Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 724]**PEER REVIEWED**

... Benzene metabolism is a requirement for bone marrow toxicity.
[Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 726]**PEER REVIEWED**

/Researchers/ examined the blood counts of 161 workers for whom pre-employment counts were done prior to exposure in the rubber factory. The results indicated that during the first year of employment in the rubber factory, employees exposed to benzene levels higher than the median exposure (estimated at 40-54 ppm) had significantly lower white and red blood cell counts than employees exposed to benzene levels below the median exposure.
[Cody RP et al; J Occup Med 35 (8): 776-82 (1993) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.45 (1997)]**PEER REVIEWED**

Leukopenia was observed ... in Chinese workers exposed to 0.69-140 ppm (mean = 6 ppm) benzene for more than 1 year.
[Xia Z-L et al; Biomed Environ Sci 8: 30-4 (1995) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.47 (1997)]**PEER REVIEWED**

After a fatal occupational exposure to benzene vapors on a chemical cargo ship for only minutes, autopsy reports on three victims revealed hemorrhagic respiratory tissues, and second degree burns on the face, trunk, and limbs.
[Avis SP, Hutton CJ; J Forensic Sci 38 (3): 599-602 (1993) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.55 (1997)]**PEER REVIEWED**

Skin irritation has been noted at occupational exposures of greater than 60 ppm for up to three weeks.
[Midzenski MA et al; Am J Ind Med 22: 553-65 (1992) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.55 (1997)]**PEER REVIEWED**

A retrospective cohort study of incident cases of hematopoietic neoplasms and related disorders among 74,828 benzene-exposed workers employed between January 1, 1972 to December 31, 1987 in 672 factories in 12 Chinese cities was conducted. Workers (35,805) not occupationally exposed to benzene employed in 109 factories during the same period were used for comparison. Follow-up of both exposed and nonexposed workers was carried out using occupational and medical records, and histopathologic material were reviewed for all patients with hematopoietic malignancies to ensure correct classification. Among benzene-exposed workers, 82 patients with hematopoietic neoplasms and related disorders were diagnosed: 32 (39%) cases of acute leukemia, 9 (11%) aplastic anemia, 7 (9%) myelodysplastic syndrome, 9 (11%) chronic granulocytic leukemia, 20 (24%) malignant lymphoma and related disorders, and 5 (6%) others. Among the nonexposed group, 13 hematologic malignancies were diagnosed: 6 (46%) patients with acute leukemia, 2 (15%) chronic granulocytic leukemia, 3 (23%) malignant lymphoma, and 2 (15%) others. The hematopathologic features of acute nonlymphocytic leukemia associated with benzene exposure resembled the hematological features following chemotherapy or radiotherapy. In addition, this study documented myelodysplastic syndrome in association with benzene exposure.
[Travis LB et al; Leukemia and Lymphoma 14: 91-102 (1994) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.80 (1997)]**PEER REVIEWED**

... Benzene metabolites can adversely affect human topoisomerases, enzymes involved in DNA replication and repair. /Benzene metabolites/
[Chen H, Eastmond DA; Carcinogenesis 16 (10): 2301-7 (1995) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.218 (1997)]**PEER REVIEWED**

Skin, Eye and Respiratory Irritations:

Benzene is irritant to skin.
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1308]**PEER REVIEWED**

A severe eye and moderate skin irritant.
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 334]**PEER REVIEWED**

Skin irritation has been noted at occupational exposures of greater than 60 ppm for up to three weeks.
[Midzenski MA et al; Am J Ind Med 22: 553-65 (1992) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.55 (1997)]**PEER REVIEWED**

Drug Warnings:

Protected intercourse may be prudent following high exposure to benzene. As well, nursing mothers may be advised to discontinue nursing for 5 days following high exposure.
[Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 712]**PEER REVIEWED**

Medical Surveillance:

IF INDIVIDUALS ARE KNOWN TO BE EXPOSED TO BENZENE VAPORS IN THEIR WORKING ENVIRONMENT PROPHYLACTIC MEASURES SHOULD BE TAKEN. ALL POSSIBLE METHODS SHOULD BE USED TO PROTECT SUCH PERSONS AGAINST BREATHING THE FUMES. THEY SHOULD HAVE PERIODIC PHYSICAL EXAM, INCL BLOOD STUDIES. IN ADDN THE URINE SHOULD BE EXAM AT INTERVALS TO DETERMINE EXTENT OF EXCRETION OF BENZENE CONJUGATION PRODUCTS. ONCE POISONING HAS DEVELOPED, IT IS ESSENTIAL TO PREVENT FURTHER EXPOSURE.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 906]**PEER REVIEWED**

Assessment of fitness should incl consideration of previous medical ... & occupational history. Occupational history should take into account any previous exposure to benzene, radiomimetic substances or ionizing radiations. Medical exam should incl thorough physical ... & hematological examination. The latter ... should cover hemoglobin determination, red cell, white cell & platelet counts, white cell differential count & red cell & leukocyte morphology. Protect young persons of either sex under 18 yr of age from exposure to benzene since ... adolescents have lower resistance to bone-marrow poisons. Pregnant women & nursing mothers should not be exposed ... & special precautions are necessary where women of childbearing age are exposed to benzene hazard. ... Subjects with liver diseases & ... microcytemia should /be protected from exposure/. ... Periodic exam should be carried out in same way as pre-employment examination. ... Particular attention should be paid to any hematological abnormalities found during 1st periodic examination. ... Whenever there is slightest suspicion of leukemia, a bone-marrow biopsy is warranted.
[International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 260]**PEER REVIEWED**

Biological monitoring: Medical surveillance should incl blood pressure check, lung functions, blood chemistry, hematology, urinalysis & skin exam.
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1326]**PEER REVIEWED**

PRECAUTIONS FOR "CARCINOGENS": ... In relation specifically to cancer hazards, there are at present no health monitoring methods that may ensure the early detection of preneoplastic lesions or lesions which may preclude them. Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning additional tests that might become useful or mandatory. /Chemical Carcinogens/
[Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 23]**PEER REVIEWED**

Populations at Special Risk:

INDIVIDUALS WITH G6PD /GLUCOSE 6-PHOSPHATE DEHYDROGENASE/ DEFICIENCY HAVE ... BEEN FOUND TO BE MORE SUSCEPTIBLE TO HEMOLYTIC EFFECTS OF ... BENZENE ...
[Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975., p. 139]**PEER REVIEWED**

... /It has been observed/ that levels of leukocyte agglutins were elevated in selected individuals exposed to benzene. ... /This/ suggested that in some people benzene toxicity may be accounted for in part by an allergic blood dyscrasia.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 117 (1982)]**PEER REVIEWED**

... Workers with higher activities of /cytochrome P-450(2E1)/ are at more risk /of benzene hematoxicity/.
[International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998., p. 1.2]**PEER REVIEWED**

... It has been suggested that Thalassemia minor, and presumably other disorders in which there is increased bone marrow turnover, may predispose a person to benzene-induced aplastic anemia.
[International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998., p. 1.2]**PEER REVIEWED**

People living near hazardous waste sites who are chronically exposed to contaminated air, water, or soil may be at a higher risk for respiratory effects from exposure to /benzene/ ...
[U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.192 (1997)]**PEER REVIEWED**

Probable Routes of Human Exposure:

Human populations are primarily exposed to benzene through inhalation of contaminated ambient air particularly in areas with heavy traffic and around filling stations. In addition, air close to manufacturing plants which produce or use benzene may contain high concentrations of benzene(1,2). Another source of exposure is from inhalation of tobacco smoke(1). Although most public drinking water supplies are free of benzene or contain <0.3 ppb, exposure can be very high from consumption of contaminated sources drawn from wells contaminated by leaking gasoline storage tanks, landfills, etc(SRC).
[(1) IARC; Monograph, Some Industrial Chem and Dyestuffs 29: 99-106 (1982) (2) Graedel TE; Chem Compounds in the Atmos, NY, NY Academic Press (1978)]**PEER REVIEWED**

Rough estimates of average ambient ground-level benzene concentrations over an 8 hour period were calculated based on an emission rate of 100 g/sec from a manufacturing plant. Benzene concentrations (in pg/cu m) are estimated to be 11,000 at 0.15 km, 6,100 at 0.3 km, 3,800 at 0.45 km, 2,800 at 0.6 km, 2,100 at 0.75 km, 740 at 1.6 km, 370 at 2.5 km, 220 at 4.0 km, 120 at 6.0 km, 62 at 9.0 km, 34 at 14.0 km, and 20 at 20.0 km distance from the manufacturing plant(1).
[(1) Mara SJ, Shonh SL; Assesment of Human Exposures to Atmospheric Benzene. Menlo Park, CA: SRI. USEPA-450/3-78-031. NTIS PB 284 203 (1978)]**PEER REVIEWED**

NIOSH (NOES Survey 1981-1983) has statistically estimated that 272,275 workers (143,066 of these are female) are potentially exposed to benzene in the US(1). Occupational exposure to benzene may occur through inhalation and dermal contact with this compound at workplaces where benzene is produced or used(SRC). The general population may be exposed to benzene via inhalation of ambient air(2-4), ingestion of drinking water(5), and dermal contact with gasoline products(6) containing benzene(SRC).
[(1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Trost B et al; Atmos Environ 31: 3999-4008 (1997) (3) Singh HB, Zimmerman PB; Adv Environ Sci Technol 24: 177-235 (1992) (4) Wallace L; Environ Health Perspect 104: 1129-1136 (1996) (5) Krill RM, Sonzogni WC; J Am Water Works Assoc 78: 70-5 (1986) (6) Fruscella W; Kirk-Othmer Encycl Chem Technol. 4th ed. NY, NY: John Wiley and Sons 4: 80 (1992)]**PEER REVIEWED**

Benzene was detected in 3 out of 70 samples taken from 46 spray painting workshops in Sydney, Australia at a concn of 1 mg/cu m in 1989(1). In a study of in-auto and in-bus exposures to volatile organic compounds for commutes on an urban-suburban route in Korea from November 21 to December 22, 1994, revealed that mean in-auto concns of benzene were 30.6 ug/cu m along urban routes and 18.3 ug/cu m along suburban routes while mean in-bus concns were 20.2 ug/cu m along urban routes and 11.7 ug/cu m along suburban routes(2). In a 200-trip study of in-vehicle air of Los Angeles commuters, an avg concn of benzene at 40 ug/cu m during rush hour was detected(3).
[(1) Winder C et al; Ann Occup Hyg 36: 385-94 (1992) (2) Jo WK et al; Air Waste Manage Assoc 46: 749-754 (1996) (3) Wallace L; Environ Health Perspect 104: 1129-1136 (1996)]**PEER REVIEWED**

Body Burden:

Benzene was detected in all 8 samples of mothers' milk from women living in 4 USA urban areas(1). Breath samples from persons without specific exposure to benzene ranged from 8 to 20 ppb(2). Whole blood samples from 250 subjects (121 males, 129 females) ranged from not detected to 5.9 ppb, (mean 0.8 ppb)(3). In FY82, the National Human Adipose Tissue Survey specimens found that of 46 composite samples, 96% tested positive to benzene (concns were >4 ppb for wet tissue) with a max concn of 97 ppb max(4).
[(1) Pellizzari ED et al; Environ Sci Technol 16: 781-5 (1982) (2) IARC; Monograph. Some Industrial Chemicals and Dyestuffs. 29: 99-106 (1982) (3) Antoine SR et al; Bull Environ Contam Toxicol 36: 364-71 (1986) (4) Stanley JS; Broad Scan Analysis of the FY82 National Human Adipose Tissue Survey Specimens Vol. I Executive Summary p. 5 USEPA-560/5-86-035 (1986)]**PEER REVIEWED**

In a 1980's study of non-occupational benzene exposure, it was found that smokers had an avg benzene body burden about 6 to 10 times that of nonsmokers, and received about 90% of their benzene exposure from smoking(1). The mean benzene concn found in the breath and blood of 1,683 individuals was 13.1 and 131 ng/l, respectively(1).
[(1) Wallace L; Environ Health Perspect 104: 1129-1136 (1996)]**PEER REVIEWED**

Average Daily Intake:

Two recent studies of benzene levels in foods have confirmed the conclusion that ingesting food and beverages are an unimportant pathway for benzene exposure(1). In a study of more than 50 foods, most contained benzene below 2 ng/g ppbw(1). A Canadian review of benzene exposures concluded that food and drinking water each contributed only about 0.02 ug/kg benzene per day compared to a total intake of 2.4 ug/kg per day from airborne exposures (3.3 ug/kg/day if exposed to cigarette smoke). In a 1980's study of non-occupational benzene exposure, it was found that more than 99% of the total personal exposure was through air and that a global avg personal exposure for benzene was about 15 ug/cu m(1). Roughly half the total benzene exposure in the United States was borne by smokers(1). For non-smokers, most benzene exposure ultimately was derived from auto exhaust or gasoline vapor emissions(1). A series of experiments were conducted in a 290 sq m single-family residence from June 11-13, 1991 to ascertain the human exposure to benzene from a contaminated groundwater source(1). It involved an individual taking a 20 min shower with the bathroom door closed, followed by five minutes for drying and dressing, and then opening the bathroom door and allowing the individual to leave and have his blood, breath and urine sampled(1). Whole air samples were collected from the bathroom, shower and living room. The inhalation exposure to benzene of an individual in the living room avgd 72 ug for the three days(1). The individual taking the shower had an avg inhalation dose of 113 ug and an avg dermal dose of 168 ug (exposure = 40% inhalation, 60% dermal)(1). There may be a large number of cases where well water is contaminated by benzene at low concns(1). A number of studies have reported finding benzene at levels on the order of 5 ng/l in surface and well waters(1). However, these levels correspond to a daily intake of <10 ng benzene, assuming 2 liters of water drunk daily(1). This amount is only 0.5% of the avg daily intake for nonsmokers of 200 ng from air(1). Thus, it is concluded that the effect of contaminated water on total benzene intake is negligible(1).
[(1) Wallace L; Environ Health Perspect 104: 1129-1136 (1996)]**PEER REVIEWED**

Minimum Fatal Dose Level:

Benzene exposure is rapidly fatal at concentrations approaching 20,000 ppm.
[Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 724]**PEER REVIEWED**

... Probable human oral lethal dose would be between 50-500 mg/kg. Human inhalation of approximately 20,000 ppm (2% in air) was fatal in 5-10 min.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-8]**PEER REVIEWED**

Estimated oral doses from 9-30 g have proved fatal.
[WHO; Environmental Health Criteria 150: Benzene p.46 (1993)]**PEER REVIEWED**

Emergency Medical Treatment:

Antidote and Emergency Treatment:

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and teat if necessary ... . Monitor for shock and treat if necessary... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Benzene and related compounds.
[Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 184-5]**PEER REVIEWED**

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Benzene and related compounds/
[Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 185]**PEER REVIEWED**

Animal expt show that benzene sensitizes the myocardium to epinephrine, so that the endogenous hormone may precipitate sudden & fatal ventricular fibrillation.
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-398]**PEER REVIEWED**

Animal Toxicity Studies:

Toxicity Summary:

IDENTIFICATION: Benzene is an aromatic hydrocarbon used as a solvent. It is a clear liquid with a sweet odor. Origin of the substance: Benzene occurs naturally but is primarily produced from petroleum products. Uses: 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. HUMAN EXPOSURE: 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 hematotoxicity, including aplastic anemia, pancytopenia, or any combination of anemia, leukopenia, and thrombocytopenia Chronic benzene exposure is associated with an increased risk of leukemia. 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 hematological effects include anemia, thrombocytopenia, leukopenia, pancytopenia, chromosomal abberations, and leukemia. Dermal exposure may cause skin irritation. 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. In the United States, smoking accounts for approximately half of the total population exposure to benzene. In countries where benzene is used as a household cleaner, accidental or suicidal ingestion may occur. 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. 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 and adhesives by shoemakers led to a high degree of exposure in these industries. Routes of entry Oral: Acute oral exposure is uncommon and usually results from accidental ingestion or attempted suicide. Benzene is a contaminant in drinking water. Inhalation: Inhalation is the primary route of exposure for benzene, both in the occupational and environmental setting. The relatively high vapor pressure of benzene creates a significant hazard when adequate workplace safeguards are not in place. Dermal: Dermal exposure may occur in the occupational setting, although it is quantitatively less important than inhalation exposure. Eye: Ocular exposure may occur through splashing or high vapor concentrations. 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. In rodents the percentage of retained benzene decreased as the inhaled vapor concentration increased from 10 to 1000 ppm. In vitro dermal absorption in humans is 0.2% over a period of 13.5 hours. Distribution by route of exposure: 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. Exposure to 25 ppm of benzene for two hours produced an average maximum blood benzene concentration of 0.2 mg/L. 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. 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. 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. 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. 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. 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. In another human study, 30% of absorbed dermally applied benzene was excreted as phenol in the urine. Mode of action: Acute benzene exposure produces central nervous system excitation and depression. In chronic exposures, benzene metabolites are considered the toxic agents, not the parent compound. The relative contribution of different benzene metabolic pathways may be dose related, with more toxic agents produced by high affinity low capacity pathways. Chronic benzene exposure can cause bone marrow stem cell depression, apparently through a cytotoxic effect on all lineages of hematopoietic 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. Hydroquinone and phenol are known hematotoxins. Toxicity: Human data: Adults: Inhalation exposure at 20,000 ppm for five to ten minutes may be fatal. Exposure to 150 to 650 ppm for 4 months to 15 years caused pancytopenia. 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. Carcinogenicity: In epidemiologic studies, chronic exposure to benzene is associated with the development of acute myelogenous leukemia and its variants including erythroleukemia. Other forms of leukemia including acute lymphoblastic anemia, acute monocytic leukemia, and preleukemia have also been reported following benzene exposure. Other hematopoietic malignancies have been described in association with benzene exposure including malignant lymphoma, myeloid metaplasia, and multiple myeloma. The relative risk for leukemia was 6.97 times the risk in the unexposed group. 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. 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. In a study of 1165 workers in a rubber hydrochloride factory there were 9 deaths from leukemia. 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. Teratogenicity: Benzene crosses the placenta and is present in cord blood in concentrations equal to or greater than maternal blood. 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. Mutagenicity: In studies of occupational exposure, benzene was found to cause chromosome changes at concentrations that induced blood dyscrasias. 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 hematological effects. 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. Interactions: Ethanol can increase the extent of hematotoxicity from benzene exposure. Previous administration of phenobarbital may decrease benzene hematotoxicity. Toluene reduces the metabolizm of benzene and reverses the benzene induced decrease in incorporation of iron into red blood cells. Hepatitis B may also increase the incidence of hematopoietic effects from benzene exposure. 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. 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. Death may be due to CNS depression, asphyxiation, or respiratory or circulatory arrest. In fatal cases autopsy has revealed haemolysis, cyanosis, and multiple organ hemorrhage. In chronic benzene exposures, patients developing minor hematologic 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. Chronic ingestion of benzene for therapeutic purposes reportedly led to bladder irritability and impotence in some patients. 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. Decreases in cellular immunity have been documented through leucopenia. ANIMAL STUDIES: In animal models, benzene is well absorbed by the oral route, ranging from over 90% in rabbits to over 97% in rats and mice. 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. Metabolism: 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. 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. 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. 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. 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. Exposure in utero to 20 ppm of benzene for 6 hr/day on days 6 to 15 of gestation in mice resulted in hematopoietic abnormalities. Exposures in rats to less than 10 ppm of benzene during pregnancy did not cause adverse fetal changes. 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. One report of sudden death after running and acute benzene exposure was felt to be due to benzene induced myocardial sensitivity to endogenous catecholamines. Immunological: 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 Eschericha 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. 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. Animal experiments exposing pregnant mice, rats, and rabbits demonstrated fetotoxicity associated with maternal toxicity, specifically fetal skeletal variants and reduced fetal weight.
[International Programme on Chemical Safety; Poisons Information Monograph: Benzene (PIM 063) (1999) Available from http://www.inchem.org/pages/pims.html as of October 24, 2005. ]**PEER REVIEWED**

Evidence for Carcinogenicity:

Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient; Overall summary evaluation of carcinogenic risk to humans is group 1: The chemical is carcinogenic to humans. /From table/
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. S7 120 (1987)]**PEER REVIEWED**

A1; Confirmed human carcinogen.
[ American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinatti, OH, 2005, p. 13]**QC REVIEWED**

WEIGHT-OF-EVIDENCE CHARACTERIZATION: Benzene is classified as a "known" human carcinogen (Category A) under the Risk Assessment Guidelines of 1986. Under the proposed revised Carcinogen Risk Asessment Guidelines (USEPA, 1996), benzene is characterized as a known human carcinogen for all routes of exposure based upon convincing human evidence as well as supporting evidence from animal studies. Epidemiologic studies and case studies provide clear evidence of a causal association between exposure to benzene and acute nonlymphocytic leukemia and also suggest evidence for chronic nonlymphocytic leukemia and chronic lymphocytic leukemia. Other neoplastic conditions that are associated with an increased risk in humans are hematologic neoplasms, blood disorders such as preleukemia and aplastic anemia, Hodgkin's lymphoma, and myelodysplastic syndrome. These human data are supported by animal studies. The experimental animal data add to the argument that exposure to benzene increases the risk of cancer in multiple species at multiple organ sites (hematopoietic, oral and nasal, liver, forestomach, preputial gland, lung, ovary, and mammary gland). It is likely that these responses are due to interactions of the metabolites of benzene with DNA ... Recent evidence supports the viewpoint that there are likely multiple mechanistic pathways leading ... to leukemogenesis from exposure to benzene. HUMAN CARCINOGENICITY DATA: Benzene is a known human carcinogen based upon evidence presented in numerous occupational epidemiological studies. Significantly increased risks of leukemia, chiefly acute myelogenous leukemia, have been reported in benzene-exposed workers in the chemical industry, shoemaking and oil refineries. ANIMAL CARCINOGENICITY DATA:... many experimental animal studies, both inhalation and oral, also support the evidence that exposure to benzene increases the risk of cancer in multiple organ systems, including the hematopoietic system, oral and nasal cavities, liver, forestomach, preputial gland, lung, ovary, and mammary gland ....
[U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Benzene (71-43-2). Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000]**PEER REVIEWED**

Non-Human Toxicity Excerpts:

Inhalation of air saturated with benzene vapor resulted in ventricular extrasystole in the cat & primate, with periods of ventricular tachycardia that occasionally terminated in ventricular fibrillation. ... In rabbit, sudden death from ventricular fibrillation has also been observed. ... In acute inhalation by male rats, benzene-induced resp paralysis occurred, followed by ventricular fibrillation.
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1318]**PEER REVIEWED**

... DOGS INHALING BENZENE ... DEVELOPED HYPERTENSION. THIS WAS SOON FOLLOWED BY PARALYSIS OF VASOMOTOR SYSTEM DUE TO EFFECT OF BENZENE ON SMOOTH MUSCLE OF BLOOD VESSELS.
[Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963., p. 1221]**PEER REVIEWED**

Benzene in rabbit eye is a moderate irritant, causes conjunctival irritation, & ... transient slight corneal injury.
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1318]**PEER REVIEWED**

IN SERIES OF CHRONIC STUDIES, BILATERAL CATARACTS WERE FOUND IN 50% OF RATS EXPOSED /TO/ ... 50 PPM FOR 600 HR ...
[National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 689]**PEER REVIEWED**

Rats, guinea-pigs, & rabbits exposed to 80-88 ppm (256-281 mg/cu m) for 7 hr/day for 30-40 wk had incr testicular wt & degeneration of seminiferous tubules. ... Alteration of estrous cycles has been reported in rats exposed to 1.6 or 9.4 ppm (5 or 30 mg/cu m) for 4 mo ... but there was no effect on their subsequent fertility or litter size. ... In C3H(JAX) mice whose ovaries were painted directly ... & which were later mated, a high incidence of sc hemorrhages & tail defects was observed in offspring, which persisted through 4 generations.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 111 (1982)]**PEER REVIEWED**

... STUDIES HAVE DEMONSTRATED THE INDUCTION OF CHROMOSOMAL ABERRATIONS IN BONE-MARROW CELLS FROM MICE, RATS, AND RABBITS TREATED WITH SINGLE OR MULTIPLE DAILY DOSES OF BENZENE RANGING FROM ABOUT 0.2 TO 2.0 ML/KG PER DAY & GIVEN EITHER SC OR IP. MOST OF THE INDUCED ABERRATIONS WERE BREAKS OR DELETIONS; BUT CHROMOSOME-TYPE ABERRATIONS ALSO OCCURRED, PARTICULARLY AFTER PROLONGED EXPOSURE, WHEN TOXICITY, MANIFESTED BY A DROP IN PERIPHERAL BLOOD LEUCOCYTE COUNT, APPEARED. ... A SIGNIFICANT ELEVATED LEVEL OF ABERRATIONS ARE SEEN UP TO 8 DAYS AFTER A SINGLE IP INJECTION OF 0.5 ML/KG BODY WT IN RATS, WHEREAS ABERRATIONS WERE SIGNIFICANTLY INCR IN MICE 24 HR BUT NOT 7 DAYS AFTER RECEIVING A SIMILAR DOSE, 0.5 ML/KG BODY WT.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 115 (1982)]**PEER REVIEWED**

... 30 MALE AKR, DBA2, C3H OR C57BL6 MICE WERE GIVEN WEEKLY SC INJECTIONS OF 0.001 ML BENZENE IN 0.1 ML OLIVE OIL FOR LIFE. NO TUMORS WERE FOUND IN MICE OF DBA2, C3H OR C57BL6 STRAINS, THE MAX LIFESPAN BEING 730 DAYS. BETWEEN 7TH & 16TH MO OF TREATMENT 16/30 TREATED AKR MICE DIED WITH LEUKEMIA, IN ADDITION, 8 DIED BEFORE AGE OF 9 MO WITHOUT LEUKEMIA. HOWEVER, LEUKEMIA WAS ALSO OBSERVED IN 30/35 AKR UNTREATED MICE WHICH LIVED, ON AVG, LONGER THAN TEST ANIMALS.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V7 209 (1974)]**PEER REVIEWED**

... AFTER 5 TO 8 WK OF 5 HR/DAY, 5 DAYS/WK EXPOSURE AT 44 & 47 PPM, RATS DEVELOPED A MODERATE DEGREE OF LEUKOPENIA, BUT ... NONE RESULTED FROM 15 TO 31 PPM. ... DECR IN THE WHITE CELL COUNTS OF RATS /WAS OBSERVED/ FOLLOWING 756 HR OF EXPOSURE AT 50 PPM OF BENZENE ON A SCHEDULE OF 8 HR/DAY, 5 DAY/WK. REDUCED AMT OF DNA IN THE WHITE CELLS, A DEPRESSION IN MYELOCYTIC ACTIVITY, & AN INCR IN THE RELATIVE NUMBER OF RED CELL PRECURSORS IN THE BONE MARROW WERE ALSO OBSERVED.
[American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986., p. 50]**PEER REVIEWED**

SPRAGUE-DAWLEY RATS WERE EXPOSED TO 100, 300, & 2200 PPM OF BENZENE VAPOR IN AIR FOR 6 HR DAILY ON DAYS 6-15 OF GESTATION. THE MEAN BODY WT & CROWN-RUMP LENGTH WERE LOWER THAN CONTROL GROUPS ONLY AT THE HIGHEST EXPOSURE LEVEL. SKELETAL EXAM SHOWED AN INCR IN THE NUMBER OF FETUSES WITH DELAYED OSSIFICATION OF STERNEBRAE IN THE 300- & 2200-PPM GROUPS. THE FEMALE OFFSPRING APPEARED TO BE AFFECTED TO A GREATER EXTENT THAN MALE FETUSES WITH RESPECT TO THE INCIDENCE OF DELAYED OSSIFICATION OF STERNEBRAE. LIFETIME EXPOSURE OF C57BL/6J MICE TO 100 OR 300 PPM (320 OR 958 MG/CU M) BENZENE PRODUCES ANEMIA, LYMPHOCYTOPENIA & NEUTROPHILIA ASSOC WITH A RELATIVE INCR IN THE NUMBER OF IMMATURE LEUCOCYTES & DECR IN MATURE LEUCOCYTES IN CIRCULATION. SC ADMIN BENZENE LED TO A SELECTIVE DEPRESSION IN B-LYMPHOCYTES IN RABBITS, WHEREAS T LYMPHOCYTES WERE MORE RESISTANT.
[GREEN JD ET AL; TOXICOL APPL PHARMACOL 46 (1): 9-18 (1978)]**PEER REVIEWED**

Male Charles River CD-1 mice (number unspecified) were exposed for 6 hr/day, 5 days/wk, for life to atmospheres containing ... levels of 0 (control), 100 ppm (320 mg/cu m) or 300 ppm (958 mg/cu m). Two mice in high-exposure group develop myelogenous (myeloid) leukemia. ... There was no evidence of leukemic response in 45 male 6 wk old Sprague-Dawley rats exposed to ... 900 mg/cu m (300 ppm) ... for 6 hr/day, 5 days/wk, for life. Exposure was terminated at wk 99 when the last test animal died. Controls were 27 males of same strain & age. ... Sprague-Dawley rats & AKR mice exposed to benzene (300 ppm, 958 mg/cu m) for 6 hr/day, 5 days/wk for life had lymphocytopenia, with little evidence of anemia. AKR mice were more sensitive to benzene-induced leucopenia than ... rats. /Mice also displayed agranulocytosis & reticulocytosis. No evidence of leukemia was reported/.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 108 (1982)]**PEER REVIEWED**

Single sc injection of 3 ml/kg body wt ... on 1 of days 11-15 of gestation to CFI mice caused cleft palate, agnathia & micrognathia in offspring ... . (No controls were used, & it is very likely that these effects were produced by stress of the injection). Several other studies in pregnant mice exposed to benzene, (2 & 4 ml/kg body wt sc, 0.3 to 1.0 ml/kg body wt orally or 500 ppm (1597 mg/cu m) by inhalation for 7 hr/day all failed to show any teratogenic effect, although reduced fetal wt & occasional embryolethality were observed. Similarly, several inhalation studies in rats have shown embryolethality & reduced fetal wt but only occasional teratogenic effects: Sprague-Dawley rats exposed to 10, 50, or 500 ppm (32, 160 & 1600 mg/cu m) for 7 hr/day had low incidence of brain & skeletal defects but no embryolethality at 50 or 500 ppm, & no abnormality or embryolethality at lower levels ... . No teratogenic effect was seen in pregnant rats exposed to 10 or 40 ppm (32 or 128 mg/cu m) for 6 hr/day ..., to 313 ppm (1000 mg/cu m) for 24 hr/day or for 6 hr/day ... or to 400 mg/cu m (125 ppm) for 24 hr/day (Tatrai et al 1980). No teratogenic effect has been reported in rabbits injected sc with 0.25 ml/kg of a 40% benzene soln daily during pregnancy ... or in rabbits exposed by inhalation to 500 ppm (1600 mg/cu m) for 7 hr/day on days 6-18 of pregnancy.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 111 (1982)]**PEER REVIEWED**

Rabbits and rats injected subcutaneously with 0.2 mg/kg/day showed an incr frequency of bone marrow mitoses.
[Dobrokhotov VB; Gig Sanit 37: 36 (1972)]**PEER REVIEWED**

Bone marrow cells from mice orally dosed with 56-2050 mg/kg on two successive days showed dose-related incr in incidences of chromosomal gaps and single breaks, multiple breaks at or above 139 mg/kg, pulverization at or above 348 mg/kg, and cytotoxicity at 2050 mg/kg.
[Siou G et al; Mutat Res 90: 273-8 (1981)]**PEER REVIEWED**

Mice orally dosed with 0.22-1.65 g/kg showed a positive dose-related increase in polychromatic erythrocytes in the micronucleus test.
[Schmidt W; Mutat Res 31: 9-15 (1975)]**PEER REVIEWED**

Rats exposed continuously to 209.7 ppm for 10 days prior to breeding showed a complete absence of pregnancy. 1/10 rats exposed to 19.8 ppm had resorbed embryos. Females showed an inverse relationship between dose (0.3-209.7 ppm) and number of offspring.
[Gofmekler VA; Hyg Sanit 33: 327 (1968)]**PEER REVIEWED**

Chromosomal abnormalities in bone marrow cells have been reported as a consequence of experimental benzene exposure in a number of species including rats, rabbits, mice, and amphibians.
[USEPA; Ambient Water Quality Criteria: Benzene p.C-44 (1980) EPA 440/5-80-018]**PEER REVIEWED**

Chromatid deletions in metaphase chromosomes of bone marrow cells have been found in rats given single doses of subcutaneous benzene at 2 ml/kg and in rats given 1 g/kg/day for 12 days.
[USEPA; Ambient Water Quality Criteria: Benzene p.C-44 (1980) EPA 440/5-80-018]**PEER REVIEWED**

After rats were dosed with 0.5 ml/kg intraperitoneally, no dominant lethality was found; however, incr chromatid and chromosomal aberrations were reported.
[USEPA; Ambient Water Quality Criteria: Benzene p.C-44 (1980) EPA 440/5-80-018]**PEER REVIEWED**

Benzene is a mitotic poison, producing a decr in DNA synthesis in animal bone marrow cells in vitro.
[USEPA; Ambient Water Quality Criteria: Benzene p.C-45 (1980) EPA 440/5-80-018]**PEER REVIEWED**

Weanling male C57BL/6N mice were subcutaneously injected twice weekly for 44 weeks and once weekly for the last 10 weeks, gradually incr the dose from 450 mg/kg to 1.8 g/kg. The mice were killed 104 weeks after the first injection, and no evidence of carcinogenic activity was found in either the benzene-treated mice or the negative controls. Butylnitrosourea induced leukemia, lymphomas, and/or intestinal neoplasms/were observed/ in almost all the positive controls.
[USEPA; Ambient Water Quality Criteria: Benzene p.C-48 (1980) EPA 440/5-80-018]**PEER REVIEWED**

TWO GROUPS OF 40 MALE C57BL/6J MICE, 6 WK OLD, WERE EXPOSED TO ATMOSPHERES CONTAINING 0 OR 900 MG/CU M (300 PPM) BENZENE FOR 6 HR/DAY, 5 DAYS/WK, FOR LIFE. THE EXPOSURE ENDED AFTER 488 DAYS WITH THE DEATH OF THE LAST TEST MOUSE. IN ADDN TO ANEMIA, LYMPHOCYTOPENIA, NEUTROPHILIA & BONE-MARROW HYPERPLASIA, 6 OF 40 MICE EXPOSED ... DEVELOPED LYMPHOCYTIC LYMPHOMA WITH THYMIC INVOLVEMENT (P< 0.01 FOR LYMPHOMAS, ACCORDING TO PETO'S LOG-RANK METHOD), 1 PLASMACYTOMA & 1 HEMATOCYTOBLASTIC LEUKEMIA. AVG SURVIVAL TIME OF THE 8 TUMOR-BEARING MICE WAS 262 DAYS. TWO OF THE 40 CONTROL ANIMALS DIED FROM LYMPHOCYTIC LYMPHOMA WITH NO THYMIC INVOLVEMENT AFTER 282 & 608 DAYS, RESPECTIVELY. DIFFERENCES IN INCIDENCE & INDUCTION TIME OF TUMORS BETWEEN THE GROUPS WERE STATISTICALLY SIGNIFICANT (SNYDER ET AL 1980). (THE WORKING GROUP NOTED THAT THYMUS WAS NOT EXAM ROUTINELY).
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 108 (1982)]**PEER REVIEWED**

THREE GROUPS OF 30 OR 35 MALE & ... FEMALE SPRAGUE-DAWLEY RATS, 13 WK OLD, RECEIVED 50 OR 250 MG/KG BODY WT BENZENE (PURITY UNSPECIFIED) DISSOLVED IN PURE OLIVE OIL BY STOMACH TUBE ONCE DAILY ON 4 OR 5 DAYS EACH WK DURING 52 WEEKS. GROUPS OF 30 MALE & 30 FEMALE CONTROLS RECEIVED OLIVE OIL ONLY. THE RATS WERE ALLOWED TO LIVE UNTIL SPONTANEOUS DEATH OR WERE KILLED AT 144 WEEKS, THE END OF EXPT; AVG SURVIVAL TIMES WERE UNSPECIFIED. OF FEMALES OF THE CONTROL, LOW- & HIGH-DOSE GROUPS, 0/30, 2/30 & 8/32, RESPECTIVELY, DEVELOPED ZYMBAL GLAND CARCINOMAS (COCHRAN-ARMITAGE TEST FOR POS TREND; P= 0.001; FISHER EXACT TEST FOR CONTROL VERSUS HIGH-DOSE GROUP: P= 0.003); 3/30, 4/30 & 7/32 DEVELOPED MAMMARY GLAND CARCINOMAS; & 1/30, 2/30 & 1/32 DEVELOPED LEUKEMIAS. NO SUCH TUMORS WERE FOUND IN MALES, EXCEPT THAT LEUKEMIAS OCCURRED IN 4/32 HIGH-DOSE MALES (COCHRAN-ARMITAGE TEST FOR POS TREND; P= 0.008; FISHER EXACT TEST: P< 0.069). BACKGROUND INCIDENCE OF ZYMBAL GLAND CARCINOMAS IN SEVERAL THOUSAND MALE & FEMALE RATS OF SAME STRAIN ... /WAS/ ABOUT 0.7%. AVG LATENT PERIOD OF MAMMARY GLAND CARCINOMAS WAS 88 WK IN EACH TEST GROUPS VERSUS 110 WK IN CONTROL ... .
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 106 (1982)]**PEER REVIEWED**

BLUE CRAB JUVENILES WHEN EXPOSED TO SUBLETHAL CONCN OF BENZENE (0.1 OR 5.0 PPM) IN A STATIC SYSTEM SHOWED AN INCR IN THE TIME NEEDED TO COMPLETE A MOLT CYCLE (50 DAYS IN CASE OF BENZENE-EXPOSED CRAB, AS COMPARED TO 33 DAYS FOR CONTROLS), A SLOWER RATE OF GROWTH OF REGENERATING LIMB BUDS, & A DEPRESSED ACTIVITY OF ATPASE IN MITOCHRONDRIA. OXYGEN CONSUMPTION BY THE CRAB DECR FROM EXPOSURE TO 1.0 PPM BENZENE.
[CANTELMO A ET AL; PHYSIOL MECH MAR POLLUT TOXIC (PROC SYMP POLLUT MAR ORG): 349-89 (1982)]**PEER REVIEWED**

Toxicity threshold (cell multiplication inhibition test): bacteria (Pseudomonas putida) 92 mg/l; algae (Microcystis aeruginosa) >1400 mg/l; green algae (Scenedesmus quadricauda) >1400 mg/l; protozoa (Entosiphon sulcatum) >700 mg/l, & (Uronema parduczi Chatton-Lwoff) 486 mg/l. Algae (Chlorella vulgaris) /showed/ 50% reduction of cell numbers versus controls after 1 day incubation at 20 deg C at 525 ppm. Inhibition of photosynthesis (of a freshwater, nonaxenic unialgal culture of Selenastrum capricornutum) at 10 mg/l, 95% carbon-14 fixation (versus controls); at 100 mg/l, 84% carbon-14 fixation (versus controls); at 1000 mg/l, 5% carbon-14 fixation (versus controls). ... Young Coho salmon /showed/ no significant mortalities up to 10 ppm after 96 hr in artificial seawater at 8 deg C ... Mortality /was/ 12/20 at 50 ppm after 24 hr up to 96 hr & 30/30 at 100 ppm after 24 hr in artificial seawater at 8 deg C. Herring & anchovy larvae (Clupea pallasi & Engraulis mordex) /studies showed that/ 35-45 ppm caused delay in development of eggs & /produced/ abnormal larvae; 10-35 ppm caused delay in development of larvae, decrease in feeding & growth, & increase in respiration.
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 257]**PEER REVIEWED**

Groups of 5 to 10 pregnant Swiss-Webster mice were exposed to concentrations of 0, 5, 10, or 20 ppm benzene from days 6 through 15 of gestation and offspring of exposed dams were examined for untoward effects. Litter sizes, fetal weights, numbers of dead, resorbed, or malformed fetuses were within control limits. In the fetuses (day 16 of gestation), the number of mature erythroid precursor cells (CFU-E) was decreased at 20 ppm benzene. In the neonates, the number of CFU-E cells was increased at 20 ppm benzene. Granulocytic colony forming cells (GM-CFU-C) were affected by the 2 higher exposure concentrations. Adult mice treated in utero when re-exposed to benzene showed a more severe decrease in splenic GM-CFU-C than controls.
[Keller KA, Snyder CA; Toxicology 42: 171-81 (1986)]**PEER REVIEWED**

The best evidence that benzene must be metabolized to produce bone marrow depression is based on: 1) the observation that benzene toxicity is prevented by coadministration of toluene, which inhibits benzene metabolism; and 2) that partial hepatectomy (which decreases benzene metabolism) also decreases benzene toxicity.
[USEPA; ECAO Atlas Document: Benzene IV-11 (1980)]**PEER REVIEWED**

Reports indicate that protection against benzene toxicity in phenobarbital treated animals reflects the fact that phenobarbital increased the detoxification rate of benzene in the liver. Inhibition of metabolism by toluene and by aminotriazole has been found to protect animals by decreasing the rate of formation of toxic metabolites.
[USEPA; ECAO Atlas Document: Benzene IV-11 (1980)]**PEER REVIEWED**

The principal hydroxy metabolites of benzene, hydroquinone, catechol and phenol were assayed in tests for mitotic segregation induction in Aspergillus nidulans diploid strain 19. Hydroquinone was the most effective chemical, increasing the frequency of mitotic segregants up to 10 fold at 1-3 mM. Catechol was similarly active at 10-20 mM and phenol was weakly positive at 15 mM. Genetic characterization of induced abnormal segregating colonies by replating and complementary assays with haploid strain 35 suggest that gross chromosomal aberrations, instead of numerical abnormalities, are the primary genetic damages induced by hydroxybenzenes in Aspergillus. The protecting activity exerted by L-cysteine against equimolar concentrations of hydroquinone supports a free radical mechanism for hydroxy metabolite genotoxicity in Aspergillus nidulans.
[Crebelli R et al; Mutagenesis 2 (3): 235-8 (1987)]**PEER REVIEWED**

Benzene hematotoxicity and leukemogenesis were investigated to verify epidemiological estimates to the effect that leukemia had developed in human beings exposed to benzene for about 15% of their lifetime, and that the levels of exposure reached at times as high as 250 to 300 ppm for at least a portion of working day. Based on a review of the literature and ongoing studies, mice were exposed to benzene vapor for 6 hr/day, 5 days/week for 16 weeks. Exposure of male CBA/Ca mice to 300 ppm benzene proved to be highly carcinogenic and leukemogenic compared to unexposed controls. Male and female CBA/Ca mice exposed to 100 ppm benzene, according to the same schedule, showed 30% mortality as compared to 12% in controls, while for neoplasms the respective figures were 10% and 1%. In this case, exposure to benzene reduced the cellularity of the bone marrow and the number of stem cells, while DNA synthesis increased. /Data indicates/ that benzene is carcinogenic in both animals and man and although it is unlikely that the slope for animals and man would be the same, the investigation of the linearity of the response would be helpful.
[Cronkite BP; Blood Cells 12 (1): 129-37 (1986)]**PEER REVIEWED**

A review of recent advances in the metabolism and toxicity of benzene was presented. Metabolism of benzene was discussed including the microsomal metabolism of benzene, mitochondrial metabolism of benzene, effect and its metabolites on replication and transcription, and covalent binding of reactive metabolites of benzene with macromolecules. The toxicity of benzene, including genotoxicity, carcinogenicity, hematopoietic toxicity, and immunotoxicity, was reviewed. Mutagenicity and cytogenic toxicity were also covered. Effects on stem cells, progenitor cells, and on the stromal microenvironment were discussed. Cytogenetic effects observed in animals and humans following exposure to benzene were reviewed. Myeloclastogenic effects and clastogenic effects were covered. Leukemias and related diseases in humans, associated with repeated exposure to benzene at relatively high concentrations, were discussed. Aplastic anemia from benzene poisoning was also discussed. Progress made in understanding the bioactivation of benzene and in the elucidation of metabolites produced in the liver and bone marrow was discussed.
[Kalf GF; CRC Crit Rev Toxicol 18 (2): 141-59 (1987)]**PEER REVIEWED**

Environmental exposure to benzene results in both myelotoxicity and immunotoxicity. Although benzene induced immunotoxicity has been well documented, no studies to date have addressed the possibility that benzene toxicity is due in part to altered differentiation of marrow lymphoid cells. The effect of acute exposure to the benzene metabolite, hydroquinone, on murine bone marrow B-lymphopoiesis was investigated. Bone marrow cell suspensions from B6C3F1 (C57BL/6J x C3H/HeJ) mice were depleted of mature surface IgM+ B cells and cultured for 0, 24, 48, or 72 hr and production of newly formed B cells was assayed both by mature surface expression and colony formation in soft agar cultures. One hr exposure of bone marrow cells to hydroquinone before culture reduced the number of mature surface cells generated in liquid cultures. Small pre-B cells (cytoplasmic mu heavy chain+, sIgM-) were numerically elevated as compared with control cultures. Hydroquinone exposure also decreased the number of adherent cells found in cultures of bone marrow cells. These results suggest that short-term exposure to hydroquinone, an oxidative metabolite of benzene, may in some way block the final maturation stages of B cell differentiation. This apparent differentiation block resulted in reduced numbers of B cells generated in culture and a corresponding accumulation of pre-B cells. Reduction of adherent cells in treated cultures may also suggest that toxicity to regulatory cells for the B lineage may be in part responsible for this aspect of hydroquinone myelotoxicity.
[King AG et al; Mol Pharmacol 32 (6): 807-12 (1987)]**PEER REVIEWED**

Benzene is a potent bone marrow toxin in animals and man. Animal studies have shown that exposure to benzene can alter lymphocyte functions and decrease the resistance of animals to Listeria monocytogenes and transplanted tumor cells. Mononuclear phagocytes participate in host resistance to Listeria and tumor cells. The purpose of the studies presented here was to determine the effects of benzene and benzene metabolites on macrophage functions and the ability of macrophages to be activated for functions which are important in host defense. Benzene had no effects on macrophage function or activation for any of the functions tested. Conversely, metabolites of benzene, catechol, hydroquinone, benzquinone, and 1,2,4-benzenetriol had potent and varied effects on macrophage function and activation. Benzoquinone inhibited the broadest range of functions including release of hydrogen peroxide, Fc receptor-mediated phagocytosis, interferon gamma priming for tumor cell cytolysis, and bacterial lipopolysaccharide triggering of cytolysis. Benzoquinone was also the most potent metabolite causing inhibition at lower concentrations than the other metabolites. Hydroquinone inhibited hydrogen peroxide release and priming for cytolysis and 1,2,4-benzenetriol inhibited phagocytosis and priming for cytolysis. Catechol only inhibited the release of hydrogen peroxide. None of the compounds tested inhibited the induction of class II histocompatibililty antigens on the cell surface. All of the effects measured occurred using concentrations of compounds which did not disrupt the cell integrity or inhibit general functions such as protein synthesis. Taken together these data suggest that benzene metabolites alter macrophage function through several mechanisms including inhibition of output enzymes and disruption of signal transduction systems.
[Lewis JG et al; Toxicol Appl Pharmacol 92 (2): 246-54 (1988)]**PEER REVIEWED**

Female Wistar rats were exposed to various solvent vapors 8 hr/day for 7 days. The leukocyte suspension and serum were prepared from peripheral blood and utilized for the determination of alkaline phosphatase activity with disodium phenyl phosphate as a substrate (leukocyte alkaline phosphatase and serum assay). While the exposure to benzene at 20 or 50 ppm did not cause significant changes in leukocyte alkaline phosphatase assay activity, the exposure at 100 to 300 ppm resulted in a dose-dependent increase of leukocyte alkaline phosphatase assay activity up to more than 100% over the control. No further increase was observed at 1000 or 3000 ppm. Similar exposure at 300 ppm to either toluene, m-xylene, n-hexane, trichloroethylene, methyl ethyl ketone, ethyl acetate, or methyl alcohol did not induce any changes in leukocyte alkaline phosphatase assay activity. Thus, the increase in leukocyte alkaline phosphatase assay activity was considered to be specific to benzene exposure. When the animals were exposed to toluene (300 ppm) in combination with benzene (300 ppm), not only was the benzene induced leukopenia alleviated as previously reported, but the benzene induced increase in leukocyte alkaline phosphatase assay activity was no longer observed. The parallel inhibitory effects of toluene on benzene induced increase in leukocyte alkaline phosphatase assay and leukopenia suggest that a relation may exist between increase in leukocyte alkaline phosphatase assay activity and leukopenia. No changes in serum alkaline phosphatase assay activities were observed in the rats under the exposure conditions examined.
[Li GL et al; J Toxicol Environ Health 19 (4): 581-9 (1986)]**PEER REVIEWED**

A review was presented of data for ... chemicals for which either ovarian toxicity or carcinogenicity, or both, have been documented in recent studies /conducted by/ the National Toxicology Program. In most cases, ovarian atrophy was commonly found after 90 days of exposure, and ovarian hyperplasia and neoplasia after longer periods. Benzene administered by gavage produced ovarian atrophy, cysts, hyperplasia and neoplasia in mice.
[Maronpot RR; Environ Health Perspect 73: 125-30 (1987)]**PEER REVIEWED**

Based on literature, the mechanism of multitoxic effects of benzene and lesions in the peripheral blood of affected animals were postulated. The effects of chronic benzene poisoning upon erythrocytes and erythropoiesis, granulocytes and granulopoiesis, lymphocytes and lymphopoiesis, thrombocytes and thrombopoiesis were presented. Differences were pointed out in toxic effects of benzene varying with the kind, concentration and administration route of benzene and quantitative and qualitative differences in the fodder given to animals during the experiment.
[Moszczynski P, Lisiewicz J; Med Pr 36 (5): 316-24 (1985)]**PEER REVIEWED**

The effect of a single dose of benzene (0.5 ml/kg body wt ip) on the heme saturation of tryptophan pyrrolase activity in liver was examined /in female albino rats/. There was a significant decrease in the heme saturation of hepatic tryptophan pyrrolase, suggesting depletion of regulatory heme. After benzene administration there was significant increase in delta-aminolevulinate synthetase activity while delta-aminolevulinate dehydratase activity was significantly decreased, however, ferrochelatase and heme oxygenase activities were unaltered. Administration of tryptophan to benzene pretreated rats showed a reversal of benzene effects on heme synthesizing enzymes: there is an increase in the heme saturation of tryptophan pyrrolase and decrease in delta-aminolevulinate synthetase. However, there was no significant alteration in the activity of delta-aminolevulinate dehydratase.
[Siddiqui SM et al; Toxicol 48 (3): 245-51 (1988)]**PEER REVIEWED**

The effects of five straight alkane petroleum hydrocarbons (nC6 to nC10), as well as benzene and toluene upon lysosomal enzymes of the lung were investigated. Pulmonary alveolar macrophages were obtained from adult male Sprague Dawley rats and from 3 month old New-Zealand white rabbits by bronchial lavage. These cells were cultured and subsequently exposed to hydrocarbons in Leighton tubes. All hydrocarbons examined were cytotoxic to cultured pulmonary alveolar macrophages in a dose dependent manner, with benzene and toluene being least toxic. The concentration of hydrocarbon producing death in 50% of treated rat cells was 1.0 millimolar (mM) for nC8, 2.0 mM for nC7, 5 mM for nC9, and about 10 mM for nC6, nC10, benzene and toluene. Concentrations of hydrocarbons that killed 50% of rabbit macrophages were about half those observed in the rat. Cathepsin-D and, to a lesser extent, cathepsin-B release were stimulated upon addition of hydrocarbons to the cell media. A similar but more pronounced release of cathepsins was observed in isolated lysosomes as well. A significant decrease in cell respiration rate and a time and dose dependent increase in lipid peroxidation were also observed following exposure of macrophages to the tested hydrocarbons, particularly nC7 and nC8 alkanes. These results support the concept of an association between chain length and cytotoxicity of hydrocarbons in pulmonary alveolar macrophages.
[Suleiman SA; Arch Toxicol 59 (6): 402-7 (1987)]**PEER REVIEWED**

... Under the conditions of these 2 yr 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. For 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, squamous cell papillomas, and squamous cell carcinomas of the oral cavity. For male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), Harderian gland adenomas, and squamous cell carcinomas of the preputial gland. For female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benigh mixed tumors, carcinomas and carcinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcinomas. ...
[Toxicology & Carcinogenesis Studies of Benzene in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 289 (1986) NIH Publication No. 86-2545 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709]**PEER REVIEWED**

In animal models, benzene induces anemia, lymphocytopenia, and hypoplastic bone marrow. In addition, it has been suggested recently that this myelotoxicity may be a result of altered differentiative capacity in bone marrow-derived lymphoid cells.
[Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 380]**PEER REVIEWED**

... Solid tumors have been reported in animals exposed to benzene by inhalation or orally, suggesting that in mice and rats benzene may produce tumors in nonhematopoietic organs.
[Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 742]**PEER REVIEWED**

When Sprague-Dawley rats and CD-1 mice of either sex were exposed to benzene by inhalation 6 hr/day, 5 d/wk for 13 wk at 1, 10, 30, or 300 ppm, treatment-related pathology was observed in the high-dose (300 ppm) groups of both species. In mice, hematologic changes included decreased hematocrit, total hemoglobin, erythrocyte/leukocyte count, platelet count, and myeloid: erythroid ratio. In rats, decreased lymphocyte count and a relative increase in neutrophil count were the only exposure-related clinical changes. Histopathological changes were observed in the testes and ovaries at concentrations below 300 ppm, and lesions were observed in the thymus, bone marrow, lymph nodes, spleen, ovaries, and testes in mice inhaling 300 ppm. The alterations were more severe in the males than in the females. In rats, the only exposure-related pathology was a slight reduction in femoral marrow cellularity at 300 ppm.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-2]**PEER REVIEWED**

Hematopoietic depression in rodents was observed at benzene concentrations as low as 103 ppm after a 5 day exposure.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-2]**PEER REVIEWED**

In a lifetime carcinogenicity bioassay in which oral doses of benzene were administered at 50 and 250 mg/kg body weight/day, 4-5 days per week for 52 weeks, there was a dose-dependent increase in total cancers. The most prominent rat tumors observed were Zymbal gland carcinomas, mammary carcinomas, and leukemia. When Wistar rats and Swiss mice were given benzene at 500 mg/kg/day, 4 days/wk for 104 wk or 5 days/wk for 78 wk, the numbers of Zymbal gland carcinomas, hemolymphoreticular neoplasias, and total malignant tumors were increased in the rats; increases in mouse Zymbal gland dysplasia and carcinomas, mammary carcinomas, pulmonary tumors, and total malignant tumors were observed.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-2]**PEER REVIEWED**

/Researchers/ conducted an inhalation study in which pregnant Sprague-Dawley rats were exposed 7 hr/d to benzene at 10, 50, or 500 ppm on days 6 to 15 of gestation. Significant reductions in mean maternal body weight gain occurred. Mean fetal body weight was reduced. Fetal crown-to-rump distance was decreased significantly at 500 ppm, and developmental delay was evidence upon examination of the fetal skeletons. Benzene was judged ... to be fetotoxic in rats at 50 and 500 ppm and to manifest teratogenicity at 500 ppm.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-3]**PEER REVIEWED**

/Researchers/ exposed CFLP mice and NZ rabbits 24 hr/day to benzene at 154 or 308 ppm throughout days 6 to 15 of gestation. Benzene was detected in fetal blood and in amniotic fluid. At 308 ppm, retarded skeletal development and reduced fetal body weight were observed in mouse fetuses, and spontaneous abortions were reported in rabbits.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-3]**PEER REVIEWED**

/Researchers/ found a concentration-dependent increase in DBA/2 mouse bone marrow lymphocytes after a single 4-hr inhalation study of benzene at 28-3000 ppm; an increase in SCE was detected at 28 ppm. This response was strain-dependent because DBA/2 mice were more sensitive than C57BL/6 mice, young DBA/2 mice (3 mos old) were more sensitive than older mice (10 mos old), and male mice were more sensitive than female mice. Following intraperitoneal injection, a linear dose-dependent increase in SCE was observed in DBA/2 mice.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-4]**PEER REVIEWED**

When male DBA/2 mice inhaled benzene at 0, 10, 100, or 1000 ppm or male Sprague-Dawley rats inhaled benzene at 0, 0.1, 0.3, 1, 3, 10, or 30 ppm for 6 hr, significant (concentration-dependent) increases in SCE and micronuclei were observed in mice at greater than or equal to 10 ppm, and increased SCE and micronuclei were observed in rats inhaling greater than or equal to 3 ppm and at 1 ppm, respectively. These data are the lowest concentrations of inhaled benzene that have been reported to induce genotoxicity.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-4]**PEER REVIEWED**

/Benzene/ has been shown to be fetotoxic following inhalation exposure in mice (1600 ug/cu m, 7 hr/day, gestation days 6-15) and in rabbits.
[WHO; Environmental Health Criteria 150: Benzene p.16 (1993)]**PEER REVIEWED**

Toluene and benzene administered concurrently were reported to have an additive effect on induction of chromosomal aberrations. Toluene reduced the number of sister chromatid exchanges induced by benzene when both compounds were administered intraperitoneally to DBA/2 mice and reduced the clastogenic activity of benzene when the two compounds were simultaneously administered orally to CD-1 mice, intraperitoneally to Sprague-Dawley rats, or subcutaneously to NMRI mice.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V47 99 (1989)]**PEER REVIEWED**

Rats exposed to 3,526-8,224 ppm of benzene in a closed chamber for 15 min exhibited an increased number of ectopic ventricular beats.
[Magos GA et al; Neurotoxicol Teratol 12 (2): 119-24 (1990) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.43 (1997)]**PEER REVIEWED**

Sprague-Dawley SD/Tex rats were exposed to benzene vapor at 0 or 500 ppm for 5 days per week, 6 hr/day for 3 wk. Blood from the animals was evaluated for hematologic changes and the bone marrow for the presence of multinucleated erythroblasts. Animals exposed to 500 ppm showed decreased lymphocyte and leukocyte counts. Erythrocytes and hemoglobin values increased. In the bone marrow differential counts, rats showed a relative decrease in lymphoid and myeloid cells at the 500 ppm dose level and an increase in erythroid cells. In a companion study, purebred Duroc-Jersey pigs were exposed to 0, 20, 100, and 500 ppm benzene vapors 6 hr/day, 5 days/wk for 3 wk.
[Dow; EPA/OTS Doc # 88-920003196 (1992) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.49 (1997)]**PEER REVIEWED**

Granulocytic hyperplasia has been detected in the bone marrow of mice exposed to 300 ppm benzene in air for 6 hr/day, 5 days/wk for 16 wk, and held 18 mos after the last exposure.
[Farris GM et al; Fundam Appl Toxicol 20 (4): 503-7 (1993) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.50 (1997)]**PEER REVIEWED**

/Researchers/ observed a 26% decrease in spleen weight in male Kunming mice exposed to 12.52 ppm benzene 2 hr/day, 6 days/wk for 30 days. Examination of the bone marrow showed decreases in myelocytes, premyelocytes, myeloblasts, and metamyeloblasts at the same dose level.
[Li L et al; Biomed Environ Sci 5 (4): 349-54 (1992) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.61 (1997)]**PEER REVIEWED**

Experimental DBA/2 mice were exposed to 300 ppm benzene for 6 hr/day for 5 days/wk (Regimen 1) or 3 day/wk (Regimen 2) for a duration of 1-13 wk. Polychromatic erythrocytes were affected by benzene inhalation independent of exposure duration and regimen, while normochromatic erythrocytes were affected only following Regimen 1 exposure. Males were more sensitive to benzene inhalation than females.
[Luke CA et al; Mutat Res 203: 251-71 (1988) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.75 (1997)]**PEER REVIEWED**

Sprague-Dawley rats received a single dose of 950 mg/kg benzene by gavage and were sacrificed 2 hr after treatment. The control group received nothing. Brains were dissected ... Results showed that benzene decreased acetylcholine content of rat hippocampus. 3,4-Dihydroxyphenylalanine and norepinephrine content decreased in the rat midbrain. Dopamine, serotonin and 5-hydroxyindoleacetic acid content increased in the rat midbrain. Dopamine, 3,4-dihydroxyphenylacetic acid, norepinephrine, and 5-hydroxyindoleacetic acid content increased and serotonin content decreased in the rat hypothalamus after oral administration of benzene. Increased dopamine, homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, and serotonin content of rat medulla oblongata was observed. Decreased norepinephrine and 5-hydroxyindoleacetic acid content of rat medulla oblongata by benzene treatment was observed.
[Kanada M et al; Ind Health 32: 145-64 (1994) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.117 (1997)]**PEER REVIEWED**

In /a/ study of cultured rat embryos, /researchers/ evaluated the embryotoxic effects of benzene and several of its metabolites. Benzene at 1.6 mM produced little embryotoxicity, with or without hepatic activating enzymes, but phenol showed significant embryotoxicity in the presence of hepatic activation at concentrations as low as 0.01 mM. Trans,trans-muconaldehyde was embryotoxic at 0.01 mM and embryolethal at 0.05 mM; hydroquinone, catechol, and benzoquinone were all 100% embryolethal at 0.1 mM.
[Chapman DE et al; Toxicol Appl Pharmacol 128 (1): 129-37 91994) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.208 (1997)]**PEER REVIEWED**

MICE WERE GIVEN SINGLE DOSES OF BENZENE SC & ITS EFFECT ON (59)FE UPTAKE WAS EVALUATED. NO SUPPRESSION WAS FOUND AFTER 1 & 12 HR & ALSO 72 HR, WHEREAS DOSE-DEPENDENT INHIBITION OF (59)FE UPTAKE WAS OBSERVED 24 HR & 48 HR AFTER TREATMENT WITH 440 OR 2200 MG/KG DOSE. THUS, THE DATA CAN BE INTERPRETED TO SUGGEST THAT (1) BENZENE DID NOT INTERFERE WITH AN INCORPORATION OF IRON INTO HEME, (2) BENZENE INTERFERED WITH PROLIFERATION OF NORMOBLASTS & PRONORMOBLASTS, & (3) BENZENE DID NOT DAMAGE HEMOPOIETIC STEM CELLS WHICH WERE IN THE G0 STATE AT THE TIME OF BENZENE INJECTION.
[LEE EW ET AL; ENVIRON HEALTH PERSPECTIVE 39: 29-37 (1981)]**PEER REVIEWED**

When mitochondria are incubated in vitro with 2200 mg/kg of benzene there is an inhibition of RNA synthesis. Benzene also caused a dose-dependent inhibition of RNA synthesis in vitro in mitoplasts derived from cat and rabbit bone marrow mitochondria. Exogenous NADPH is required for inhibition of mitochondrial RNA synthesis in all these systems which suggests that benzene must be bioactivated within the organelle. Toluene does not inhibit RNA synthesis and the simultaneous addition of equimolar toluene and benzene results in protection against benzene inhibition. Both liver and bone marrow mitochondria incubated (3H) with benzene appear to activate benzene to a metabolite which can covalently bind to guanine residues of DNA. Benzene also inhibits mitochondrial translation.
[Kalf GF et al; Chem-Biol Interact 42 (3): 353-70 (1982)]**PEER REVIEWED**

... Benzene hydroxylation was stimulated when rats were pretreated with phenobarbital and then exposed to 1,000 ppm of benzene vapor for 8 hr/day for 2 wk.
[Ikeda M, Ohtsuji H; Toxicol Appl Pharmacol 20: 30-43 (1971) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.232 (1997)]**PEER REVIEWED**

National Toxicology Program Studies:

Two yr toxicology and carcinogenesis studies of benzene (greater than 99.7% pure) were conducted in groups of 50 F344/N rats and 50 B6C3F1 mice of each sex and for each dose. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil (5 ml/kg) were administered by gavage to male rats, 5 days/wk for 103 wk. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 wk. ... Under the conditions of these 2 yr 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. For 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, squamous cell papillomas, and squamous cell carcinomas of the oral cavity. For male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), Harderian gland adenomas, and squamous cell carcinomas of the preputial gland. For female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benigh mixed tumors, carcinomas and carcinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcinomas. ...
[Toxicology & Carcinogenesis Studies of Benzene in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 289 (1986) NIH Publication No. 86-2545 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 Abstract available at http://ntp.niehs.nih.gov/index.cfm?objectid=084801F0-F43F-7B74-0BE549908B5E5C1Cional Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 Abstract available at ]**PEER REVIEWED**

Non-Human Toxicity Values:

LD50 MOUSE INTRAPERITONEAL 0.34 ML/KG 95% CONFIDENCE LIMITS 0.28 TO 0.42
[KOCSIS JJ ET AL; SCIENCE 160: 427 (1968)]**PEER REVIEWED**

LD50 Rat oral 3306 mg/kg
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 334]**PEER REVIEWED**

LC50 Rat ihl 10,000 ppm/7 hr
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 334]**PEER REVIEWED**

LD50 Rat ip 2890 ug/kg
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 334]**PEER REVIEWED**

LD50 Mouse oral 4700 mg/kg
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 334]**PEER REVIEWED**

LC50 Mouse ihl 9980 ppm
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 334]**PEER REVIEWED**

LD50 Mouse ip 340 mg/kg
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 334]**PEER REVIEWED**

LD50 Mouse ip 340 mg/kg
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 334]**PEER REVIEWED**

Ecotoxicity Values:

LC100 Tetrahymena pyriformis (ciliate) 12.8 mmole/l/24 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 241]**PEER REVIEWED**

LC50 Palaemonetes pugio (grass shrimp) 27 ppm/96 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 261]**PEER REVIEWED**

LC50 Cancer magister (crab larvae) stage 1, 108 ppm/96 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LC50 Crangon franciscorum (shrimp) 20 mg/l/96 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LC50 Morone saxatilis (bass) 5.8 to 11 mg/l/96 hr /Conditions of bioassay not specified/
[NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997., p. 259]**PEER REVIEWED**

LC50 Poecilia reticulata (guppy) 63 mg/l/14 days /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 259]**PEER REVIEWED**

LC50 Salmo trutta (brown trout yearlings) 12 mg/l/1 hr (static bioassay)
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 259]**PEER REVIEWED**

LC50 Ambystoma mexicanum (Mexican axolotl) (3-4 wk after hatching) 370 mg/l/48 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 259]**PEER REVIEWED**

LC50 Clawed toad (3-4 wk after hatching) 190 mg/l/48 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 259]**PEER REVIEWED**

LC50 Carassius auratus (goldfish) 46 mg/l/24 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LC50 Lepomis macrochirus (bluegill sunfish) 20 mg/l/24 to 48 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LD100 Lepomis macrochirus (bluegill sunfish) 34 mg/l/24 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LD100 Lepomis macrochirus (bluegill sunfish) 60 mg/l/2 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LC50 Brine shrimp 66-21 mg/l/24-48 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LC50 Pimephales promelas (fathead minnow) 35 to 33 mg/l/24 hr-96 hr (soft water) /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LC50 Pimephales promelas (fathead minnow) 24 to 32 mg/l/24-96 hr (hard water) /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LC50 Bluegill 22 mg/l/24-96 hr (soft water) /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LC50 Carassius auratus (goldfish) 34.4 mg/l/24-96 hr (soft water) /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

TLm Lebistes reticulata (guppy) 36 mg/l/24-96 hr (soft water) /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

LC50 Gambusia affinis (mosquito fish) 395 mg/l/24-96 hr /Conditions of bioassay not specified/
[Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996., p. 258]**PEER REVIEWED**

Ongoing Test Status:

The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for benzene is completed, and the chemical is in review for further evaluation. Route: gavage; Species: transgenic model evaluation II, mice.
[NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21]**QC REVIEWED**

TSCA Test Submissions:

An evaluation of fertility was made in female Charles River CD rats (26/group) exposed by inhalation to benzene at 0, 1, 10, 30 and 300 ppm for 6 hrs/day, 5 days/week during a 10 week pre-mating treatment period and ensuing mating period, and continued exposure for mated females daily for 6 hrs/day during gestation to day 20. Daily exposure was resumed on day 5 of lactation until weaning (day 21 of lactation). There were significant differences between treated and control animals in the following: decrease in pup survival index (for lactation day 4-21 at 10 ppm, no dose-response), decreased mean pup weights (days 14 and 21 of lactation for high-dose level), and decreased mean absolute liver weights (high-dose female pups). There were no significant differences between treated and control animals in the following: maternal mortality, body weights, in-life observations, pregnancy rates, mean number dead pups, mean liver weights (male pups at all levels), mean relative liver weights (female pups at all levels), mean relative and absolute kidney weights (all female pups), or gross postmortem examinations of adult females or pups.
[Bio Dynamics Inc.; An Inhalation Female Fertility Study With Benzene in Rats, Final Report. (1980), EPA Document No. FYI-AX-0481-0110, Fiche No. 0110-0 ]**UNREVIEWED**

Teratogenic effects were evaluated in pregnant female Sprague Dawley rats (40/group) exposed via inhalation to benzene at 0 (two groups), 1, 10, 40 and 100 ppm for 6 hrs/day from days 6-15 of gestation. On day 20 of gestation, the dams were sacrificed and the fetuses removed by cesarean section. There were significant differences between treated and control groups only in the decreased mean fetal body weights of fetuses from dams exposed at the high-dose level. There were no significant differences between treated and control dams in the following: mortality, clinical observations, body weight data, maternal gross pathology, pregnancy rates, mean number of corpora and implantations, or implantation efficiencies. There were no significant differences between fetuses from treated and control dams in the following: mean incidence of fetal resorptions, mortality, mean percentage of male fetuses/litter, mean fetal body lengths, or fetal development.
[Hazelton Laboratories America, Inc.; Inhalation Teratology Study in Rats, Benzene, Final Report. (1982), EPA Document No. FYI-AX-0482-0127, Fiche No. 0127-0 ]**UNREVIEWED**

The mutagenicity of benzene was evaluated in dominant lethal assay using four groups of 20 male Sprague-Dawley rats receiving whole body exposures to nominal concentrations of test material at 1, 10, 30 and 300ppm in a dynamic air flow chamber for 6hours/day, 5days/week for ten consecutive weeks. Following exposure, each male was mated with two untreated females per week for two consecutive weeks. There was no effect of treatment for all dosed male rats as indicated by: mortality, body weight data and in-life physical observations. Pregnancy rates and implantation efficiency ratios of females mated to treated males was not significant different from control group females. Slight increases in the mean number of dead implantations and mean mutagenic ratios (i.e. no. dead implants/total implants) were noted for each week of the post treatment mating period for females mated to high dose males, but these differences were not statistically significant compared to controls. Males were sacrificed after a 10-week post mating period and microscopic examination of testis/epididymides revealed two-high dose males with testicular lesions.
[Bio/dynamics Inc.; A Dominant-Lethal Inhalation Study with Benzene in Rats, Final Report, (1980), EPA Document No. FYI-AX-0481-0110, Fiche No. OTS0000110-0 ]**UNREVIEWED**

As part of subchronic inhalation study, the ability of benzene to cause chromosome aberrations was evaluated in bone marrow cells of (50/sex) CD-1 mice receiving whole body exposures to nominal concentrations of 0, 1, 10, 30 and 300ppm in dynamic air flow chamber for 6hours/day, 5days/week for 13 weeks. Following the last day of exposure, animals received a single intraperitoneal injection of colchicine and were sacrificed. Bone marrow slides of mice at the highest concentration (300ppm) exhibited statistically significant increases chromosome aberrations relative to the control.
[Hazleton Laboratories America Inc.; Subchronic Inhalation Study in Mice and Rats, Final Report, (1983), EPA Document No. FYI-AX-0783-0203, Fiche No. OTS0000203-1 ]**UNREVIEWED**

As part of subchronic inhalation study, the ability of benzene to cause chromosome aberrations was evaluated in bone marrow cells of (50/sex) Sprague Dawley rats receiving whole body exposures to nominal concentrations of 0, 1, 10, 30 and 300ppm in dynamic air flow chamber for 6hours/day, 5days/week for 13 weeks. Following the last day of exposure, animals received a single intraperitoneal injection of colchicine and were sacrificed. Bone marrow slides of female rats at all exposure levels exhibited statistically significant increases in chromosome aberrations relative to the control. No-exposure related cytogenic effects were apparent in any of the male rats.
[Hazleton Laboratories America Inc.; Subchronic Inhalation Study in Mice and Rats, Final Report, (1983), EPA Document No. FYI-AX-0783-0203, Fiche No. OTS0000203-1 ]**UNREVIEWED**

The ability of benzene to increase the incidence of micronucleated polychromatic erythrocytes was evaluated in male and female CD-1 mice receiving nominal concentrations of 1, 10, 30 and 300ppm for 6hours/day, 5days/week for 13 weeks (Micronucleus Test). Groups of 20 mice (10/sex/sample time) were sacrificed after 0, 15, 30, 60 and 90 days of exposure. Exposure to 300ppm benzene caused a significant increases in micronucleated polychromatic erythrocytes (PCEs) and monochromatic erythrocytes (NCEs) in male and female mice at all sample times. Male mice exhibited a greater response than female mice. The frequency of micronucleated PCEs and the frequency micronucleated NCEs achieved steady state by the 30 day sample time. The rate of erythropoiesis, as measured by per cent of polychromatic erythrocytes in the peripheral blood, was not significantly altered by treatment.
[Brookhaven National Laboratory; Evaluation of Micronuclei Frequency in the Peripheral Blood of Male and Female CD-1 Mice Exposed Chemically to Benzene for 90 Days, Final Report, (1985), EPA Document No. FYI-AX-1085-0393, Fiche No. OTS0000393-1 ]**UNREVIEWED**

The levels of benzene and it's metabolites in the blood were evaluated in twenty male Sprague-Dawley rats and eighty male Swiss albino mice receiving nominal concentration of benzene at 300ppm in a dynamic air flow chamber. Sixteen mice and four rats were removed from the chamber after 1, 2, 4, 8 and 12 hours for eye bleeding. The mean levels of benzene in the rat blood were < 1.0, 4.7, 4.8, 5.7, 5.3, and 7.1ppm at intervals of 0, 1, 2, 4, 8 and 12 hours respectively. No free metabolites (phenol, catechol & hydroquinone) were detected at any of the time intervals in rats. The mean levels of benzene in mouse blood were < 1.0, 3.7, 3.0, 2.4, 3.0 and 1.3ppm at intervals of 0, 1, 2, 4, 8 and 12 hours, respectively. The mean levels of free phenol in mouse blood were 2.0, 2.4, 2.2, 2.3, 2.5 and 2.3ppm at respective intervals. No free catechol or hydroquinone were detected at any of the time intervals in mice. Also determined were levels of conjugates in rat and mouse blood. The mean levels of conjugated phenol in rat blood were < 1.0, 3.0, 5.3, 4.2, 7.1 and 4.7ppm and the mean levels in the mouse blood were 2.7, 7.2, 8.7, 8.4, 9.1, and 3.7 at intervals 0, 1, 2, 4, 8 and 12 hours, respectively. No conjugated catechol or hydroquinone were detected at any of the time intervals in rats or mice. It was concluded, that its takes approximately one hour to achieve a steady state level of benzene in rat and mouse blood.
[Bio/dynamics Inc.; Determination of Time to Steady State Level in Blood During Inhalation Exposure of Benzene to Rats and Mice, (1980), EPA Document No. FYI-AX-0281-0104, Fiche No. OTS0000104-0 ]**UNREVIEWED**

The levels of benzene and its's metabolites in blood were evaluated in male Sprague Dawley rats (4/group) and male Swiss albino mice (16/group) receiving nominal concentrations of benzene at 0, 3, 30, 300 or 1000ppm in dynamic air flow chamber for 6 hours. The mean levels of benzene in rat blood were < 1.0, < 1.0, < 1.0, 8.3 and 33.6ppm at exposure levels 0, 3, 30, 300 and 1000ppm, respectively. No free metabolites (phenol, catechol & hydroquinone) were detected at any exposure level in rat blood. The mean levels of benzene in the mouse blood were < 1.0, < 1.0, < 1.0, 1.44 and 29.5ppm at exposure levels 0, 3, 30, 300 and 1000ppm, respectively. A mean level of 1.2ppm of free phenol was only detected at the high dose level in mice. No free catechol or hydroquinone were detected in mouse blood. Also determined were the levels of conjugates in rat and mouse blood. The mean level of conjugated phenol in rat blood were < 1.0, < 1.0, 1.7, 6.0 and 6.3ppm and the mean levels of conjugated phenol in mouse blood were < 1.0, 1.1, 2.9, 7.9 and 15.5ppm at exposure levels of 0, 30, 300 and 1000ppm, respectively. No conjugated catechol or hydroquinone were detected at any exposure level in rats or mice. It was concluded that there was a direct correlation between increased exposure to benzene and increased blood concentration levels of benzene and conjugated phenol. Mice exposed to 1000ppm benzene had double the concentration of conjugated phenol in the blood relative to the 300ppm mice. In contrast, this effect was not observed in rats.
[Bio/dynamics Inc.; Determination of Benzene, Phenol, Catechol and Hydroquinone in the Blood of Rats and Mice After Inhalation Exposure to Benzene at Various Concentrations, (1980), EPA Document No. FYI-AX-0281-0104, Fiche No. OTS0000104-0 ]**UNREVIEWED**

The concentration of benzene and it's metabolites were determined after 12, 24, 48 and 72 hours in the urine of five exposed male Sprague Dawley rats and 25 male Swiss albino mice which received a nominal concentration of benzene at 300ppm in dynamic air flow chamber for 6 hours. No level of benzene at or above the detection limit (1.0ppm) were detected in rat and mice urine at any of the sampling intervals. The level of free phenol in the rat urine were 2.0, 2.2, 1.7 and 3.2ppm and in mouse urine were 15.6, 4.7, 5.8 and 4.3ppm at 12, 24, 48 and 72 hours, respectively. The mean levels of free catechol in rat urine were < 2.0, 0.46, 0.32 and < 2.0ppm and in mouse urine were 1.09, 1.29, 1.56 and 7.76ppm at 12, 24, 48 and 72 hours, respectively. No free hydroquinone at or above the detection limit were determined in rat urine at any sampling time. The mean levels of free hydroquinone in mouse urine were 12.87, 1.49, 1.46 and 0.31ppm at 12, 24, 48 and 72 hours, respectively. The expired air of rats was bubbled through dichloromethane and the mean total levels of benzene detected were 440.6, 101.4, not detected and 22.2ug/sampling interval ending at 6, 12, 24 and 48 hours, respectively. Benzene in expired air of mice was only detected at the 48 hour sampling interval.
[Bio/dynamics Inc.; Part II: Determination of Material Balance in Rats, (1980), EPA Document No. FYI-AX-0281-0104, Fiche No. OTS0000104-0 ]**UNREVIEWED**

The in vitro percutaneous absorption of 14C-benzene was evaluated in mammalian skin samples maintain in a dynamic culture system. C3H Mice (primary test subject), HRS mice, rabbit and guinea pig (strain not specified) dorsal skin, and human skin from elective surgery were all placed in culture medium chamber for penetration analysis. 14C-Benzene (20ul) was topically applied to cultured C3H mouse skin samples and radioactivity was detected in the effluent medium 15 minutes following treatment with no apparent lag phase. Penetration was linear and the rates were 2.97 +/- 0.03 and 3.70 +/- 0.03%/hr for metabolically viable (fresh skin) and nonviable skin (frozen skin), respectively. Analysis of the effluent medium indicated negligible conversion of benzene to phenol. Different rates of in vitro skin permeation were observed between male and female C3H mice, however this difference was not observed between sexes in similar studies with hairless HRS mice. In vitro penetration of benzene in hairless mice skin (2.44 +/- 0.07%) was lower than C3H mice. Additional in vitro penetration studies with 14C-benzene (20ul) were preformed with metabolically viable guinea pig, rabbit and human skin with rates of penetration of 0.04 +/- 0.01, 0.55 +/- 0.02 and 0.23 +/- 0.04%/hr, respectively. The lag phase of these additional studies were between 45-60 minutes and two hours from application followed by linear radioactivity. Toluene and unleaded gasoline containing 14C-benzene (20ul) produced rates of permeation of 2.32 +/- 0.04 and 2.81 +/- 0.4%/hr, respectively in C3H mice which appeared linear.
[ Oak Ridge National Laboratory; Toxicokinetics of Percutaneo us Penetration of Petroleum Products, Draft Final Report, (no date), EPA Documen t No. FYI-AX-0685-0356, Fiche No. OTS0000356-1 ]**UNREVIEWED**

The benzene uptake rate was evaluated in five male Sprague Dawley rats and twenty five male Swiss albino mice receiving benzene at a nominal concentration of 300ppm in a dynamic air flow chamber for 6 hours. Five individual rats were determined to have an internal mean benzene uptake rate of 152ml/min prior to conducting the six hour test and an mean pretest respiratory minute volume of 145ml/min. The mean benzene uptake rates as compared to pretest values for rats decreased to 33, 22 and 9% of the mean test value 1, 3 and 6 hours after administration, respectively. The mean minute volume for rats decreased to 85, 78 and 66% of the pretest at 1, 3 and 6 hours after administration, respectively. Rats had an estimated retained dose of 56mg/kg. Mice (5/group) had a mean total pretest benzene uptake rate of 188ml/min and a mean pretest total respiratory minute volume of 189ml/min. The mean total benzene uptake for the mice decreased 65, 76 and 81% of the pretest value, after 1, 3 and 6 hours of exposure, respectively. The mean total minute volume for groups of mice decreased 96, 84 and 69% of the pretest after 1, 3 and 6 hours, respectively. The mean total retained dose per mice was estimated to be 377mg/kg.
[Bio/dynamics Inc.; Part I: Determination of Benzene Uptake by the Lungs in Rats and Mice, Under Conditions of Prolonged Exposure, (no date), EPA Document No. FYI-AX-0281-0104, Fiche No. OTS0000104-0 ]**UNREVIEWED**

The dermal absorption of benzene vapor was examined in 2 Rhesus monkeys exposed to the test article at saturated concentrations for 30 minutes using a hydration controlled chamber which was held tightly against the skin of the back. The radioactivity measured in the urine was used to determined absorption rate. A correction factor was included to account for radioactivity excreted by other routes. Under the 2 skin conditions, of 40% hydration and 100% hydration, the absorption rates were determined to be 0.02 microliter/sq cm and .15 microliter/sq cm, respectively. Total absorption was found to be 7.5-fold higher from a 100% relative humidity environment than from a 40% relative humidity environment. In a benzene liquid exposure experiment, the concentration of benzene was given by its density of 0.8787 gm/cu cm and the dermal absorption was 5.4 microliter/sq cm. The authors suggested that benzene absorption from the liquid state was less than expected due to a dehydrating effect on the stratum corneum.
[American Petroleum Institute; Absorption of Petroleum Products Across the Skin of Monkey and Man, Final Report, (1987), EPA Doc. No. FYI-AX-1087-0185, Fiche No. OTS0000185-1]**UNREVIEWED**

Metabolism/Pharmacokinetics:

Metabolism/Metabolites:

... In human system /benzene/ is metabolized through a variety of major & minor pathways. The primary site of action is liver, where benzene is oxidized to phenol (hydroxybenzene), catechol (1,2-dihydroxybenzene), or quinol (1,4-dihydroxybenzene). Phenol is subsequently conjugated with inorganic sulfate to phenylsulfate, the other hydroxybenzenes are conjugated to a lesser extent, & all excreted in urine. Minor pathways incl further oxidation of catechol to hydroxyhydroquinol (1,2,4-trihydroxybenzene) or catabolism to cis, cis- or trans, trans-muconic acids, & phenol conjugation with glucuronic acid to form glucuronides, or with cysteine to produce 2-phenylmercapturic acid.
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1320]**PEER REVIEWED**

METABOLIC PRODUCTS IN RAT ... ARE PHENOL, HYDROQUINONE, CATECHOL, HYDROXYHYDROQUINONE, & PHENYLMERCAPTURIC ACID. CONJUGATED PHENOLS HAVE BEEN REPORTED ... EXCEPT FOR A SMALL AMT OF FREE PHENOL, ALL THE PHENOLIC METABOLITES WERE EXCRETED IN CONJUGATED FORM. WHEN (3)H-BENZENE WAS ADMIN TO MICE, (3)H2O WAS ALSO RECOVERED FROM URINE.
[National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 688]**PEER REVIEWED**

YIELDS N-ACETYL-S-PHENYL-CYSTEINE IN RAT. YIELDS BENZYL ALCOHOL IN GUINEA PIGS. ... YIELDS CIS-1,2-DIHYDRO-1,2-DIHYDROXYBENZENE IN PSEUDOMONAS. PHENOL IN PSEUDOMONAS & ACHROMOBACTER. YIELDS CIS,CIS-MUCONIC ACID IN RABBIT. /FROM TABLE/
[Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. B-4]**PEER REVIEWED**

In the rabbit, the major hydroxylation product of benzene was phenol, which along with some catechol and hydroquinone, was found in the urine conjugated with ethereal sulfate or glucuronic acid.
[USEPA; Ambient Water Quality Criteria: Benzene p.C-11 (1980) EPA 440/5-80-018]**PEER REVIEWED**

Unconjugated phenol has been found in mouse and rat urine after benzene administration.
[USEPA; Ambient Water Quality Criteria: Benzene p.C-11 (1980) EPA 440/5-80-018]**PEER REVIEWED**

The formation of benzene oxide, an epoxide of benzene is involved in the metabolism of benzene. This highly unstable intermediate rearranges non-enzymatically to form phenol. This step accounts for the occurrence of phenol as the major metabolite of benzene in urine. Catechol formation is thought to result from the hydration of benzene oxide by the enzyme epoxide hydratase followed by oxidation to catechol. It appears that catechol and phenol are formed by two distinctly different metabolic pathways. Hydroquinone is thought to result from a second passage of phenol through the mixed function oxidases.
[Jerina D, Daly JW; Science 185: 573 (1974) as cited in USEPA; Ambient Water Quality Criteria: Benzene p.C-12 (1980) EPA 440/5-80-018]**PEER REVIEWED**

The metabolism of benzene in vitro can be altered by the use of enzyme inducers administered to animals prior to sacrifice or by the addition of inhibitors to the mixtures. Benzene, phenobarbital, 3-methylcholanthrene and dimethyl sulfoxide are all microsomal stimulants for the metabolism of benzene. Benzene metabolism in vitro can be inhibited by carbon monoxide, aniline, metyrapone, SKF-525A /proadifen/, aminopyrine, cytochrome c, aminotriazole, or toluene.
[USEPA; Ambient Water Quality Criteria: Benzene p.C-12 (1980) EPA 440/5-80-018]**PEER REVIEWED**

Benzene, when administered sc at 880 mg/kg twice daily for 3 days, decreased erythropoiesis much more markedly in DBA/2 mice than in C57BL/6 mice. Total urinary benzene metabolites and the % of the dose excreted in the urine were the same in both strains. Although the metabolic profile differed between the two strains, it was very similar when equitoxic doses of benzene were administered. The levels of both free and covalently bound benzene were higher in all organs of the DBA/2 mice. Phenol, hydroquinone, resorcinol, and catechol had no effect on erythopoiesis.
[Snyder R et al; Adv Exp Biol 136A: 245-56 (1982)]**PEER REVIEWED**

The urinary metabolites isolated by DEAE Sephadex A-24 anion-exchange chromatography from mice treated with radiolabeled benzene included phenol as the major component, as well as catechol, hydroquinone, and phenylmercapturic acid. The phenolic metabolites were excreted primarily as glucronides with the exception of a small amount of free phenol.
[Longacre SL et al; Adv Exp Med Biol 136A: 307-17 (1982)]**PEER REVIEWED**

Benzene reduced the incorporation of (59)Fe into red cells by 75% at the higher dose when administered at 440 or 880 mg/kg to mice pretreated with (59)Fe 48 hr earlier. However, when toluene was administered simultaneously with benzene in a ratio of 2:1, the depression of (59)Fe uptake was prevented. Toluene reduced the appearance of benzene metabolites to 45% of controls at the higher dose and 30% at the lower dose. Thus toluene appears to inhibit benzene metabolism and by so doing, alleviates its toxicity.
[Snyder R et al; Adv Mod Environ Toxicol 4: 123-36 (1983)]**PEER REVIEWED**

A sensitive high performance liquid chromatography method is described which separates urinary metabolites from benzene-treated male CD-1 mice. Phenol, trans, trans-muconic acid and quino in the 48 hr urine, accounted, respectively for 12.8-22.8, 1.8-4.7 and 1.5-3.7% of the orally administered single dose of benzene (880, 440, and 220 mg/kg body wt). Catechol occurred in trace amounts. Trans, trans-muconic acid was identified and was unique to benzene as none was detected in urine of mice dosed orally with phenol, catechol, or quinol. The potential existence of a toxic metabolite in the form of an aldehyde precursor of muconic acid in vivo is discussed.
[Gadel K et al; Xenobiotica 15: 211-20 (1985)]**PEER REVIEWED**

In humans, phenol sulfate is the major metabolite of benzene until 400 mg/l levels are reached in the urine. Beyond than level, glucuronide conjugates are also present in the urine.
[USEPA; Health Advisories for 25 Organics: Benzene p.19 (1987) PB 87-235578]**PEER REVIEWED**

Male Wistar rats were tested to determine the effect of enzymes with different kinetic characteristics on the metabolism of benzene, in vitro. Kinetic analysis of the enzymes in the liver of rats fed a normal diet revealed the presence of two benzene hydroxylases with low Michaelis constant values of 0.01 millimolar and 0.07 millimolar, respectively. After 1 day of food deprivation, the isozyme with a constant equal to 0.01 millimolar disappeared while the activity of the second isozyme increased. Following the administration of phenobarbital there was evidence of a third benzene metabolizing enzyme in the liver of the animals exposed to benzene in concentrations ranging from 0.0055 to 6.25 millimolar, in vitro; the value of the Michaelis constant for this enzyme was equal to 4.5 millimolar and was not evident in control animals. Treatment with phenobarbital failed to affect the activity of the other low Michaelis constants of benzene hydroxylases identified in the liver of normal rats. Treatment with ethanol resulted in significant increase in the activity of both normally occurring benzene hydroxylases in the normal liver.
[Nakajima T et al; Biochemical Pharmacol 36 (17): 2799-804 (1987)]**PEER REVIEWED**

Mitoplasts (mitochondria with the outer membrane removed) from the bone marrow of rabbits were incubated sequentially with (3)H-labeled deoxyguanosine triphosphate and (14)C-labeled benzene to study the DNA adducts formed from benzene metabolites in mitochondria. Following isolation and isopycnic density gradient centrifugation in CsCl, the doubly labeled DNA was hydrolyzed to deoxynucleosides and separated on a Sephadex LH 20 column. At least seven deoxyguanosine adducts and one deoxyadenine adduct were present.
[Snyder R et al; Arch Toxicol 60 (1-3): 61-4 (1987)]**PEER REVIEWED**

Primary metabolism of benzene occurs predominantly in the liver via cytochrome P-450, the principal product being phenol. Phenol, in turn, undergoes further oxidation via cytochrome P-450 to produce the polyphenolic metabolites of benzene (principally hydroquinone), or alternatively, oxidation via peroxidases in extrahepatic tissues to form biphenols, hydroquinone, and its terminal oxidation product, p-benzoquinone. Muconic acid /is/ ... a minor urinary metabolite of benzene ...
[Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 726]**PEER REVIEWED**

... Literature identifies the following metabolites after incubation of benzene with mouse liver microsomes: phenol, hydroquinone, trans,trans-muconaldehyde, 6-oxo-trans,trans-2,4-hexadienoic acid, 6-hydroxy-trans,trans,2-4,-hexadienal, and 6-hydroxy-trans,trans-2,4-hexadienoic acid. Beta-hydroxymuconaldehyde, a new metabolite, was also identified.
[Zhang Z et al; Biochem Pharmacol 50 (1): 1607-17 (1995) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.142 (1997)]**PEER REVIEWED**

Data produced in vitro by mouse and rat liver microsomes ... indicate species differences in benzene metabolism. Quantitation of metabolites from the microsomal metabolism of benzene indicated that after 45 min, mouse liver microsomes from male B6C3F1 mice had converted 20% of the benzene to phenol, 31% to hydroquinone, and 2% to catechol. In contrast, rat liver microsomes from male Fischer 344 rats converted 23% to phenol, 8% to hydroquinone, and 0.5% to catechol. Mouse liver microsomes continued to produce hydroquinone and catechol for 90 min, whereas rat liver microsomes had ceased production of these metabolites by 90 min. Muconic acid production by mouse liver microsomes was <0.04 and <0.2% from phenol and benzene, respectively, after 90 min.
[Schlosser PM et al; Carcinogenesis 14: 2477-86 (1993) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.148 (1997)]**PEER REVIEWED**

Subjects who inhaled concentrations of 340 mg/cu m (106 ppm) benzene in air for 5 hr excreted 29% as phenol, 3% as catechol and 1% as hydroquinone in the urine, mostly as ethereal sulfates.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 117 (1982)]**PEER REVIEWED**

Absorption, Distribution & Excretion:

BENZENE IS READILY ABSORBED VIA LUNG, & ABOUT 40-50% IS RETAINED. ... IT IS TAKEN UP PREFERENTIALLY BY FATTY & NERVOUS TISSUES, & ABOUT 30-50% ... IS EXCRETED UNCHANGED VIA LUNG; A 3-PHASE EXCRETION PATTERN IS SEEN AT ... /APPROX/ 0.7-1.7 HR, 3-4 HR, & 20-30 HR.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V7 211 (1974)]**PEER REVIEWED**

When benzene was placed on skin under closed cup it was absorbed at rate of 0.4 mg/sq cm/hr (Hanke et al 1961) ...
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 117 (1982)]**PEER REVIEWED**

MICE TREATED SC WITH 2 ML (3)H-LABELED BENZENE/KG CONTAINED IRREVERSIBLY BOUND RADIOACTIVITY WITH DECREASING BINDING MAGNITUDE IN THE FOLLOWING ORGANS: LIVER, BRAIN, KIDNEY, SPLEEN, FAT. MICE TREATED WITH 2 DAILY SC DOSES OF 0.5 ML (3)H-BENZENE/KG FOR 1-10 DAYS SHOWED A RADIOACTIVITY BINDING WITH LIVER & BONE MARROW RESIDUES WHICH INCREASED WITH TREATMENT DURATION, EXCEPT IN THE CASE OF BINDING TO BONE MARROW WHICH DECREASED AFTER DAY 6.
[SNYDER R ET AL; RES COMMUN CHEM PATHOL PHARMACOL 20 (1): 191-4 (1978)]**PEER REVIEWED**

When administered to mice subcutaneously, 72% of dose is recovered in expired air.
[Andrews LS et al; Biochem Pharmacol 26: 293 (1977)]**PEER REVIEWED**

Rats were exposed to 500 ppm benzene for 30 min to eight hr. Benzene concentrations reached steady state within four hr in blood (steady-state concn= 11.5 ug/g), six hr in fat (concn= 164.4 ug/g), and two hr in bone marrow (concn= 37.0 ug/g). Lesser concn were detected in the kidney, lung, liver, brain, and spleen.
[Rickert DE et al; Toxicol Appl Pharmacol 49: 417-23 (1979)]**PEER REVIEWED**

Benzene is absorbed from the gastrointestinal tract when ingested.
[Goodman LS, Gilmann A; The Pharm Basis of Therapeutics p.936 (1970)]**PEER REVIEWED**

BENZENE CROSSES THE HUMAN PLACENTA, & LEVELS IN CORD BLOOD ARE SIMILAR TO THOSE IN MATERNAL BLOOD. ... THE MOST FREQUENT ROUTE BY WHICH HUMANS ARE EXPOSED TO BENZENE IS VIA INHALATION. TOXIC EFFECTS IN HUMANS HAVE BEEN ATTRIBUTED TO COMBINED EXPOSURE BY BOTH RESPIRATION & THROUGH THE SKIN ... IT IS ELIMINATED UNCHANGED IN EXPIRED AIR ... IN MEN & WOMEN EXPOSED TO 52-62 PPM (166-198 MG/CU M) BENZENE FOR 4 HR, A MEAN OF 46.9% WAS TAKEN UP, 30.2% WAS RETAINED & THE REMAINING 16.8% EXCRETED AS UNCHANGED BENZENE IN EXPIRED AIR. ... WHEN HUMANS WERE EXPOSED TO 100 PPM (300 MG/CU M) BENZENE, IT WAS DETECTED IN EXPIRED AIR 24 HR LATER, SUGGESTING THAT IT IS POSSIBLE TO BACK-EXTRAPOLATE TO THE BENZENE CONCENTRATION IN THE INSPIRED AIR.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 117 (1982)]**PEER REVIEWED**

... In female & male rats with large body fat content, benzene was eliminated more slowly & stored longer than in lean animals. ... Distribution in rabbit was highest in adipose tissue, high for bone marrow, & lower for brain, heart, kidney, lung, & muscle, although direct binding was higher in liver than in bone marrow.
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1323]**PEER REVIEWED**

The solubility characteristics of benzene are such that it is easily taken up by the stratum corneum. Once in the stratum corneum, it does not meet many restraining forces to impede its movement and diffuses easily. The permeability constant for benzene, as determined in vitro, is higher than that of many other small molecules, particularly those having one or more polar groups. ... Even though these uncertainties exist, and more data are needed to support the ... conclusion that there is good overall agreement between in vitro and in vivo data. ... An adult working in ambient air containing 10 ppm of benzene, with 100 cm of glaborous skin in contact with gasoline containing 5% benzene, and his entire skin (2 sq m) in contact with ambient air, will absorb in an hr, 7.5 ul of benzene from inhalation, 7.0 ul from contact with gasoline, and 1.5 ul from body exposure to ambient air. Since ... in vitro techniques measure the penetration of benzene through strongly hydrated stratum corneum, the calculated flux may be higher than under some in vivo conditions. Nevertheless, it seems that unless good hygiene is maintained and care is taken to prevent lengthy exposure to solvents containing benzene, significant amounts of benzene may enter the body through the skin.
[Blank IH, McAuliffe DJ; J Investigat Dermatol 85: 522-6 (1985)]**PEER REVIEWED**

Subjects who inhaled concentrations of 340 mg/cu m (106 ppm) benzene in air for 5 hr excreted 29% as phenol, 3% as catechol and 1% as hydroquinone in the urine, mostly as ethereal sulfates. Most of the phenol and catechol was excreted within 24 hr, and the hydroquinone within 48 hr.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 117 (1982)]**PEER REVIEWED**

In men and women exposed to 52-62 ppm (166-198 mg/cu m) benzene for 4 hr, a mean of 46.9% was taken up, 30.2% was retained and the remaining 16.8% excreted as unchanged benzene in expired air.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 117 (1982)]**PEER REVIEWED**

In animals, expired air is the main route of elimination of unmetabolized benzene, while urine is the major route of excretion of benzene metabolites (with very little fecal excretion).
[WHO; Environmental Health Criteria 150: p.54 (1993)]**PEER REVIEWED**

In a series of experiments conducted in a single-family residence from June 11 to 13, 1991, exposure to benzene through contaminated residential water was monitored. The residential water was contaminated with benzene and other hydrocarbons in 1986. Exposure was monitored for a person taking a 20-min shower and for people in other parts of the house during and after the shower. An average dermal dose of 168 ug was calculated for a 20-min shower using this water. The total benzene dose resulting from the shower was estimated to be approximately 281 ug (40% via inhalation, 60% via dermal), suggesting a higher potential exposure to benzene via dermal contact from the water than through vaporization and inhalation. This exposure was 2-3.5 times higher than the mean 6-hr inhalation dose received by the sampling team members in other parts of the house.
[Lindstrom AB et al; Journal of Exposure Analysis and Environmental Epidemiology 4 (2): 183-95 (1994) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.135 (1997)]**PEER REVIEWED**

In Sprague-Dawley rats administered a single dose of 0.15, 1.5, 15, 150, or 500 mg/kg of 14C-benzene by gavage, benzene was rapidly absorbed and distributed to various organs and tissues within 1 hr of administration. One hour after rats were dosed with 0.15 or 1.5 mg/kg of benzene, tissue distribution of benzene was highest in liver and kidney, intermediate in blood, and lowest in the Zymbal gland, nasal cavity tissue, and mammary gland. At higher doses, beginning with 15 mg/kg, benzene disproportionately increased in the mammary glands and bone marrow. Bone marrow and adipose tissue proved to be depots of benzene at the higher dose levels. The highest tissue concentrations of benzene's metabolite hydroquinone 1 hr after administration of 15 mg/kg of benzene were in the liver, kidney, and blood, while the highest concentrations of the metabolite phenol were in the oral cavity, nasal cavity, and kidney. The major tissue sites of benzene's conjugated metabolites were blood, bone marrow, oral cavity, kidney, and liver for phenyl sulfate and hydroquinone glucuronide; muconic acid was also found in these sites. Additionally, the Zymbal gland and nasal cavity were depots for phenyl glucuronide, another conjugated metabolite of benzene. The Zymbal gland is a specialized sebaceous gland and a site for benzene-induced tumors. Therefore, it is reasonable to expect that lipophilic chemicals like benzene would partition readily into this gland. However, benzene did not accumulate in the Zymbal gland; within 24 hr after administration, radiolabel derived from 14C-benzene in the Zymbal gland constituted less than 0.0001% of the administered dose.
[Low LK et al; Environ Health Perspect 82: 215-22 (1989) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.139 (1997)]**PEER REVIEWED**

Monkeys were dosed intraperitoneally with 5-500 mg/kg radiolabeled benzene, and urinary metabolites were examined. The proportion of radioactivity excreted in the urine decreased with increasing dose, whereas the dose increased, more benzene was exhaled unchanged. This indicated saturation of benzene metabolism at higher doses. Phenyl sulfate was the major urinary metabolite. Hydroquinone conjugates and muconic acid in the urine decreased as the dose increased.
[Sabourin PJ et al; Toxicol Appl Pharmacol 114 (2): 277-84 (1992) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.159 (1997)]**PEER REVIEWED**

Biological Half-Life:

The excretion of unchanged benzene from the lung of rats was reported to be biphasic, suggesting a two-compartment model for distribution and a half-life of 0.7 hr. This agreed with experimental half-life values for various tissues that ranged from 0.4 to 1.6 hr.
[Rickert DE et al; Toxicol Appl Pharmacol 49: 417 (1979) as cited in USEPA; Ambient Water Quality Criteria: Benzene p.C-11 (1980) EPA 440/5-80-018]**PEER REVIEWED**

... The half-time of benzene in /high lipid content/ tissues is approximately 24 hours.
[Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 146]**PEER REVIEWED**

Mechanism of Action:

COVALENT INTERACTION OF A BENZENE METABOLITE WITH DNA WAS SHOWN IN VIVO, BUT NO INFORMATION WAS GIVEN ABOUT THE CHEM NATURE OF THIS METABOLITE. A LIKELY INTERMEDIATE IN BENZENE METABOLISM IS BENZENE OXIDE. IN NEUTRAL AQ MEDIA IT REARRANGES ONLY SLOWLY TO THE PHENOL SO THAT ITS LIFETIME COULD BE LONG ENOUGH FOR DIFFUSION FROM THE SITE OF ACTIVATION TO THE DNA. ALTERNATIVELY, THE METABOLIC APPEARANCE OF POLYHYDROXY DERIVATIVES SUGGESTS THE FORMATION OF A PHENOL EPOXIDE, SO THAT THE REACTIVE MOLECULE COULD BE A SECONDARY METABOLITE.
[LUTZ WK, SCHLATTER C; CHEM BIOL INTERACT 18 (2): 241-6 (1977)]**PEER REVIEWED**

THE AVAILABLE EVIDENCE SUPPORTS THE CONCEPT THAT BENZENE TOXICITY IS CAUSED BY ONE OR MORE METABOLITES OF BENZENE. ... BENZENE METABOLITES CONTAINING 2 OR 3 HYDROXYL GROUPS INHIBITED MITOSIS. TOLUENE, WHICH INHIBITS BENZENE METABOLISM, PROTECTED ANIMALS AGAINST BENZENE-INDUCED MYELOTOXICITY. BENZENE TOXICITY COULD BE CORRELATED WITH THE APPEARANCE OF BENZENE METABOLITES IN BONE MARROW. ALTHOUGH IT IS CLEAR THAT BENZENE CAN BE METABOLIZED IN BONE MARROW, THE OBSERVATION THAT PARTIAL HEPATECTOMY PROTECTS AGAINST BENZENE TOXICITY SUGGESTS THAT A METABOLITE FORMED IN LIVER IS ESSENTIAL FOR BENZENE TOXICITY.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 113 (1982)]**PEER REVIEWED**

... IMPORTANCE OF POLYHYDROXYLATED DERIVATIVES OF BENZENE & THEIR SEMIQUINONES. ... /IT HAS BEEN/ SHOWN THAT HYDROQUINONE INHIBITS RAT BRAIN MICROTUBULE POLYMERIZATION; THAT HYDROQUINONE & PARA-BENZOQUINONE ARE THE MOST POTENT INHIBITORS OF T- & B-LYMPHOCYTE FUNCTION, AS MEASURED IN MOUSE SPLEEN CELLS IN CULTURE; THAT HYDROQUINONE INHIBITS LECTIN-STIMULATED LYMPHOCYTE AGGLUTINATION IN RAT SPLEEN PREPN IN VITRO; & THAT PARA-BENZOQUINONE IS THE METABOLITE MOST LIKELY TO BE RESPONSIBLE FOR SUPPRESSION OF LYMPHOCYTE TRANSFORMATION & MICROTUBULE ASSEMBLY IN RAT SPLEEN CELLS IN CULTURE. HOWEVER, ADMIN OF THESE CMPD TO ANIMALS DOES NOT PRODUCE THE TYPICAL PICTURE OF BENZENE TOXICITY ... ADMIN /OF/ MAJOR METABOLITES OF BENZENE TO MICE ... FAILED TO ... DECR ... RED BLOOD CELL PRODUCTION, USING THE (59)FE UPTAKE TECHNIQUE ... /IT'S BEEN/ SUGGESTED THAT RING-OPENING PRODUCTS MAY PLAY A ROLE IN BENZENE TOXICITY. ... IN MICE BENZENE TREATMENT SUPPRESSED SUBSEQUENT COLONY FORMING UNIT-C FORMATION FROM BONE-MARROW CELLS IN VITRO. TREATING THE ANIMALS WITH PHENOL, HYDROQUINONE OR BENZENE DIHYDRODIOL FAILED TO SUPPRESS COLONY FORMING UNIT-C. THUS, THE TOXIC METABOLITES OF BENZENE HAVE YET TO BE IDENTIFIED.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 113 (1982)]**PEER REVIEWED**

... RADIOACTIVITY /HAS BEEN DEMONSTRATED/ IN A NUCLEIC ACID FRACTION FROM RAT LIVER FOLLOWING ADMIN OF EITHER (3)H- OR (14)C-LABELLED BENZENE. IT HAS BEEN SHOWN THAT BENZENE BINDS COVALENTLY TO PROTEIN IN LIVER, BONE MARROW, KIDNEY, LUNG, SPLEEN, BLOOD, & MUSCLE. LESS COVALENT BINDING WAS OBSERVED TO THE PROTEIN OF BONE MARROW, BLOOD, & SPLEEN OF C57BL/6 MICE, WHICH ARE MORE RESISTANT TO THE BENZENE-INDUCED EFFECTS ON RED CELL PRODUCTION, THAN TO THAT OF SENSITIVE DBA/2 MICE. ... COVALENT BINDING OF BENZENE TO PROTEIN IN PERFUSED BONE-MARROW PREPN /HAS BEEN DEMONSTRATED/. ... A METABOLITE OF PHENOL BINDS TO LIVER PROTEIN MORE EFFICIENTLY THAN DOES BENZENE OXIDE, & THEY HAVE ELECTROPHORETICALLY SEPARATED HEPATIC PROTEINS TO WHICH BENZENE PREFERENTIALLY BINDS. ... COVALENT BINDING TO MITOCHONDRIA IS A PROMINENT FEATURE OF BENZENE METABOLISM. ... THERE IS RELATIVELY MORE RADIOACTIVITY IN A NUCLEIC ACID-RICH FRACTION OF A BENZENE METABOLITE ISOLATED FROM MOUSE BONE-MARROW CELLS THAN IN A SIMILAR FRACTION FROM LIVER.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V29 113 (1982)]**PEER REVIEWED**

EVIDENCE INDICATES THAT BENZENE MUST BE METABOLICALLY ACTIVATED IN ORDER TO EXERT ITS CHARACTERISTIC TOXICITY ON BONE MARROW. SOME OF THE HYDROXYLATED BENZENE METABOLITES, PHENOL, CATECHOL, HYDROQUINONE, RESORCINOL & SOME TRIHYDROXYLATED DERIVATIVES IN URINE OF RABBITS ARE SUGGESTED TO BE THE TOXIC METABOLITES.
[SNYDER R ET AL; BIOLOGICAL REACTIVE INTERMEDIATES II, PART A, PLENUM PUBLISHING CORP 245 (1982)]**PEER REVIEWED**

THE MECHANISM OF BENZENE OXYGENATION IN LIVER MICROSOMES & IN RECONSTITUTED ENZYME SYSTEMS FROM RABBIT LIVER WAS INVESTIGATED. THE RESULTS INDICATE THAT THE MICROSOMAL CYTOCHROME P450 DEPENDENT OXIDATION OF BENZENE IS MEDIATED BY HYDROXYL RADICALS FORMED IN A MODIFIED HABER-WEISS REACTION BETWEEN HYDROGEN PEROXIDE & SUPEROXIDE ANIONS & SUGGEST THAT ANY CELLULAR SUPEROXIDE-GENERATING SYSTEM MAY BE SUFFICIENT FOR THE METABOLIC ACTIVATION OF BENZENE & STRUCTURALLY RELATED COMPOUNDS.
[JOHANSSON I, INGELMAN-SUNDBERG M; J BIO CHEM 258 (12): 7311-6 (1983)]**PEER REVIEWED**

Animal expt show that benzene sensitizes the myocardium to epinephrine, so that the endogenous hormone may precipitate sudden & fatal ventricular fibrillation.
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-398]**PEER REVIEWED**

The protective effects of pyridine and xylene against benzene, benzo(a)pyrene, or cyclophosphamide clastogenicity were studied in mice. Swiss-ICR mice were treated orally with 220 to 880 mg/kg benzene, 150 mg/kg benzo(a)pyrene, or intraperitoneally with 50 mg/kg cyclophosphamide with or without 0 to 500 mg/kg pyridine or xylene. The mice were killed 24 to 72 hours later and the femurs were removed. The bone marrow was isolated and assayed for micronuclei. Xylene inhibited the induction of micronuclei of benzene only when given at an equimolar dose or greater. No delay in the peak micronuclei response was seen. Pyridine at 60 mg/kg completely blocked the induction of micronuclei by 880 mg/kg benzene of 24 hours. Pyridine at 25 mg/kg completely blocked the clastogenic effect of 440 mg/kg benzene at 36 to 76 hours and partially blocked micronuclei induction at 24 hours. The clastogenicity of benzo(a)pyrene was inhibited by pyridine only at doses of 100 mg/kg or more. Pyridine showed no protective effect against micronuclei induction by cyclophosphamide at any concn; micronuclei formation was enhanced by 60 to 260 mg/kg pyridine. Since the results suggested that the biological activation of benzene was due to different cytochrome p450 isozymes than the ones activating benzo(a)pyrene or cyclophosphamide, DBA/2 mice (aryl hydrocarbon hydrolase noninducible) and C57B1/6 mice with or without pretreatment with methylcholanthrene were dosed once or three times with benzene and the effects on bone marrow micronuclei were examined as before. Micronuclei formation was greater in DBA/2 mice. The effect was potentiated by methylcholanthrene. The cytochrome p450 isozyme involved in activating benzene is one of the enzymes induced by methylcholanthrene, independent of the high affinity aryl hydrocarbon hydrolase receptor.
[Harper BL, Legator MS; Mutat Res 179 (1): 23-31 (1987)]**PEER REVIEWED**

Interactions:

DMSO pretreatment enhances benzene metabolism and toxicity in male Wistar rats.
[Kocsis JJ et al; Science 160: 427 (1968)]**PEER REVIEWED**

BENZENE & ETHANOL INDUCED A COMMON CYTOCHROME P450 SPECIES IN RABBIT LIVER SPECIFICALLY EFFECTIVE IN HYDROXYL RADICAL-MEDIATED OXYGENATION OF ETHANOL. BENZENE OXIDATION BY THE BENZENE-INDUCIBLE FORM OF CYTOCHROME P450 WAS ALMOST COMPLETELY INHIBITED BY CATALASE, SUPEROXIDE DISMUTASE, DMSO, & MANNITOL.
[INGELMAN-SUNDBERG M ET AL; DEV BIOCHEM 23 (ISS CYTOCHROME P450, BIOCHEM BIOPHYS ENVIRON IMPLIC): 19-26 (1982)]**PEER REVIEWED**

Simultaneous treatments with both benzene and toluene, or benzene and piperonyl butoxide, increased the excretion of unchanged benzene in the expired air. These compounds apparently act by inhibiting benzene metabolism.
[USEPA; ECAO Atlas Document: Benzene IV-12 (1980)]**PEER REVIEWED**

Toluene, Aroclor 1254, phenobarbital, acetone, and ethanol are known to alter the metabolism and toxicity of benzene.
[U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.232 (1997)]**PEER REVIEWED**

SKF-525A inhibited benzene metabolism in the rat. Injection of 80 mg/kg of SKF-525A in rats resulted in a depression of phenol excretion. It also prolonged phenol excretion and interfered in the conversion of benzene to glucuronides and free phenols.
[Ikeda M et al; Xenobiotica 2: 101-6 (1972) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.233 (1997)]**PEER REVIEWED**

Carbon monoxide, aniline, aminopyrine, cytochrome C, and metyrapone inhibited benzene metabolism in vitro by mouse liver microsomes.
[Gonasun LM et al; Toxicol Appl Pharmacol 26: 398-406 (1973) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.233 (1997)]**PEER REVIEWED**

Pharmacology:

Therapeutic Uses:

MEDICATION (VET): HAS BEEN USED AS A DISINFECTANT. /FORMER USE/
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 179]**PEER REVIEWED**

Drug Warnings:

Protected intercourse may be prudent following high exposure to benzene. As well, nursing mothers may be advised to discontinue nursing for 5 days following high exposure.
[Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 712]**PEER REVIEWED**

Interactions:

DMSO pretreatment enhances benzene metabolism and toxicity in male Wistar rats.
[Kocsis JJ et al; Science 160: 427 (1968)]**PEER REVIEWED**

BENZENE & ETHANOL INDUCED A COMMON CYTOCHROME P450 SPECIES IN RABBIT LIVER SPECIFICALLY EFFECTIVE IN HYDROXYL RADICAL-MEDIATED OXYGENATION OF ETHANOL. BENZENE OXIDATION BY THE BENZENE-INDUCIBLE FORM OF CYTOCHROME P450 WAS ALMOST COMPLETELY INHIBITED BY CATALASE, SUPEROXIDE DISMUTASE, DMSO, & MANNITOL.
[INGELMAN-SUNDBERG M ET AL; DEV BIOCHEM 23 (ISS CYTOCHROME P450, BIOCHEM BIOPHYS ENVIRON IMPLIC): 19-26 (1982)]**PEER REVIEWED**

Simultaneous treatments with both benzene and toluene, or benzene and piperonyl butoxide, increased the excretion of unchanged benzene in the expired air. These compounds apparently act by inhibiting benzene metabolism.
[USEPA; ECAO Atlas Document: Benzene IV-12 (1980)]**PEER REVIEWED**

Toluene, Aroclor 1254, phenobarbital, acetone, and ethanol are known to alter the metabolism and toxicity of benzene.
[U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.232 (1997)]**PEER REVIEWED**

SKF-525A inhibited benzene metabolism in the rat. Injection of 80 mg/kg of SKF-525A in rats resulted in a depression of phenol excretion. It also prolonged phenol excretion and interfered in the conversion of benzene to glucuronides and free phenols.
[Ikeda M et al; Xenobiotica 2: 101-6 (1972) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.233 (1997)]**PEER REVIEWED**

Carbon monoxide, aniline, aminopyrine, cytochrome C, and metyrapone inhibited benzene metabolism in vitro by mouse liver microsomes.
[Gonasun LM et al; Toxicol Appl Pharmacol 26: 398-406 (1973) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.233 (1997)]**PEER REVIEWED**

Minimum Fatal Dose Level:

Benzene exposure is rapidly fatal at concentrations approaching 20,000 ppm.
[Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 724]**PEER REVIEWED**

... Probable human oral lethal dose would be between 50-500 mg/kg. Human inhalation of approximately 20,000 ppm (2% in air) was fatal in 5-10 min.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. BENZENE-8]**PEER REVIEWED**

Estimated oral doses from 9-30 g have proved fatal.
[WHO; Environmental Health Criteria 150: Benzene p.46 (1993)]**PEER REVIEWED**

Environmental Fate & Exposure:

Environmental Fate/Exposure Summary:

Benzene's production, existence in gasoline, and use in the production of ethylbenzene and styrene as well as many other chemicals may result in its release to the environment through various waste streams. Benzene is found in volcanoes, as a constituent of crude oil, from forest fires, and as a plant volatile. If released to air, a vapor pressure of 94.8 mm Hg at 25 deg C indicates benzene will exist solely as a vapor in the ambient atmosphere. Vapor-phase benzene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 13 days. Vapor-phase benzene is also degraded by ozone radicals and nitrate found in the atmosphere but at such low rates as to not be important. Since benzene is very water soluble, it may be removed from the atmosphere by rain. If released to soil, benzene is expected to have high mobility based upon a Koc of 85. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 5.56X10-3 atm-cu m/mole. Benzene may volatilize from dry soil surfaces based upon its vapor pressure. Benzene is expected to biodegrade in soils based on a biodegradation study in a base-rich para-brownish soil where 20 ppm benzene was 24% degraded in 1 week, 44% in 5 weeks, and 47% in 10 weeks. If released into water, benzene is not expected to adsorb to sediment and suspended solids in water based upon the Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1 hr and 3.5 days, respectively. Biodegradation of benzene in water is expected based on an experiment using an enriched aerobic bacterial culture in which benzene began to degrade 12 hrs after incubation in an aqueous (soil-free) solution with 50% of benzene degrading after 60 hrs and almost complete degradation within 90 hrs. In aqueous solution, benzene will react with hydroxyl radical (OH radical ave concn = 1.0X10-17 molec/cu cm) at a reaction rate of 7.8X10+9 L/mol sec which results in an estimated half-life of 103 days. A BCF ranging from 1.1-20 suggests bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to benzene may occur through inhalation and dermal contact with this compound at workplaces where benzene is produced or used. The general population may be exposed to benzene via inhalation of ambient air, ingestion of drinking water, and dermal contact with gasoline products containing benzene. Benzene is widely detected in atmospheric samples due to its presence in gasoline. (SRC)
**PEER REVIEWED**

Probable Routes of Human Exposure:

Human populations are primarily exposed to benzene through inhalation of contaminated ambient air particularly in areas with heavy traffic and around filling stations. In addition, air close to manufacturing plants which produce or use benzene may contain high concentrations of benzene(1,2). Another source of exposure is from inhalation of tobacco smoke(1). Although most public drinking water supplies are free of benzene or contain <0.3 ppb, exposure can be very high from consumption of contaminated sources drawn from wells contaminated by leaking gasoline storage tanks, landfills, etc(SRC).
[(1) IARC; Monograph, Some Industrial Chem and Dyestuffs 29: 99-106 (1982) (2) Graedel TE; Chem Compounds in the Atmos, NY, NY Academic Press (1978)]**PEER REVIEWED**

Rough estimates of average ambient ground-level benzene concentrations over an 8 hour period were calculated based on an emission rate of 100 g/sec from a manufacturing plant. Benzene concentrations (in pg/cu m) are estimated to be 11,000 at 0.15 km, 6,100 at 0.3 km, 3,800 at 0.45 km, 2,800 at 0.6 km, 2,100 at 0.75 km, 740 at 1.6 km, 370 at 2.5 km, 220 at 4.0 km, 120 at 6.0 km, 62 at 9.0 km, 34 at 14.0 km, and 20 at 20.0 km distance from the manufacturing plant(1).
[(1) Mara SJ, Shonh SL; Assesment of Human Exposures to Atmospheric Benzene. Menlo Park, CA: SRI. USEPA-450/3-78-031. NTIS PB 284 203 (1978)]**PEER REVIEWED**

NIOSH (NOES Survey 1981-1983) has statistically estimated that 272,275 workers (143,066 of these are female) are potentially exposed to benzene in the US(1). Occupational exposure to benzene may occur through inhalation and dermal contact with this compound at workplaces where benzene is produced or used(SRC). The general population may be exposed to benzene via inhalation of ambient air(2-4), ingestion of drinking water(5), and dermal contact with gasoline products(6) containing benzene(SRC).
[(1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Trost B et al; Atmos Environ 31: 3999-4008 (1997) (3) Singh HB, Zimmerman PB; Adv Environ Sci Technol 24: 177-235 (1992) (4) Wallace L; Environ Health Perspect 104: 1129-1136 (1996) (5) Krill RM, Sonzogni WC; J Am Water Works Assoc 78: 70-5 (1986) (6) Fruscella W; Kirk-Othmer Encycl Chem Technol. 4th ed. NY, NY: John Wiley and Sons 4: 80 (1992)]**PEER REVIEWED**

Benzene was detected in 3 out of 70 samples taken from 46 spray painting workshops in Sydney, Australia at a concn of 1 mg/cu m in 1989(1). In a study of in-auto and in-bus exposures to volatile organic compounds for commutes on an urban-suburban route in Korea from November 21 to December 22, 1994, revealed that mean in-auto concns of benzene were 30.6 ug/cu m along urban routes and 18.3 ug/cu m along suburban routes while mean in-bus concns were 20.2 ug/cu m along urban routes and 11.7 ug/cu m along suburban routes(2). In a 200-trip study of in-vehicle air of Los Angeles commuters, an avg concn of benzene at 40 ug/cu m during rush hour was detected(3).
[(1) Winder C et al; Ann Occup Hyg 36: 385-94 (1992) (2) Jo WK et al; Air Waste Manage Assoc 46: 749-754 (1996) (3) Wallace L; Environ Health Perspect 104: 1129-1136 (1996)]**PEER REVIEWED**

Body Burden:

Benzene was detected in all 8 samples of mothers' milk from women living in 4 USA urban areas(1). Breath samples from persons without specific exposure to benzene ranged from 8 to 20 ppb(2). Whole blood samples from 250 subjects (121 males, 129 females) ranged from not detected to 5.9 ppb, (mean 0.8 ppb)(3). In FY82, the National Human Adipose Tissue Survey specimens found that of 46 composite samples, 96% tested positive to benzene (concns were >4 ppb for wet tissue) with a max concn of 97 ppb max(4).
[(1) Pellizzari ED et al; Environ Sci Technol 16: 781-5 (1982) (2) IARC; Monograph. Some Industrial Chemicals and Dyestuffs. 29: 99-106 (1982) (3) Antoine SR et al; Bull Environ Contam Toxicol 36: 364-71 (1986) (4) Stanley JS; Broad Scan Analysis of the FY82 National Human Adipose Tissue Survey Specimens Vol. I Executive Summary p. 5 USEPA-560/5-86-035 (1986)]**PEER REVIEWED**

In a 1980's study of non-occupational benzene exposure, it was found that smokers had an avg benzene body burden about 6 to 10 times that of nonsmokers, and received about 90% of their benzene exposure from smoking(1). The mean benzene concn found in the breath and blood of 1,683 individuals was 13.1 and 131 ng/l, respectively(1).
[(1) Wallace L; Environ Health Perspect 104: 1129-1136 (1996)]**PEER REVIEWED**

Average Daily Intake:

Two recent studies of benzene levels in foods have confirmed the conclusion that ingesting food and beverages are an unimportant pathway for benzene exposure(1). In a study of more than 50 foods, most contained benzene below 2 ng/g ppbw(1). A Canadian review of benzene exposures concluded that food and drinking water each contributed only about 0.02 ug/kg benzene per day compared to a total intake of 2.4 ug/kg per day from airborne exposures (3.3 ug/kg/day if exposed to cigarette smoke). In a 1980's study of non-occupational benzene exposure, it was found that more than 99% of the total personal exposure was through air and that a global avg personal exposure for benzene was about 15 ug/cu m(1). Roughly half the total benzene exposure in the United States was borne by smokers(1). For non-smokers, most benzene exposure ultimately was derived from auto exhaust or gasoline vapor emissions(1). A series of experiments were conducted in a 290 sq m single-family residence from June 11-13, 1991 to ascertain the human exposure to benzene from a contaminated groundwater source(1). It involved an individual taking a 20 min shower with the bathroom door closed, followed by five minutes for drying and dressing, and then opening the bathroom door and allowing the individual to leave and have his blood, breath and urine sampled(1). Whole air samples were collected from the bathroom, shower and living room. The inhalation exposure to benzene of an individual in the living room avgd 72 ug for the three days(1). The individual taking the shower had an avg inhalation dose of 113 ug and an avg dermal dose of 168 ug (exposure = 40% inhalation, 60% dermal)(1). There may be a large number of cases where well water is contaminated by benzene at low concns(1). A number of studies have reported finding benzene at levels on the order of 5 ng/l in surface and well waters(1). However, these levels correspond to a daily intake of <10 ng benzene, assuming 2 liters of water drunk daily(1). This amount is only 0.5% of the avg daily intake for nonsmokers of 200 ng from air(1). Thus, it is concluded that the effect of contaminated water on total benzene intake is negligible(1).
[(1) Wallace L; Environ Health Perspect 104: 1129-1136 (1996)]**PEER REVIEWED**

Natural Pollution Sources:

... Benzene has been reported to be a natural constituent of fruits, vegetables, meats, and dairy products with concentrations ranging from 2 ug/kg in canned beef to 2100 ug/kg for eggs.
[Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 724]**PEER REVIEWED**

Benzene is found naturally in the environment from volcanoes, as a natural constituent of crude oil, from forest fires and as a plant volatile(1,2). Benzene concns range from 100-200 parts per trillion over the Pacific and Atlantic Oceans due to seepage and spillage of oil into the oceans(3).
[(1) IARC; Monograph. Some Industrial Chemicals and Dyestuffs 29: 99-106 (1982) (2) Graedel TE; Chemical Cmpds in the Atmos. NY, NY: Academic Press (1978) (3) Singh HB, Zimmerman PB; Adv Environ Sci Technol 24: 177-235 (1992)]**PEER REVIEWED**

Artificial Pollution Sources:

Benzene enters the environment from production, storage, transport, venting, and combustion of gasoline; and from production, storage, and transport of benzene itself. Other sources result from its use as an intermediate in the production of other chemicals, and as a solvent, from spills, including oil spills; from its indirect production in coke ovens; from nonferrous metal manufacture, ore mining, wood processing, coal mining and textile manufacture, and from cigarette smoke(1,2).
[(1) IARC; Monograph. Some Industrial Chemicals and Dyestuffs 29: 99-106 (1982) (2) Graedel TE; Chemical Cmpds in the Atmos, New York, NY: Academic Press (1978)]**PEER REVIEWED**

Benzene's production and use in the production of ethylbenzene/styrene (53%), cumene/phenol (22%), cyclohexane (12%), nitrobenzene/aniline (5%), detergent alkylate (3%), chlorobenzenes and other products (5%) may result in its release to the environment through various waste streams(SRC). Benzene has been detected in cigarette smoke ranging from 47-64 ppm(2). The world wide release of benzene into the environment is estimated to be 4-5 Tg/yr with 0.6 Tg/yr coming from the United States alone(3). Leachate from landfills is also a source of benzene in the environment(4).
[(1) Chemical Marketing Reporter; Chemical Profile Benzene. June 24 pp. 25 and 49 NY, NY: Schnell Pub Co. (1996) (2) Clayton GD, Clayton FE; Patty's Industrial Hygiene And Toxicology, 4th Ed.; NY, NY: John Wiley & Sons, Vol IIB pg. 1302 (1994) (3) Singh HB, Zimmerman PB; Adv Environ Sci Technol 24: 177-235 (1992) (4) Johnston JJ et al; J Contam Hydrol 23: 263-283 (1996)]**PEER REVIEWED**

Environmental Fate:

TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 85(2), indicates that benzene is expected to have high mobility in soil(SRC). Volatilization of benzene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 5.56X10-3 atm-cu m/mole(3). The potential for volatilization of benzene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 94.8 mm Hg(4). Benzene is expected to biodegrade in soils based on a biodegradation study in a base-rich para-brownish soil where 20 ppm benzene was 24% degraded in 1 week, 44% in 5 weeks, and 47% in 10 weeks(5). Anaerobic degradation of benzene in soil is not expected to be an important loss process based on various studies(6,7). In one study of chemical biotransformation under nitrate- and sulfate-reducing conditions, benzene was found to be stable for 60 days(6). In a related study, benzene did not undergo biodegradation in situ nor in laboratory controlled soil samples under denitrifying conditions(7).
[(1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hodson J, Williams NA; Chemosphere 17: 67-77 (1988) (3) Mackay D et al; Environ Sci Tech 13: 333-36 (1979) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (5) Haider K et al; Arch Microbiol 96: 183-200 (1974) (6) Reinhard M et al; Div Environ Chem Preprints Ext Abst 36: 210-212 (1996) (7) Hutchins SR, Wilson JT; pp. 157-72 in In Situ Bioreclamation. Hinchee RE, Olfenbuttel RF, eds. Stoneham, MA: Butterworth-Heinmann (1991)]**PEER REVIEWED**

AQUATIC FATE: Based on a classification scheme(1), a Koc value of 85(2), indicates that benzene is not expected to adsorb to sediment and suspended solids in water(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 5.56X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1 hr and 3.5 days, respectively(SRC). Anaerobic degradation of benzene in water is not expected to be an important loss process based on various studies(5). In one study of chemical biotransformation under nitrate- and sulfate-reducing conditions, benzene was found to be stable for 60 days(5). In aqueous solution, benzene will react with hydroxyl radical at a reaction rate of 7.8X10+9 L/mol sec; using the average OH radical concentration (1.0X10-17 molec/cu cm), benzene would have a half-life of 103 days(6). According to a classification scheme(7), a BCF ranging from 1.1-20(8) suggests the potential for bioconcentration in aquatic organisms is low.
[(1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hodson J, Williams NA; Chemosphere 17: 67-77 (1988) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Mackay D et al; Environ Sci Tech 13: 333-36 (1979) (5) Reinhard M et al; Div Environ Chem Preprints Ext Abst 36: 210-212 (1996) (6) Buxton GV et al; J Phys Chem Ref Data 17: 513-882 (1988) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) (8) Neff JM, Sauer TC; Environ Sci Res 53: 163-75 (1996)]**PEER REVIEWED**

AQUATIC FATE: Evaporation was the primary loss mechanism in winter in a mesocosm experiment which simulated a northern bay where the half-life was 13 days(1). In spring and summer the half-lives were 23 and 3.1 days, respectively(1). In these cases biodegradation plays a major role and takes about 2 days(1). However, acclimation is critical and this takes much longer in the colder water in spring(1). According to one experiment, benzene has a half-life of 17 days due to photodegradation(2) which could contribute to benzene's removal. In situations of cold water, poor nutrients, or other conditions less conducive to microbial growth, photolysis will play a important role in degradation(SRC). The half-life of benzene in sea water is about 5 hrs(3) based on its high Henry's Law constant of 5.56X10-3 atm-cu m/mole(4).
[(1) Wakeham SG et al; Bull Environ Contam Toxicol 31: 582-4 (1983) (2) Hustert K et al; Chemosphere 10: 995-8 (1981) (3) Neff JM, Sauer TC; Environ Sci Res 53: 163-75 (1996) (4) Mackay D et al; Environ Sci Tech 13: 333-36 (1979)]**PEER REVIEWED**

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), benzene, which has a vapor pressure of 94.8 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase benzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 13 days(SRC), calculated from its rate constant of 1.23X10-12 cu cm/molecule-sec at 25 deg C(3). The half-life in polluted atmospheres which contain nitrogen oxides or sulfur dioxide has been observed to shorten to 4-6 hrs(4). Vapor-phase benzene is also degraded in the atmosphere by atmospheric ozone radicals at an extremely slow rate; the half-life for this reaction in air is estimated to be 170,000 days(5). The reaction rate of benzene with nitrate radical in the atmosphere is estimated to be less than 0.3X10-16 cu cm/molecule sec at 25 deg C(3); the half-life for this reaction in air is estimated to be greater than or equal to 111 days based on an average concentration of nitrate radicals of 2.4X10+8 molec/cu cm(6). Benzene has a maximum absorbance frequency of 253 nm suggesting that direct photolysis will not be an important degradation process(7). Due to benzene's high water solubility, it may be removed from the atmosphere by rainfall(8).
[(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (3) Atkinson R; J Phys Chem Ref Data, Monograph No. 2 (1994) (4) Korte F, Klein W; Ecotox Environ Safety 6: 311-27 (1982) (5) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 3rd ed. NY, NY: Van Nostrand Reinhold p. 250 (1996) (6) Atkinson, R et al; Atmos Env 24: 2647-54 (1990) (7) Trost B et al; Atmos Environ 31: 3999-4008 (1997) (8) May WE et al; J Chem Ref Data 28: 197-200 (1983)]**PEER REVIEWED**

Environmental Biodegradation:

No degradation of benzene as measured by BOD was reported in coarse-filtered (through 1 cm cotton layer) Superior harbor water incubated at 21 deg C for 12 days(1). Biodegradation half-lives of 28 and 16 days were reported in die-away tests for degradation of up to 3.2 ul/l benzene using groundwater and water from Lester River, Minnesota, respectively, under aerobic conditions(2). The half-life in estuarine water was 6 days as measured by radiolabeled C02 produced(3). In a base-rich para-brownish soil, 20 ppm benzene was 24% degraded in 1 week, 44% in 5 weeks, and 47% in 10 weeks(4). In a marine ecosystem biodegradation occurred in 2 days after an acclimation period of 2 days and 2 weeks in the summer and spring, respectively, whereas no degradation occurred in winter(5).
[(1) Vaishnav DD, Babeu L; J Great Lakes Res 12: 184-91 (1986) (2) Vaishnav DD, Babeu L; Bull Environ Contam Toxicol 39: 237-44 (1987) (3) Lee RF, Ryan C; Microbial Degradation of Pollutants in Marine Environments. pp. 443-50 USEPA-600/9-72-012 (1979) (4) Haider K et al; Arch Microbiol 96: 183-200 (1974) (5) Wakeman SG et al; Bull Environ Contam Toxicol 31: 582-4 (1983)]**PEER REVIEWED**

Benzene, in a mixture with toluene and xylenes, is readily biodegraded (total degradation of 7.5 ppm total mixture) in shallow ground water in the presence of oxygen in the unconfined sand aquifer at Canada Forces' Base Borden, Ontario; laboratory batch experiments demonstrated that the degradation could be attributed to biodegradation(1). Complete biodegradation in 16 days was reported under simulated aerobic groundwater conditions at 20 deg C(2). Reported metabolites of benzene using pure cultures of microorganisms include phenol and unidentified phenols(3), catechol and cis-1,2-dihydroxy-1,2-dihydrobenzene(4).
[(1) Barker JF et al; Ground Water Monit Rev 7: 64-72 (1987) (2) Delfino JJ, Miles CJ; Soil Crop Sci Soc FL Proc 44: 9-14 (1985) (3) Smith RV, Rosazza SP; Arch Biochem Biophys 161: 551-8 (1974) (4) Gibson DT et al; Biochem 7: 2653-62 (1968)]**PEER REVIEWED**

Benzene at 50 ppm was 90% degraded by industrial wastewater seed incubated at 23 deg C for 6 hrs(1). Benzene inhibited industrial seed at concn of 100 ppm and above and municipal seed at 50 ppm and above(1). In a bench scale activated-sludge reactor with an 8 hour retention time, complete degradation occurred with 0.5% of the benzene being lost by air stripping(2). In laboratory systems, low concentrations of benzene are degraded in 6-14 days(3,4). 44-100% removal occurred at a sewage treatment plant; percentage by evaporation and biodegradation were not determined(5).
[(1) Davis EM et al; Water Res 15: 1125-7 (1981) (2) Stover EL, Kincannon DF; J Water Pollut Control Fed 55: 97-109 (1983) (3) Setzkorn EA, Huddleston RL; J Amer Oil Chem Soc 42: 1081-4 (1965) (4) Tabak HH et al; J Water Pollut Control Fed 53: 1503-18 (1981) (5) Feiler HD et al; Proc Natl Conf Munic Sludge Manag 8th, pp. 72-81 (1979)]**PEER REVIEWED**

AEROBIC: Benzene present at 100 mg/l, reached 39-41% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(1). Benzene reached 24% of its theoretical oxygen demand in a non-acclimated microbial population after 15 days(2). Benzene is metabolized by the avocado fruit and grapes to carbon dioxide(3). Aerobic biodegradation of benzene was studied in pre-equilibrated soil-water slurry microcosms(4). Using an enriched aerobic bacterial culture, benzene began to degrade 12 hrs after incubation in an aqueous(soil-free) solution with 50% of benzene degrading after 60 hrs and almost complete degradation within 90 hrs(4). Using a pre-equilibrated soil-water slurry microcosm, benzene did not begin to degrade until 3 days after application and reached complete degradation after about 12 days(4). The decrease in biodegradation is based on benzene's sorption to soil and organic particles(4).
[(1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 3-1 (1992) (2) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 3rd ed. NY, NY: Van Nostrand Reinhold pg. 251 (1996) (3) Clayton GD, Clayton FE; Patty's Industrial Hygiene And Toxicology, 4th Ed. NY, NY: John Wiley and Sons Vol IIB p. 1325 (1994) (4) Zhang WX, Bouwer EJ; Biodegradation 8: 167-175 (1997)]**PEER REVIEWED**

ANAEROBIC: Benzene was degraded under methanogenic conditions in an enrichment culture fed ferulic acid for five years. It was also degraded under sulfate-reducing conditions in microcosms containing benzene-contaminated aquifer sediment(1). The biotransformation of benzene in aquifer sediment down gradient of the Wilder's Grove sanitary landfill near Raleigh, NC U.S.A. was studied under anaerobic conditions(1). According to the study, benzene was not found to biodegrade(1). In a study of chemical biotransformation under nitrate- and sulfate-reducing conditions, benzene was found to be stable under these anaerobic conditions for 60 days(2). In a related study, benzene did not undergo biodegradation in situ nor in laboratory controlled soil samples under denitrifying conditions(3). Although benzene appears to be recalcitrant under anaerobic conditions, there was one experiment in which benzene underwent degradation under methanogenic conditions. The microbial inoculum employed in the study originally had been enriched from anaerobic municipal sludge(4). Benzene was transformed into phenol by the microbial inoculum by using water as a source of oxygen(4).
[(1) Johnston JJ et al; J Contam Hydrol 23: 263-283 (1996) (2) Reinhard M et al; Div Environ Chem Preprints Ext Abst 36: 210-212 (1996) (3) Hutchins SR, Wilson JT; pp. 157-72 in In Situ Bioreclamation. Hinchee RE, Olfenbuttel RF eds. Stoneham, MA: Butterworth-Heinmann (1991) (4) Grbic-Galic, D; Geomicrobiology J 8: 167-200 (1990)]**PEER REVIEWED**

Environmental Abiotic Degradation:

While benzene is considered to be relatively unreactive in photochemical smog situations (in the presence of nitrogen oxides), its rate of degradation is accelerated with about 16% decrease in concentration in 5 hr(1). A typical experiment in the presence of active species such as NOx and SO2 showed that benzene photodegradation was considerably accelerated above that in air alone(2). Its half-life in the presence of active species was 4-6 hr with 50% mineralization to CO2 in approximately 2 days(3). Products of degradation include phenol, 2-nitrophenol, 4-nitrophenol, 2,4-dinitrophenol, 2,6-dinitrophenol, nitrobenzene, formic acid, and peroxyacetyl nitrate(4-6). Hydrolysis is not a significant process for benzene due to the lack of hydrolyzable functional groups(7).
[(1) Farley FF; Inter Conf on Photochemical Oxidant Pollution and Its Control. pp. 713-27 USEPA-600/3-77-001B (1977) (2) Yanagihara S et al; Proc Int Clean Air Cong 4th, pp. 472-7 (1977) (3) Korte F, Klein W; Ecotox Environ Saftey 6: 311-27 (1982) (4) Nojima K et al; Chemosphere 4: 77-82 (1975) (5) Hoshino M et al; Kokuritsu Kogai Kekyusho Kenkyu Hokoku 5: 43-59 (1978) (6) Kopczynski SL; Int J Air Water Pollut 8: 107-20 (1964) (7) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. NY: McGraw-Hill pp. 7-4 (1982)]**PEER REVIEWED**

The rate constant for the vapor-phase reaction of benzene with photochemically-produced hydroxyl radicals is 1.23X10-12 cu cm/molecule-sec(1). This corresponds to an atmospheric half-life of about 13 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). The half-life in polluted atmospheres which contain nitrogen oxides or sulfur dioxide has been observed to shorten to 4-6 hrs(2). Vapor phase benzene is also degraded in the atmosphere by atmospheric ozone radicals at an extremely slow rate; the half-life for this reaction in air is estimated to be 170,000 days(3). Reaction of benzene with nitrate radical is estimated to be <0.3X10-16 cu cm/molecule sec at 25 deg C(1); the half-life for this reaction in air is estimated to be greater than or equal to 111 days based on an average concentration of nitrate radicals of 2.4X10+8 molec/cu cm in the ambient atmosphere(4). Benzene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(5) nor to directly photolyze since benzene has a maximum absorbance frequency of 253 nm(6). However, slight shifts in wavelength of absorption might be expected in more representative environmental media, such as water(7); eg, a half-life of 16.9 days was reported for photolysis of benzene dissolved in deionized water saturated with air exposed to sunlight(8). Benzene has an estimated lifetime under photochemical smog conditions in southeastern England of 28 hrs(3). Benzene has an estimated global life-time of 16 days and 4.8 days in the tropics(9). Global conditions were considered as having an average temperature of 2 deg C, OH radical concentration of 6.0X10+5 molecule/cu cm and an ozone radical concentration of 7.4X10+11 molecule/cu cm; while tropical conditions were considered as having an average temperature of 25 deg C, OH radical concentration of 2.0X10+6 molecule/cu cm and an ozone radical concentration of 7.4X10+11 molecule/cu cm(9). In aqueous solution, benzene will react with hydroxyl radical at a reaction rate of 7.8X10+9 L/mol sec; using the average OH radical concentration(1.0X10-17 molec/cu cm), benzene would have a half-life of 103 days(10).
[(1) Atkinson R; J Phys Chem Ref Data Mongraph No. 2 p. 48 (1994) (2) Korte F, Klein W; Ecotox Environ Safety 6: 311-27 (1982) (3) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 3rd ed. NY, NY: Van Nostrand Reinhold pg. 250 (1996) (4) Atkinson, R et al; Atmos Env 24: 2647-54 (1990) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (6) Trost B et al; Atmos Environ 31: 3999-4008 (1997) (7) Howard PH, Durkin PR; Sources of Contamination, Ambient Levels, and Fate of Benzene in the Environment. USEPA-560/5-75-005 pp. 65 (1974) (8) Hustert K et al; Chemosphere 10: 995-8 (1981) (9) Singh HB, Zimmerman PB; Adv Environ Sci Technol 24: 177-235 (1992) (10) Buxton, GV et al; J Phys Chem Ref Data 17: 513-882 (1988)]**PEER REVIEWED**

Environmental Bioconcentration:

Benzene has a BCF ranging from 1.1-20(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low. The uptake and elimination rate constants for benzene in fathead minnows were studied(3). Fathead minnows were found to have an avg uptake rate of 7 L/kg/hr with an avg elimination rate of 0.384/hr which corresponds to a BCF of 19(3). In a study of BCF values for various aquatic species, benzene was found to have a BCF value of 3.5 in eels(4), 4.4 in pacific herring(5), and 4.3 in goldfish(6).
[(1) Neff JM, Sauer TC; Environ Sci Res 53: 163-75 (1996) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) (3) De Wolf W et al; Chemosphere 36: 1713-1724 (1998) (4) Ogata M, Miyake Y; Water Res 12: 1041-4 (1978) (5) Korn S et al; Fish Bull Natl Marine Fish Ser 75: 633-6 (1977) (6) Ogata M et al; Bull Environ Contam Toxicol 33: 561-7 (1984)]**PEER REVIEWED**

Soil Adsorption/Mobility:

An experimentally derived log Koc of 1.93 (Koc = 85) was obtained via reverse phase HPLC (High Performance Liquid Chromatography) with a cyanopropyl column and a mobile phase of water(1). According to a classification scheme(2), this estimated Koc value suggests that benzene is expected to have high mobility in soil. The sorption equilibrium for benzene in a soil/water mixture (ratio soil/water 0.12 kg/l) took 72 hrs(3). The Koc for benzene has also been experimentally determined to be 79(4).
[(1) Hodson J, Williams, NA; Chemosphere 17: 67-77 (1988) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Zhang WX, Bouwer EJ; Biodegradation 8: 167-175 (1997) (4) Johnston CD et al; J Cont Hydrol 33: 377-404 (1998)]**PEER REVIEWED**

Volatilization from Water/Soil:

The Henry's Law constant for benzene is 5.56X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that benzene is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1 hr(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 3.5 days(SRC). Benzene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of benzene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 94.8 mm Hg(3).
[(1) Mackay D et al; Environ Sci Technol 13: 333-36 (1979) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989)]**PEER REVIEWED**

Environmental Water Concentrations:

GROUNDWATER: Benzene was the dominant dissolved organic compound in groundwater contaminated by gasoline in the Swan Coastal Plain near Perth, Western Australia at a concn around 15,000 ug/l at depths greater than 4.5 m below ground surface(1). At a distance of 210 m from a petrol storage area, a chalk aquifer, located in the United Kingdom, contained benzene ranging from 1-10 ppb; at 120 m from the petrol storage area it contained benzene concns greater than 250 ppb; and at 10 m from the petrol storage area, benzene concns rose to 1250 ppb(2). Benzene occurs in both groundwater and surface public water supplies with higher levels occurring in groundwater supplies. Based upon U.S. Federal drinking water surveys, approximately 1.3% of all groundwater systems are estimated to contain benzene at levels greater than 0.5 ug/l. The highest level reported in the surveys for groundwater was 80 ug/l(3).
[(1) Johnston CD et al; J Contam Hydrol 33: 377-404 (1998) (2) Tester DJ, Harker RJ; Water Pollut Control 80: 614-31 (1981) (3) USEPA; Health Advisories for 25 Organics: Benzene p. 19 (1987)]**PEER REVIEWED**

DRINKING WATER: Out of 113 public drinking water supplies in 1976, 7 sites tested positive for benzene with an avg concn of <0.2 ppb(1). Of five US cities from 1974-5, benzene concns ranged from 0-0.3 ppb in drinking water supplies(2). Contaminated drinking water wells in NY, NJ, and CT ranged from 30-300 ppb; the highest benzene concns in drinking water were derived from surface water sources at 4.4 ppb(3). In three separate surveys of community water supplies: 0 of 111 samples tested positive for benzene; 7 of 113 samples tested positive with a mean concn of 4 ppb; and 4 of 16 samples tested positive with a benzene max concn of 0.95 ppb(4). In a USA Groundwater Supply Survey (GWS, 1982, finished drinking water), out of 466 samples selected at random from a 1000 sample survey, 0.6% tested positive for benzene at a median value of 3 ppb and max of 15 ppb(5). In a study of Wisconsin drinking water wells (data through Jun 1984), of 1174 community wells sampled, 0.34% tested positive for benzene while of 617 private wells, 2.9% tested positive(6).
[(1) Brass HJ et al; Drinking Water Qual Enhancement Source Prot pp. 393-416 (1977) (2) Coleman WE et al; pp. 305-27 in Analysis and Identification of Organic Substances in Water. L Keith ed, Ann Arbor MI: Ann Arbor Press Chap 21 (1976) (3) Burmaster DE; Environ 24: 6-13,33-6 (1982) (4) NAS; Drinking Water and Health, Vol 3 (1980) (5) Cotruvo JA; Sci Total Environ 47: 7-26 (1985) (6) Krill RM, Sonzogni WC; J Am Water Works Assoc 78: 70-5 (1986)]**PEER REVIEWED**

DRINKING WATER: There may be a large number of cases where well water is contaminated by benzene at low concns(1). A number of studies have reported finding benzene at levels on the order of 5 ng/l in surface and well waters(1).
[(1) Wallace L; Environ Health Perspect 104: 1129-1136 (1996)]**PEER REVIEWED**

SURFACE WATER: Surface water samples taken from 14 heavily industrialized areas with water basins between 1975-1976, contained benzene in 20% of the samples at concns ranging from 1-7 ppb(1). Benzene concns in Lake Erie from 1975-6, ranged from 0-1 ppb(2). Benzene concns in Lake Michigan from 1975-6, ranged from 0-7 ppb(2). Out of 700 random surface water sites throughout the US in 1975, benzene had an avg concn of 5.4 ppb(3). In the US EPA STORET database, out of 1,271 surface water samples, 15.0% tested positive for benzene with a median concn of 5.0 ppb(4). Benzene concns in seawater taken from the Gulf of Mexico in 1977, ranged from 5-15 parts per trillion in unpolluted areas and 5-175 parts per trillion in areas affected by anthropogenic activities(5). Approximately 3% of all surface water drinking systems are estimated to be contaminated at levels higher than 0.5 ug/l(6).
[(1) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters. USEPA-560/6-77-015 pp. 75 (1977) (2) Konasewich D et al; Great Lake Water Qual Board (1978) (3) Kraybill HF; NY Acad Sci Annals 298: 80-9 (1977) (4) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (5) Sauer TC Jr; Org Geochem 3: 91-101 (1981) (6) USEPA; Health Advisories for 25 Organics: Benzene p. 19 (1987)]**PEER REVIEWED**

RAIN/SNOW/FOG: Benzene was detected in rainwater in Japan and in the UK at a concn of 87.2 ppb(1,2).
[(1) Kato T et al; Yokohama Kokuritsu Daigaku Kankyo Kagaku Kenkyu Senta Kiyo 6: 11-20 (1980) (2) IARC; Monograph. Some Industrial Chemicals and Dyestuffs. 29: 99-106 (1982)]**PEER REVIEWED**

Effluent Concentrations:

Industries in which mean or max levels of benzene in raw wastewater exceeded 1 ppm are (number of samples, percent pos, mean, max, in ppm): raw wastewater: auto and other laundries (20 samples, 70% pos, <1.4 ppm mean, 23 ppm max), iron and steel manufacturing (mfg) (9 samples, 77.8% pos, <8.0 mean, 46 max), aluminum forming (32 samples, 56.2% pos, 0.70 mean, 2.1 max), photographic equipment/supplies (48 samples, 54.2% pos, 0.16 mean, 2.1 max), pharmaceutical mfg (9 samples, 100% pos, 12 mean, 87 max), organic chemical/plastics mfg (number of samples not reported (NR), 63 detections, 22, NR), paint and ink formulation (36 samples, 63.9% pos, 1.2 mean, 9.9 max), petroleum refining (11 samples, number of pos NR, <0.10, 2.4), rubber processing (4 samples, 100% pos, 0.60 mean, 3.4 max), timber products processing (14 samples, 92.9% pos, 0.2 mean, 2.8 max); treated wastewater: auto and other laundries (4 samples, 50% pos, 0.1 ppm mean, 0.2 ppm max), iron and steel manufacturing (mfg) (13 samples, 76.9% pos, <14 mean, 120 max), aluminum forming (21 samples, 81.0% pos, <0.0058 mean, 0.040 max), photographic equipment/supplies (4 samples, 100% pos, 0.016 mean, 0.021 max), pharmaceutical mfg (6 samples, 100% pos, 1.8 mean, 10 max), organic chemical/plastics mfg (number of samples not reported (NR), 42 detections, 26, max NR), paint and ink formulation (24 samples, 62.5% pos, 0.39 mean, 3.8 max), petroleum refining (13 samples, NR, NR, 0.012), rubber processing (5 samples, 100% pos, <0.0077 mean, 0.010 max), timber products processing (5 samples, 60% pos, 0.010 mean, 0.033 max)(1).
[(1) USEPA; Treatability Manual. p. I.9.1-1 to I.9.1-5 USEPA-600/2-82-001A (1981)]**PEER REVIEWED**

Wastewater from coal preparation plants ranged from 0.3-48 ppb while wastewater from plants which manufacture or use benzene ranged from <1-179 parts per trillion(1). Stack emissions from coking plants located in Czechoslovakia contained benzene ranging from 15-50 ppm(2). In 11.2% of groundwater samples taken from 178 CERCLA hazardous waste sites, benzene was detected(3). In the US EPA STORET database, out of 1,474 effluent samples, 16.4% tested positive for benzene at a median concn of 2.50 ppb(4).
[(1) IARC; Monograph. Some Industrial Chemicals and Dyestuffs 29: 99-106 (1982) (2) SRI; Human Exposure to Atmospheric Benzene, Menlo Park, CA: SRI, Center for Resource and Environmental (1977) (3) Plumb H Jr; Ground Water Monit Rev 7: 94-100 (1987) (4) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985)]**PEER REVIEWED**

Benzene was emitted by pre-catalyst cars at 114-153 mg/mile while with catalyst cars emissions dropped to 5-32 mg/mile(1). In 4 municipal landfill gases in Southern Finland (1989-1990 data), benzene's avg concn ranged from 0.17-9 mg/cu m with a max concn of 11 mg/cu m(1). Benzene emissions were studied from seven Swedish incineration plants before and after air pollution control systems (APCS) were introduced(2). Benzene concns emitted from plant A (3 incinerators) without APCS were 1.93, 1.95, and 21.16 ug/cu nm and with APCS were 2.46, 0.83 and 1.81 ug/cu nm, respectively. Plant B (3 incinerators) benzene levels were 21.23, 10.81, and 1.63 ug/cu nm before APCS and 14.37, 444.20, and 0.14 ug/cu nm after APCS, respectively(2). Oddly, benzene levels rose on an incinerator after APCS. At the third plant, benzene concns were 2.57 ug/cu nm before APCS and 0.79 ug/cu nm after APCS(2). At the fourth plant, benzene concns were 3.44 ug/cu nm before APCS and 1.32 ug/cu nm after APCS(2). At the fifth plant, benzene concns were 0.82 ug/cu nm before APCS and 0.37 ug/cu nm after APCS(2). At the sixth plant, benzene concns were 2.92 ug/cu nm before APCS and 1.64 ug/cu nm after APCS(2). At the seventh plant (3 incinerators) benzene concns were 4.31, 8.30 and 5.13 ug/cu nm before APCS and 1.49, 1.02, and 11.36 ug/cu nm after APCS, respectively(2).
[(1) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 3rd ed. NY, NY: Van Nostrand Reinhold p. 251 (1996) (2) Zhang XJ; J Environ Sci Health A33: 279-306 (1998)]**PEER REVIEWED**

Sediment/Soil Concentrations:

SOIL: Soil near factories where benzene was used or produced contained benzene ranging from 2-191 ug/kg(1). SEDIMENT: Surface sediments taken from Walvis Bay (off Capetown, South Africa) contained benzene ranging from 0-20 ppb(2). In the US EPA STORET database, out of 355 samples, 9% tested positive for benzene at a median concn of <5.0 ppb(3).
[(1) IARC; Monograph. Some Industrial Chemicals and Dyestuffs 29: 99-106 (1982) (2) Whelan JK et al; Geochim Cosmochim Acta 44: 1767-85 (1980) (3) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985)]**PEER REVIEWED**

Atmospheric Concentrations:

SUBURBAN/URBAN: Air samples taken in the US from 1977-1980, had an avg benzene concn of 2.8 ppb in 2292 samples(1). Avg benzene concns were 13 ppb (98 ppb max) in Toronto, Canada 1971(2). Avg benzene concns in Los Angeles, California 1966 avgd 15 ppb (57 ppb max)(2). In 24 hr sampling periods conducted in US cities in 1979, benzene concns in Los Angeles, CA in April ranged from 0.72-27.87 ppb(mean 6.04 ppb), in Phoenix, AZ from April-May benzene ranged from 0.39-59.89 ppb (mean 4.74 ppb), in Oakland, CA from June-July benzene ranged from 0.06-4.63 ppb (mean 1.55 ppb)(3). Atmospheric benzene concns were studied in New Jersey in 1978 with the following cities reporting detections: Rutherford, out of 149 samples, 3.8 ppb mean concn with 107 ppb max, Newark, out of 110 samples, 2.6 ppb mean concn with 24 ppb max, Piscataway/Middlesex, out of 18 samples, 1.0 ppb mean concn with 1.9 ppb max, Somerset county, out of 30 samples, 5.6 mean concn with 33 ppb max, Bridgewater Township, out of 22 samples, 1.4 ppb mean concn with 7.9 ppb max(4). In general, the avg concn of benzene in the urban atmosphere is estimated at 0.02 ppm(5).
[(1) Brodzinsky R, Singh HB; Volatile Organic Chemicals In The Atmosphere: An Assessment Of Available Data 198 pp. SRI Inter 68-02-3452 (1982) (2) Pilar S, Graydon WF; Environ Sci Technol 7: 628-712 (1973) (3) Singh WB et al; Atmos Environ 15: 601-20 (1981) (4) Bozzelli JW, Kebbekus BB; Analysis Of Selected Volatile Organic Substances In Ambient Air. Newark, NJ: NJ Inst Technol 80 pp. (1979) (5) IARC; monograph. Some Industrial Chemicals and Dyestuffs 29: 99-106 (1982)]**PEER REVIEWED**

URBAN/SUBURBAN: Benzene has been detected in urban air samples in London, U.K., Southampton, U.K., Budapest, Hungary, Oslo, Norweigh, St. Petersburg, Russia, Boston, Chicago, Los Angeles, Houston, Sydney, Australia, and Tokyo, Japan at 9,16, 27, 18, 30, 1, 1.3, 2.7, 18, 2.6, and 1.8 ppbv, respectively(1). The median concn of benzene in 39 U.S. cities from 1984-1985 was 12.6 ppb(2). Benzene's ambient concn was highest at night-time and lowest by mid-day due to deep convective mixing and chemical loss by OH radicals(2). Since the 1960's, the ambient atmospheric concn of benzene has declined(2). Benzene concns were reported for 586 ambient air samples collected from 10 Canadian cities(3). The overall mean was 4.4 ug/cu m, with Ottawa and Montreal ranging between 5.1 and 7.6 ug/cu m(3). Benzene concns in a traffic tunnel in London, that was poorly ventilated, ranged from 0.010-0.21 ppb(4).
[(1) Trost B et al; Atmos Environ 31: 3999-4008 (1997) (2) Singh HB, Zimmerman PB; Adv Environ Sci Technol 24: 177-235 (1992) (3) Wallace L; Environ Health Perspect 104: 1129-1136 (1996) (4) Tsani-Bazaca E et al; Environ Technol Lett 2: 303-16 (1981)]**PEER REVIEWED**

INDOOR: In a recent benzene exposure study, day and night 12-hr avg concns of benzene were measured for 58 residents of Valdez, Alaska(1). The mean benzene concns in the personal, indoor, and outdoor samples were 20, 16, and 5 ug/cu m during the summer, and 28, 25, and 11 ug/cu m during the winter, respectively(1). In a nationwide Canadian study which measured the 24-hr indoor air concns of benzene in 754 randomly selected homes, benzene had a mean indoor air concn of 6.39, 5.60, 2.72, and 6.98 ug/cu m in the winter, spring, summer, and fall seasons, respectively(1). Indoor and outdoor 48-hr avg concns of benzene were measured at 161 homes throughout much of California in which indoor samples had a mean concn of 8.3 ug/cu m compared to 6.1 ug/cu m outdoor samples(1). Concns of benzene emitted from tobacco smoke in 5 workplaces located in Finland, 1995 ranged from 1.5-8 ug/cu m(2). Gasoline leaking from an underground storage tank near an elementary school in the Midwest United States (location not specified) created elevated levels of benzene concns within the school property(3). Benzene was detected in air samples collected from the classrooms, offices/libraries/corridors, boiler room, crawl space beneath floor, soil/duct/floor interface, and outdoor/background at 0-5 ppb, 3-4 ppb, 4 ppb, approx 2600 ppb, 70-80 ppb, and 0-3 ppb, respectively(3). A series of experiments were conducted in a 290 sq m single-family residence from June 11-13, 1991 to ascertain the human exposure to benzene from a contaminated groundwater source(4). It involved an individual taking a 20 min shower with the bathroom door closed, followed by five minutes for drying and dressing, and then opening the bathroom door and allowing the individual to leave and have his blood, breath and urine sampled(4). Whole air samples were collected from the bathroom, shower and living room. Mean concn of benzene coming from the shower head for the three days was 292 ug/l(4). Peak benzene levels were measured in the shower stall at 18-20 mins (758-1670 ug/cu m), in the bathroom at 10-25 mins (366-498 ug/cu m), in the bedroom at 25.5-30 mins (81-146 ug/cu m), and in the living room at 36-70 mins (40-62 ug/cu m)(4).
[(1) Wallace L; Environ Health Perspect 104: 1129-1136 (1996) (2) Rothberg M et al; Ann Occup Hyg 42: 129-134 (1998) (3) Moseley CL, Meye MR; Environ Sci Technol 26: 185-192 (1992) (4) Lindstrom AB et al; J Exp Anal Env Epidem 4: 183-195 (1994)]**PEER REVIEWED**

RURAL/REMOTE: In 100 rural air samples taken within the US from 1977-1980, the avg concn of benzene was 1.4 ppb avg(1). Ambient air samples taken from Barrows, Alaska in 1967 contained benzene at 0.16 ppb over a 24 hr avg in 5 of 25 samples(2). Avg benzene concn in rural areas range from 0.1-17 ppb(3). Multilatitude background concns of benzene (ppb/deg North): Atlantic Ocean 0.07/35 deg N, Pacific Ocean 0.23/45 deg N, Niwot Ridge (Colorado Rockies) 0.16-0.24 ppb(4). Benzene concns in the Pacific Ocean ranged from 0.05 ppb in the Northern hemisphere to 0.01 ppb in the Southern hemisphere(5). Pacific Ocean, 0.581, Pullman, WA, 0.226, Cape Meares, OR, 0.230, Norwegian Arctic, 0.066(5). In 5 remote tropical sites, benzene concns ranged from not detected to 1.8 ppb; avg concns from the 5 sites ranged from 0.07-0.65 ppb(6).
[(1) Brodzinsky R, Singh HB; Volatile Organic Chemicals In The Atmosphere: An Assessment Of Available Data 198 pp. SRI Inter 68-02-3452 (1982) (2) Cavanagh LA et al; Environ Sci Technol 3: 251-7 (1969) (3) IARC; monograph. Some Industrial Chemicals and Dyestuffs 29: 99-106 (1982) (4) Singh HB et al; Atmos Environ 19: 1911-9 (1985) (5) Nutmagul W, Cronn DR; J Atmos Chem 2: 415-33 (1985) (6) Greenberg JP, Zimmerman PR; Am Chem Soc Div Environ Chem 192nd Natl Mtg 26: 10-3 (1986)]**PEER REVIEWED**

RURAL/REMOTE: Benzene was measured at 35 ug/cu m in the plume of a forest fire at a distance of 6 km of the seat of the fire(1). The median concn of benzene in the Southern Appalachian Mountains was 1.1 ppb(2). Benzene concns range from 100-200 parts per trillion over the Pacific and Atlantic Oceans due to seepage and spillage of oil into the oceans(2). Rural sampling for benzene in Canada found concns ranging from 0.6-1.2 ug/cu m(3). Benzene was detected (concn not specified) in ambient air samples taken from Witaker's Forest/Sierra Nevada Mountains, California from June 20-June 22, 1990(4). Measurements were performed in midsummer at high ambient temperatures and under stable meteorological conditions with high solar radiation(4). Although the area was very remote, the air samples could have been influenced by emissions from California's Central Valley and even from the San Francisco Bay area(4).
[(1) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 3rd ed. NY, NY: Van Nostrand Reinhold pg. 251 (1996) (2) Singh HB, Zimmerman PB; Adv Environ Sci Technol 24: 177-235 (1992) (3) Wallace L; Environ Health Perspect 104: 1129-1136 (1996) (4) Helmig D, Arey J; Sci Tot Env 112: 233-250 (1992)]**PEER REVIEWED**

SOURCE DOMINATED: Atmospheric benzene concns were studied throughout the USA between 1977-1980 in which out of 487 samples taken, benzene was found at an avg concn of 3.0 ppb(1). The concn of benzene near USA chemical factories where benzene is used ranged from 0.6-34 ppb, near service stations 0.0003-3.2 ppm, and in cigarette smoke 57-64 ppm(2).
[(1) Brodzinsky R, Singh HB; Volatile Organic Chemicals In The Atmosphere: An Assessment of Available Data 198 pp. SRI Inter 68-02-3452 (1982) (2) IARC; Monograph. Some Industrial Chemicals and Dyestuffs 29: 99-106 (1982)]**PEER REVIEWED**

Food Survey Values:

Benzene was found in both heat treated and canned beef at 2 ug/kg; in Jamaican rum at 120 ug/kg; in eggs ranging from 500-1900 ug/kg; and it was detected (concns not specified) in fruits, nuts, vegetables, dairy products, meat, fish, poultry, eggs, and beverages(1).
[(1) USEPA; Ambient Water Quality Criteria: Benzene p. C-5 USEPA-440/5-80-018 (1980)]**PEER REVIEWED**

In 1990, benzene was detected in fruit flavored mineral waters at concns greater than 5.0 ug/kg in Canada(1). When an investigation of benzene concns in beverages was performed, benzene was found at an avg concn of 0.042, 0.67, 0.056, 0.14, 0.29, 0.12, 0.95, 0.062, 0.79, and 0.55 ug/kg in freshly squeezed fruit, retail juice (wth benzoate additive), retail juice (without benzoate), fruit drinks (with benzoate), fruit drinks (with cranberry, without benzoate), fruit drinks (excluding cranberry, without benzoate), cranberry drinks (without benzoate), carbonated soft drinks (without benzoate), carbonated soft drinks (with benzoate), and ice tea (with benzoate), respectively(1). These data suggest the natural occurrence of benzene in fruits and fruit juices, especially from cranberies(1). Benzene is a volatile organic compound emitted by both common and pineapple guava at a concn of 0.10 ug/g(2).
[(1) Page BD et al; J AOAC Int 75: 334-340 (1992) (2) Binder RG, Flath RA; J Agric Food Chem 37: 734-736 (1989)]**PEER REVIEWED**

Plant Concentrations:

Benzene has been detected as a plant volatile(1). Benzene has been detected from 2 species of macroalgae at 20 ppb(2).
[(1) Graedel TC; Chemical Compounds in the Atmosphere. NY, NY: Academic Press (1978) (2) Whelan JK et al; Nature 299: 50-2 (1982)]**PEER REVIEWED**

Fish/Seafood Concentrations:

Benzene was detected in 5 oyster samples from the Inner Harbor Navigational Canal in Lake Pontchartrain, LA at 220 ppb wet weight(1). Composite clam samples from Chef Menteur Pass in Lake Pontchartain, LA contained benzene at 260 ppb wet weight; however clam samples from The Rigolets did not contain benzene(1).
[(1) Ferrario JB et al; Bull Environ Contam Toxicol 34: 246-55 (1985)]**PEER REVIEWED**

Milk Concentrations:

Benzene was detected in all 8 samples of mothers milk from women in 4 US urban areas(1).
[(1) Pellizzari ED et al; Environ Sci Technol 16: 781-5 (1982)]**PEER REVIEWED**

Other Environmental Concentrations:

In private homes, benzene levels in the air have been shown to be higher in homes with attached garages, or where inhabitants smoke inside the house.
[Thomas KW et al; J Expo Anal Environ Epidemiol 3 (1): 49-73 (1993) as cited in U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene (Update) p.180 (1997)]**PEER REVIEWED**

Environmental Standards & Regulations:

FIFRA Requirements:

Benzene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only.
[40 CFR 180.1001(d) (7/1/99)]**PEER REVIEWED**

Acceptable Daily Intakes:

Insufficient data are available to calculate a one-day Health Advisory for benzene. The Ten-day Health Advisory (0.235 mg/l) is considered to be adequately protective for a one-day exposure as well. ... Longer-term Health Advisories have not been calculated because of the carcinogenic potency of benzene.
[USEPA; Health Advisories for 25 Organics: Benzene p.20 (1987) PB 87-235578]**PEER REVIEWED**

CERCLA Reportable Quantities:

Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b).
[40 CFR 302.4 (7/1/99)]**PEER REVIEWED**

RCRA Requirements:

D018; A solid waste containing benzene may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste.
[40 CFR 261.24 (7/1/99)]**PEER REVIEWED**

F005; When benzene is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F005), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations.
[40 CFR 261.31 (7/1/99)]**PEER REVIEWED**

U019; As stipulated in 40 CFR 261.33, when benzene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).
[40 CFR 261.33 (7/1/99)]**PEER REVIEWED**

Atmospheric Standards:

National emission standard for equipment leaks (fugitive emission sources) of benzene prohibit detectable benzene emissions from processing equipment (eg, pumps, valves) that contains materials which have a benzene concn of 10% or more by wt.
[40 CFR 61.110 (7/1/99)]**PEER REVIEWED**

This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Benzene is produced, as an intermediate or a final product, by process units covered under this subpart.
[40 CFR 60.489 (7/1/99)]**PEER REVIEWED**

Benzene has been designated as a hazardous air pollutant under section 112 of the Clean Air Act.
[40 CFR 61.01 (7/1/99)]**PEER REVIEWED**

The actual standards, if applicable, are contained in 40 CFR Part 61 Subpart V (61.240-61.247), National Emission Standards for Equipment Leaks (Fugitive Emission Sources) and refer to standards of operation of process equipment. EPA regulations establish a national emission standard for equipment leaks of benzene. They apply to pumps, compressors, pressure relief devices, sampling connecting systems, open-ended valves or lines, valves, flanges and other connectors, product accumulator vessels, and control devices, or systems required by this subpart.
[40 CFR 61.240 (7/1/99)]**PEER REVIEWED**

Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Benzene is included on this list.
[Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990]**PEER REVIEWED**